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INVITED REVIEW

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle

Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia

	ABSTRACT

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that bind DNA and translate physiological signals into gene regulation. The therapeutic utility of NRs is underscored by the diversity of drugs created to manage dysfunctional hormone signaling in the context of reproductive biology, inflammation, dermatology, cancer, and metabolic disease. For example, drugs that target nuclear receptors generate over $10 billion in annual sales. Almost two decades ago, gene products were identified that belonged to the NR superfamily on the basis of DNA and protein sequence identity. However, the endogenous and synthetic small molecules that modulate their action were not known, and they were denoted orphan NRs. Many of the remaining orphan NRs are highly enriched in energy-demanding major mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and kidney. This review focuses on recently adopted and orphan NR function in skeletal muscle, a tissue that accounts for 35% of the total body mass and energy expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this lean tissue is involved in cholesterol efflux and secretes that control energy expenditure and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal muscle plays a considerable role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, which is the the foremost cause of global mortality (>16.7 million deaths in 2003). Therefore, it is not surprising that orphan NRs and skeletal muscle are emerging as therapeutic candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease.

metabolism; cardiovascular disease

Dyslipidemia associated with anomalous levels of the lipid triad [i.e., elevated levels of triglycerides (TG) and low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol], hypertension, obesity, sedentary lifestyle, diabetes, chronic inflammation, and smoking all constitute important independent risk factors for cardiovascular disease. Importantly, diet, metabolism (genetic predisposition), and physical activity directly influence these risk factors (3, 4, 140). Research indicates that 62% of strokes and 49% of heart attacks are caused by hypertension. High blood cholesterol (>5 mmol/l) accounts for 18% of strokes and 50% of heart disease. Aside from dietary and genetic factors, the prevalence of cardiovascular disease is exacerbated by modern sedentary lifestyles; current data suggest that 60% of the world's population do not meet current physical activity guidelines (3, 4, 140).

Approximately 20% of the global population (up to 1 billion adults) are deemed overweight and at least 300 million are clinically obese. Obesity rates have tripled in North America, Eastern Europe, the Middle East, Australia, and China. About 21% of coronary heart disease globally is attributable to an elevated body mass index (>25) (4, 185). Obesity is the trigger for the development of hypertension, dyslipidemia, and diabetes, which ultimately leads to cardiovascular disease. Furthermore, the increasing prevalence of diabetes in adults (estimated at 4.5% globally) leads to a 3- and 8-fold higher coronary heart disease risk in men and women respectively (185). Currently, 180 million people worldwide suffer from diabetes, and at least 1 in 10 deaths among adults between 35 and 64 years old is attributable to diabetes, primarily through the increased risk of cardiovascular disease (122, 140, 185).

	METABOLIC SYNDROME

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
Metabolic syndrome, or Syndrome X, represents a cluster of metabolic abnormalities that all constitute known risk factors for cardiovascular disease. The National Cholesterol Education Program: Adult Treatment Panel III guidelines define metabolic syndrome as the presence of any three features listed in Table 1 (1). The increased prevalence of metabolic syndrome has arisen primarily as a result of the global obesity epidemic with peripheral insulin resistance providing the most widely accepted and unifying feature of the syndrome (40, 162). While great inroads have been made in the identification of the relationship between the various clinical features of metabolic syndrome, the underlying pathological mechanisms are not well understood.

	SKELETAL MUSCLE CARBOHYDRATE AND LIPID METABOLISM

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
Skeletal Muscle Metabolism The three types of muscle tissues are skeletal, cardiac, and smooth. Skeletal muscle is involved in movement, posture, stability, metabolism, heat production, and cold tolerance. Skeletal muscle fibers are classified by two major functional characteristics: speed of contraction and the aerobic (oxidative)/anaerobic (glycolytic) production of ATP. The speed of the fiber reflects how fast the fiber metabolizes ATP. Fast fibers (also known as type IIb or white fibers) utilize anaerobic glycolysis, are low in mitochondria and myoglobin, rich in glycogen, and are suited to short-term intense activity. Slow fibers (also known as type I or red fibers) utilize aerobic metabolism, are rich in mitochondria and myoglobin, and are suited to endurance activity. There is an intermediate fast fiber type IIa, which combines fast twitch capacity with aerobic fatigue-resistant metabolism and intermediate glycogen levels (107).

Skeletal muscle is a "metabolically flexible" tissue and has a paramount role in energy balance; for instance, it is the primary tissue of insulin-stimulated glucose uptake (disposal), and storage (4-fold the glycogen content of liver), regulates ApoA1-dependent cholesterol efflux and strongly influences metabolism via modulation of circulating and stored lipid flux (57, 74, 78, 136). In fact, lipid catabolism supplies up to 70% of the energy requirements in a fasted individual. During the initial phase of aerobic exercise, skeletal muscle utilizes stored glycogen; however, as exercise continues, glucose and stored muscle triglycerides become important energy substrates (57, 148, 149). Prolonged exercise increasingly depends on fatty acids and lipid mobilization from other tissues. Given the fact that skeletal muscle can utilize both carbohydrate and lipid energy substrates after appropriate mechanical and hormonal cues and considering the relative mass of the tissue it is hardly surprising that normal (and abnormal) skeletal muscle metabolism has a significant impact on insulin sensitivity, the blood lipid profile and the pathogenesis of metabolic disease.

Skeletal Muscle Dysfunction in Metabolic Disease Skeletal muscle insulin resistance comprises perturbations in both glucose and fatty acid metabolism. It is well established in the literature that pathophysiological conditions that are associated with impaired insulin resistance, such as type 2 diabetes and obesity, correlate with elevations in circulating FFAs (15, 147). Considerable evidence obtained in both animal and human studies have linked accumulation of intra-myocellular lipids with insulin resistance in obesity and type 2 diabetes (49, 75, 109, 133). Investigations aimed at identifying the mechanisms underlying this association have implied an imbalance between fatty acid uptake and the rate of fatty acid oxidation. The direct link between intra-myocellular lipid accumulation and insulin resistance is supported by the observation that insulin sensitivity can be restored by treatments that promote depletion of accumulated triglycerides, such as low-fat diets, fasting, exercise, and leptin administration (125, 163). The significance of this is exemplified by NMR spectroscopy studies (86, 157) that measured intramyocellular lipids and found that levels correlated more closely with insulin resistance that other commonly used indexes, such as body mass index and waist-to-hip ratios.

Impaired mitochondrial function that directs fatty acids toward storage, as opposed to oxidation, and reduced oxidative enzyme activities may in large part contribute to muscle lipid accumulation in obesity and type 2 diabetes mellitus (76, 77, 165, 166). Moreover, the activity of carnitine palmitoyl transferase 1 (CPT1), a key step in the regulation of muscle fatty acid oxidation, has been shown to be reduced in insulin resistant muscle from obese subjects (165). In addition to this, shunting of fatty acids toward storage in skeletal muscle as opposed to oxidation triglyceride accumulation in skeletal muscle of obese and type 2 diabetic subjects was shown to be linked to elevated rates of fatty acid transport via increased sarcolemma fat/cd36 (16). Another hypothesis contends that hyperinsulinemia may increase skeletal muscle and liver lipid content due to increased lipogenesis via elevated expression of SREBP-1C (164). This hypothesis is further supported by the recent observation that SCD-1 expression and activity is elevated in the skeletal muscle of obese humans contributing to the abnormal skeletal muscle lipid partitioning seen in these individuals (63).

Impaired glucose utilization by skeletal muscle in metabolic disease is also linked to elevated circulating FFAs. As early as the 1960s, it was noted that FFA oxidation disrupts glucose catabolism via the inhibition of phosphofructokinase and pyruvate dehydrogenase. In this context, the Randle hypothesis proposed that FFAs compete with glucose for mitochondrial oxidation (144). Similarly, studies support the concept that FFAs inhibit glucose transport and key phosphorylation events (38, 147). Alternatively, mounting evidence points to direct effects of increase circulating and intracellular lipid content to perturbations in insulin signaling pathways (38, 147, 175). Excess triglyceride in insulin resistant muscle has been shown to alter insulin signaling via consequent increases in lipid intermediates, such as fatty-acyl CoA, diacylglycerol, and ceramides. Activation of protein kinase C by diacylglycerol inhibits the tyrosine kinase activity of the insulin receptor leading to reduced insulin action (159). Ceramides activate a protein phosphatase that dephosphorylates AKT/protein kinase B, subsequently inhibiting glut4 translocation and glycogen synthesis (28, 100). Lipid accumulation in skeletal muscle has also been shown to inhibit phosphorylation of Irs-1, thus inhibiting the binding and activation of phosphatidylinositol 3-kinase, a pivotal step in the normal insulin signaling cascade (38, 190).

The metabolic flexibility of skeletal muscle allows it to utilize both carbohydrate and lipid energy sources given the appropriate hormonal and mechanical signals (74, 76, 77). While the precise mechanistic basis underlying abnormal skeletal muscle function in obesity and diabetes remains unclear, it is obvious that biochemical perturbations in this tissue have a profound effect on systemic metabolic homeostasis. Therapeutic targeting of the metabolic derangements in skeletal muscle will undoubtedly promote improvement in systemic metabolic homeostasis and ultimately attenuate the pathogenesis associated with the metabolic syndrome.

	SKELETAL MUSCLE AS AN ENDOCRINE ORGAN: MYOKINES

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
Obesity-linked insulin resistance is known to be associated with a chronic systemic inflammatory response (61, 183). In recent years, it has become apparent that adipose tissue functions as more than just a reservoir for energy storage in the form of triglycerides but rather functions as a vital endocrine organ regulating systemic metabolic homeostasis via controlled storage/release of fatty acids and the secretion of biologically active "adipokines," such as adiponectin (70), resistin (169), leptin (106), adipsin (184), and TNF- (62). Similarly, the potential endocrine function of skeletal muscle is being recognized with the release of bioactive molecules now termed "myokines" (42, 132). Identification of these factors offers support for a skeletal muscle endocrine axis that is potentially pivotal to metabolic homeostasis.

Muscle tissue expresses and releases several cytokines into the circulation, for example, IL-6, -8 and -15. The autocrine actions of these factors are well documented; however, there is accumulating evidence that these cytokines exert their effect in other parts of the body. IL-15 is abundantly expressed in skeletal muscle, is induced by acute exercise, and has anabolic effects on skeletal muscle protein dynamics (141). Interestingly, administration of IL-15 in rats demonstrated a significant reduction in adipose deposition (23). Studies (142) in adipogenic 3T3 cells revealed that despite little or no expression of IL-15 mRNA, administration of IL-15 inhibited lipogenesis and stimulated the release of adiponectin. Because skeletal muscle expresses and secretes high levels of IL-15, such an observation provides strong support for the hypothesis that a skeletal muscle-adipose endocrine axis exists that modulates lean body/adipose composition and insulin sensitivity.

Another cytokine released by skeletal muscle is IL-6 and has been referred to as the "exercise factor" because its expression and release was found to increase up to 100-fold during muscle contraction and is postulated to underlie many of the metabolically beneficial effects of exercise (43). Circulating IL-6 stimulates AMPK activity, a fuel-sensing enzyme that is activated by changes in the energy state of the cell and in response to adipokines, in adipose and lean tissue (80). IL-6 transcriptional regulation in skeletal muscle is influenced by glycogen content via the p38 MAPK pathway that results in upregulated expression in response to exercise-induced glycogen depletion (26, 27). During exercise, IL-6 appears to play a glucoregulatory role via augmented hepatic glucose production and muscle glucose uptake (43). IL-6 has been shown to be a potent modulator of fatty acid metabolism via increased rates of fatty acid oxidation and reesterification and attenuation of insulin-mediated lipogenesis in both human subjects and isolated rodent muscle samples (19, 173). More recently, IL-6-driven increases in lipolysis were demonstrated in type 2 diabetic patients without the induction of adverse side effects, such as hypertriacylglyceridemia, suggesting a potential therapeutic utility of this cytokine in the treatment of metabolic syndrome (135). Paradoxically, increased circulating IL-6 has been linked to type 2 diabetes, leading to speculation that IL-6 may contribute to the induction or pathogenesis of type 2 diabetes (137, 139, 152). However, firm evidence of a causative link remains to be demonstrated. Furthermore, IL-6-deficient transgenic mice are glucose intolerant, have reduced endurance and energy expenditure, and develop late-onset obesity (180).

Finally, myostatin, a member of the TGF- superfamily, is specifically expressed in vertebrate skeletal muscle. Mice lacking myostatin have a dramatic increase in skeletal muscle growth and significantly reduced fat deposition with age (110, 111). Several mechanisms may account for the effect of myostatin on lipid metabolism, including a direct effect on adipocytes (81) or alternatively, anabolic effects in skeletal muscle may produce a metabolic shift in energy consumption resulting in a net reduction in adipose lipid storage. The latter hypothesis is plausible, given the accumulating evidence that muscle fiber composition has a favorable effect on the LDL/HDL cholesterol ratio (55) and the accepted tenet that muscle tissue has a significantly higher metabolic rate than other major tissues.

	NUCLEAR RECEPTOR REGULATION OF CARBOHYDRATE AND LIPID METABOLISM

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
The links between diets rich in free fatty acids and sugars and the increasing prevalence of dyslipidemia, type II diabetes, obesity, and cardiovascular disease are well established. Furthermore, it is becoming increasingly clear that the metabolic regualtion of both lipid and carbohydrate homeostasis are intrinsically connected. A pertinent example of this metabolic interconnection is the regulation of triglyceride catabolism by insulin, a signaling molecule known primarily as an essential regulator of glucose disposal. Insulin regulates triglyceride catabolism via inhibition of hormone sensitive lipase. The significance of this regulatory mechanism is highlighted by the demonstration that lipid accumulation and/or elevated lipoprotein lipase expression in nonadipose tissue (e.g., liver and muscle) results in insulin resistance (82, 86). Perhaps paradoxically it has become evident that diets rich in unsaturated fatty acids protect against metabolic disease prompting speculation that dietary lipids function as signaling molecules that play vital roles in controlling lipid homeostasis. The search for the mechanisms by which various lipid molecules regulate lipid homeostasis and the subsequent targets of such signaling have become an intense area of investigation in recent years in an effort to understand and control the increasing incidence of metabolic disease in modern society.

Insights into the mechanisms regulating such processes have significantly matured since the discovery that metabolism is, in part, regulated by the nuclear hormone receptors (NRs) which function as ligand (hormone)-regulated transcription factors that bind DNA and control gene expression (14, 45). A ligand or hormone can be considered any small molecule that can bind to the receptor and affect its function. For example, steroids (estrogen, testosterone, etc.), thyroid hormones, retinoids, dietary lipids, oxysterols, fatty and bile acids are signaling molecules that bind to nuclear receptors and regulate gene expression thereby controlling endocrine pathways directly relevant to disease (14, 45). Essentially, NRs function as the conduit between diet, metabolism (and environmental stimuli) and gene expression mediating a unique physiological response in a nutritionally dependent manner.

	NUCLEAR RECEPTOR FUNCTION: GENERAL CONCEPTS

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
A decade ago, gene products were identified that belonged to the NR superfamily on the basis of nucleic acid sequence identity. However, the endogenous molecules which regulate their activity were unknown and thus they were called orphan NRs. On the basis of members of the NR superfamily that have been characterized, the orphans forecast an enormous, yet unexploited opportunity for the discovery of novel signaling pathways and therapeutic agents. The potential impact of such a discovery cannot be overstated, because every known NR has been implicated in disease (14, 51, 172). All members of the NR superfamily display a highly conserved structural organization with an amino terminal region AB (that encodes activation function 1; AF-1), followed by the COOH region, which encodes the DNA binding domain; a linker region D and the COOH-terminal E region. The DE region encodes the ligand binding domain (LBD), and a transcriptional domain, denoted as AF-2 (Fig. 1) (4, 105). Nuclear receptors trans-activate the expression of target genes via the binding of DNA consensus elements within regulatory regions as either monomers, homodimers, or heterodimers with the retinoid X receptors. DNA binding is mediated by a highly conserved zinc finger DNA binding domain and in the case of heterodimerization consensus elements have been found as direct repeats, inverted repeats, or palindromic repeats (4, 105). A subgroup of the NR superfamily controls metabolism in an organ-specific manner (45).

View larger version (14K): [in this window] [in a new window]   Fig. 1. A: schematic representation of nuclear receptor functional domains. The variable NH2-terminal domain possesses AF-1 ligand independent activity (A/B), the conserved DNA binding domain (C), variable linker region (D), ligand binding and dimerization domain (E) and the AF-2 ligand-dependent transactivation domain (F). B: co-regulator binding of nuclear receptors. Many nuclear receptors are associated with co-repressor proteins in the absence of ligand. Upon ligand binding, co-repressors are displaced in favor of co-activator proteins. CoR, coenzyme receptor; CoA, coenzyme A.

Genetic and pharmacological studies have demonstrated that the liver X receptors (LXR)- and -, farnesoid X receptor, peroxisome proliferator-activated receptors (PPAR)-, -/, and -, liver receptor homolog-1 and the small heterodimeric partner regulate lipid, glucose, and energy homeostasis (45). Concordantly, dysfunctional NR signaling results in dyslipidemia, diabetes, obesity, and inflammation. Recently, additional orphan NRs have been implicated in the regulation of lipid and carbohydrate metabolism, for example, Nur77, Rev-erb- and -, that control lipolysis, and lipid absorption. Moreover, evidence for cross-talk between the -adrenergic and the Nur77 signaling pathways has appeared in the literature.

	ORPHAN NRs AS THERAPEUTIC TARGETS

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
The fundamental importance of NRs in human health is underscored by the gamut of drugs created to treat disorders associated with dysfunctional hormone signaling ranging from cancer and diabetes to reproductive, cardiovascular and inflammatory diseases (28a, 51, 52, 172).

The plethora of orphan NRs has been the catalyst for the development of a new paradigm, called "reverse endocrinology" mediated by functional genomics, high throughput screening and combinatorial chemistry. Reverse endocrinology is the process whereby the orphan NR is used to search for a previously unknown ligand/hormone and signaling pathway (85). In particular, recent studies on previously denoted orphans [e.g., PPAR-//, LXR, FXR, CAR, SXR] have uncovered a myriad of new signaling pathways that regulate metabolism, and drug tolerance, and provided new insights/treatments into many human diseases (i.e., diabetes, dyslipidemia, obesity, and metabolic syndrome) (45, 50, 90). The identification of low-affinity endogenous and/or high affinity synthetic ligands for orphan receptors has created an orphan receptor subclass often referred to as "adopted orphan" receptors (28a). Low-affinity natural agonists for this class of receptor are commonly dietary lipids and their derivatives.

Drugs targeting nuclear receptors, including the estrogen, thyroid, and glucocorticoid receptors, and PPAR- and PPAR- are among the most commonly prescribed drugs on the market and generate annual revenues in excess of $10 billion (131). Despite the proven therapeutic effectiveness of these pharmaceuticals many are accompanied by undesirable side effects prompting intense efforts to identify and develop new agents that retain the positive attributes of current drugs while avoiding unwanted side effects. Development of tissue and gene specific nuclear receptor ligands (selective modulators) is a key focus of such efforts with this concept best exemplified by the selective estrogen receptor modulators, such as tamoxifen and raloxifene (50, 68). The identification of endogenous and synthetic ligands to orphan NRs has generated considerable excitement in recent years and highlights the potential therapeutic opportunities given the wide range of biological functions of these proteins. A pertinent example of such promise was realized with the identification that the anti-diabetic/insulin sensitizing thiazolidinediones (TZDs) function largely as high-affinity ligands for PPAR-, whereas the lipid lowering fibrate class of drugs signal via PPAR- (91, 94). To date, several synthetic ligands have been identified for other orphan nuclear receptors and are being intensively studied in laboratories, and in many cases, animal and clinical trials are underway. While crystal structure analysis of orphan nuclear receptors suggest many will function as true orphan receptors unable to accommodate molecules within their LBDs, the identification of small molecules that bind to other regions of the receptor and modulate coregulator interactions and receptor function remain attractive avenues to explore (50, 114, 131, 160). In summary, the orphan receptors are key functional regulators of metabolic homeostasis and provide a scaffold with enormous scope and opportunity for the discovery of important new therapeutic agents.

	REGULATION OF SKELETAL MUSCLE METABOLISM BY ADOPTED AND ORPHAN NUCLEAR RECEPTORS

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
As discussed, skeletal muscle is a major mass peripheral tissue accounts that for >35% of the total body mass and energy expenditure, and is the major site of fatty acid and glucose oxidation. Moreover, this lean tissue mediates physical activity and cholesterol efflux, and secretes myokines (myostatin, IL-6, -8, and -15) that control inflammation, energy expenditure, and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, inflammation, and energy balance, conferring a significant role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, the foremost cause of global mortality. These risk factors are recognized by the World Health Organization as being in the top 10 global health problems and are directly influenced by diet, metabolism, and lifestyle.

Many of the recently adopted orphan NRs and skeletal muscle are rapidly emerging as critical therapeutic targets in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease. Along these lines it has been demonstrated that "ligand-dependent" NRs in skeletal muscle enhance insulin-stimulated glucose disposal, lipid catabolism, energy expenditure, cholesterol efflux, and decrease triglycerides (see below).

Surprisingly, the function of the remaining orphan NRs in skeletal muscle metabolism has not been examined. Nevertheless, given the data on the orphan NR subgroup, abundant expression in skeletal muscle, and their potential utility as therapeutic targets for the treatment of disease, the contribution of this tissue to orphan NR action requires further investigation. Along these lines, emerging stories from cell culture and animal models illustrate that the orphan NRs, including estrogen-related receptor (ERR)-, retinoic acid-related orphan receptor (ROR)-, Rev-erb ( and ), and Nur77 regulate lipid absorption, lipolysis, inflammation (IB), and myokine expression (71, 88, 102, 104, 108).

Clearly, improvements in skeletal muscle lipid and carbohydrate metabolism mediated by nuclear receptor function and pharmacological activation will yield concomitant improvements in systemic metabolic homeostasis. numerous metabolic genes regulated by nuclear receptors have been identified ranging from transport molecules, enzymes involves in lipid and carbohydrate anabolism/catabolism, lipid and carbohydrate storage, thermogenesis, and signaling pathways. For brevity, the key genes presented and discussed in this review are outlined in Table 2 with a brief explanation of their respective functional roles. This review will focus on the orphan and adopted nuclear receptors in the regulation of skeletal muscle lipid and carbohydrate metabolism and the implications for the treatment of metabolic disease (Fig. 2).

View larger version (83K): [in this window] [in a new window]   Fig. 2. Schematic representation of nuclear receptors involved in skeletal muscle lipid and carbohydrate homeostasis. Studies investigating normal and abnormal function of several orphan nuclear receptors illustrate the importance of these receptors in metabolic homeostasis. Specifically, regulation of metabolic homeostasis in skeletal muscle by these receptors may have profound effects on systemic metabolic balance, adiposity and the development of metabolic and cardiovascular disease. In this context, these receptors can be considered a physiological conduit between diet, metabolism, activity, and gene expression. PPAR, peroxisome proliferator activator receptor; LXR, liver X receptor; ERR, estrogen-related receptor, ROR, retinoic acid-related orphan receptor.

	PPARs

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

PPARs primarily function as systemic lipid sensors that regulate a variety of homeostatic functions, including metabolism, inflammation and development. Three mammalian PPAR subtypes, designated PPAR- (NR1C1), PPAR- (NR1C3), and PPAR- (NR1C2) have been identified (12, 41, 90). PPAR activity is regulated by an array of dietary lipids including saturated and unsaturated fatty acids and their respective metabolites derived through the lipoxygenase and cyclooxygenase pathways. Furthermore, PPAR activity is targeted by selective synthetic compounds including hypolipidemic fibrates (PPAR-), the insulin-sensitizing TZDs (PPAR-) (12, 41, 90), and the antisyndrome X phenoxy-acetic acid compound GW-501516 currently in clinical trials (PPAR-). Cell culture and animal studies over the last decade have revealed discrete functions for the various PPAR subtypes in the regulation of genes that control lipid and carbohydrate metabolism in a range of tissues. PPAR- and PPAR- are predominantly, though not exclusively, expressed in liver and adipose tissue, respectively, whereas PPAR- expression is relatively ubiquitous, although it is abundantly expressed in brain, intestine, skeletal muscle, spleen, macrophages, lung, fat, and adrenals (12, 41, 90). Until recently, relatively little was known about the specific function of PPAR-. Prostanoids, produced by the conversion of polyunsaturated fatty acids, have been proposed as potential endogenous ligands for PPAR-. The development and analysis of a potent and selective PPAR- agonist (GW-501516), a phenoxyacetic acid derivative, has generated intense interest by provided evidenced for a role of this PPAR subtype in the coordination of glucose tolerance, fatty acid oxidation, and energy expenditure in adipose and skeletal muscle (128).

PPAR- PPAR- is known to regulate fatty acid oxidation gene expression in the liver, a function which correlates with the lipid lowering effect of the fibrate class of drugs (12, 41, 90). PPAR--specific agonists stimulate mitochondrial -oxidation in vivo in both liver and muscle via the upregulation of genes such as mCPT1, medium chain acyl CoA dehydrogenase, and MTE1 (113, 116, 168). Furthermore, PPAR- activation promotes thermogenesis in skeletal muscle via the induction of uncoupling proteins-1, -2, and -3 (20, 79). PPAR--null mice exhibit low rates of -oxidation and lipid accumulation in hepatic and cardiac tissues (36, 96). However, these animals exhibited minimal alteration in the expression of PPAR- target genes UCP-3, CPT-1, and PDK4 after a period of starvation or exertion primarily due to a functional redundancy with PPAR- (116). Furthermore, while metabolism was significantly impaired in liver and cardiac muscle, in contrast, skeletal muscle appeared refractory to the deleterious effects of PPAR- ablation. Myocardial lipid accumulation in PPAR- null mice highlights the importance of PPAR- in mitochondrial fatty acid uptake and oxidation in this tissue (36, 176). PPAR- plays a critical role in normal cardiac lipid homeostasis and its activity is downregulated during cardiac hypertrophy, resulting in diminished fatty acid oxidation and a reversion to glucose and lactate as primary energy sources (32, 153). Ultimately, such this metabolic shift results in lipid accumulation and associated lipotoxicity of the myocardium (11).

PPAR- PPAR- is most abundantly expressed in adipose tissue, intestine and macrophages and studies using rodent cell lines demonstrate its essential role in normal fat cell development (150, 151, 154). Mouse PPAR- nulls die in utero due to cardiac and placental defects; however, embryonic transfer of mutant embryos onto wild-type placentas allowed the generation of a single live null animal, which exhibited no detectable adipose tissue (9). Human patients with loss of function mutations in the PPAR- gene present with a novel syndrome, including lipodystrophy, insulin resistance, type 2 diabetes, and hypertension (2, 13, 52, 156, 158). PPAR- has generated intense interest with the identification that the insulin sensitizing TZDs are high-affinity PPAR- ligands (94). Subsequently studies aimed at elucidating the functional mechanisms underlying the PPAR- function have demonstrated a pivotal role for PPAR- in the regulation of systemic lipid and glucose (52, 145, 150, 151). While many studies have focused on the role of PPAR- in adipogenesis and the regulation of adipocyte metabolic function accumulating evidence suggests PPAR- plays important roles in the regulation of systemic homeostasis via activities in other key tissues such as liver and skeletal muscle (187). While low levels of detectable PPAR- expression in skeletal muscle had led to the long-held assumption that the augmentation of insulin sensitivity by TZDs was facilitated primarily via PPAR- activity in adipose tissue, TZDs have been shown to exert their insulin-sensitizing effects in skeletal muscle independently of their activity in adipose tissue (21). While the activity of PPAR- in adipose tissue undoubtedly contributes to systemic, and specifically skeletal muscle, metabolic homeostasis via storage of circulating fatty acids and the release of adipokines (many of which act directly on muscle cells), numerous studies offer support for a direct role for PPAR- in muscle cells. Studies to date support the contention that augmentation of insulin sensitivity in skeletal muscle by PPAR- arises primarily via activation of FFA oxidation (25, 30). Furthermore, PPAR- can directly activate components of the insulin signaling pathway in skeletal muscle (3, 73, 83, 174). PPAR- signaling activates expression of a number of metabolic genes in isolated muscle tissue and muscle cell lines, including UCP-2, UCP-3, IRS-1, -6-desaturase, and C/EBP (53, 101, 167, 179) and promotes GLUT4 translocation (189).

More recently, muscle-specific disruption of PPAR- expression in mice resulted in severe insulin resistance with skeletal muscle remaining refractory to the insulin-sensitizing effects of TZDs, despite normal TZD responses in liver and adipose tissue and decreased plasma FFA levels (58). Paradoxically another muscle specific mouse knockout model was similarly shown to be insulin resistant, despite apparently normal skeletal muscle insulin sensitivity. In this study, it was proposed that insulin resistance and increased adiposity arose from a failure of insulin to suppress hepatic glucose production (124).

PPAR- Loss-of-function studies in the mouse have revealed a multitude of biological processes in which PPAR- is active during development. PPAR--null embryos die at an early stage due to a placental defect, with the few that survive exhibiting a lower body weight than wild-type littermates, reduced body fat mass, skin defects, and abnormal myelination (112, 134). Paradoxically, this phenotype was absent in an adipocyte specific PPAR- null model, suggesting a complex regulation of systemic lipid metabolism, as opposed to specific adipocyte functions (8).

PPAR- has generated a great deal of interest as a potential therapeutic target in obesity after the identification of potent synthetic phenoxy-acetic acid ligands. Treatment of insulin-resistant and obese rhesus monkeys and Db/Db mice with PPAR- agonists lowered fasting insulin levels, raised serum HDL cholesterol, and lowered fasting triglycerides. Although it was unclear which tissue was the major target for this activity, the classification of PPAR- as sensor of dietary triglyceride in native VLDLs released by lipoprotein lipase activity suggested skeletal muscle was a potential target tissue (29, 95, 128). Elevation of HDL cholesterol involved increases in the expression of ABCA1 in macrophages, and skeletal muscle and was accompanied by an induction of ApoA1-specific cholesterol efflux (to an even greater extent than agonists for PPAR- or PPAR-). Given the relative mass of skeletal muscle this observation is entirely consistent with the profound effects of this drug on systemic HDL-cholesterol (39, 177). Furthermore, the PPAR- agonist induced the expression of acyl-CoA synthetase (ACS), CPT1, UCP2, and UCP3 in rodent neonatal cardiomyocytes, which correlated with an increase in fatty acid oxidation (48). PPAR- has been further implicated in the regulation of skeletal muscle metabolism with reported modulation of expression of a range of genes involved in lipid absorption [LPL, fatty acid binding protein 3 (FABP3), ACS4], lipid catabolism (CPT1, PDK4), and energy expenditure (UCP2 and -3) in cultured C2C12 muscle cells treated with PPAR- agonists (39). This study also demonstrated that PPAR agonists (but not PPAR-) primarily regulate the CPT-1 promoter in skeletal muscle cells. Similarly, microarray expression profiling in GW-501516-treated rat skeletal muscle cells (L6 myotubes) and skeletal muscle of treated mice (171) identified a large panel of genes involved lipid homeostasis including CPT-1. The authors went on to demonstrate that GW-501516 treatment of mice stimulates fatty acid oxidation in skeletal muscle; in contrast, -oxidation was not induced in the liver. Starvation induces PPAR mRNA expression in murine gastrocnemius muscle with concomitant activation of fatty acid translocase/CD36 (FAT/CD36), muscle carnitine palmitoyl transferase (M-CPT1 or CPT-1) and heart FABP (59).

PPAR- is predominantly expressed in mitochondrial rich type I (oxidative, slow twitch) relative to type II (glycolytic, fast twitch) skeletal muscle. Endurance training promotes conversion into type I muscle, accompanied by an increased expression of PPAR- (103). Muscle-specific expression of activated PPAR- in mice leads to an increase in type I muscle fibers. Concordantly, increased activity of enzymes involved in oxidative (not glycolytic) metabolism has been reported. Expression analysis also revealed an induction of the genes involved in increased oxidative metabolism, glucose tolerance, preferential lipid utilization, energy expenditure (i.e., troponin-I slow, cytochrome c, UCP2, UCP3, and CPT1) (103), and increased endurance (181).

Numerous studies demonstrated that GW-501516 treatment and skeletal muscle-specific PPAR- overexpression in mice ameliorated diet induced obesity, enhanced metabolic rate, lipid oxidation, reduced intramuscular triglycerides, and increased mitochondria in skeletal muscle. Moreover, anatomical analysis revealed the resistance to increased body weight was largely due to reduced mass of visceral and epidermal fat depots. The drug treatment ameliorated the diet induced 1) hypertrophy in epidermal white adipose, and brown fat, 2) hepatic steatosis, and 3) accumulation of intramuscular lipid droplets (103, 171, 181). Interestingly, these mice have profoundly increased endurance capabilities, and resistance to fatigue relative to their wild-type littermates. Selective PPAR- agonists (i.e., GW-501516) are currently in clinical trials for the treatment of dyslipidemia, insulin resistance, and obesity.

	LXRs

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
Recent evidence suggests the Liver X Receptors (LXR and LXR) regulate lipid metabolism in skeletal muscle. Analysis of gene expression changes in both rodent quadricep muscle and cultured skeletal muscle myotubes treated with the synthetic LXR agonist T0901317 revealed an upregulation of key genes involved in lipid and cholesterol efflux and lipogenesis such as ABCA1, ApoE and SREBP-1c (119). While LXR agonists have proven utility in the treatment of hypercholesterolemia their development into an efficacious treatment for this condition has been impaired by the deleterious side effects consequential to the activation of lipogenesis. Significantly, the induction of the SREBP-1c target genes FAS, and SCD-1 involved in lipogenesis was observed in livers but not skeletal muscle of rodents treated with LXR agonists. This observation is believed to stem from the fact the LXR is the predominant isoform expressed in skeletal muscle as opposed to LXR in liver and prompted speculation that LXR specific agonists may retain the desired cholesterol lowering activity while avoiding the undesirable hypertriglyceridaemia. The observation that synthetic LXR agonists increase ABCA1 mediated cholesterol efflux in skeletal muscle cells underscores the potential of this tissue as a target of reverse cholesterol transport and HDL cholesterol regulation (119).

	ESTROGEN-RELATED RECEPTOR

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
Estrogen-related receptors (, , and ) are orphan receptors with close homology to the estrogen receptor that have implicated roles in the regulation of cellular energy metabolism. Accordingly ERRs are abundantly expressed in tissues with a high capacity for fatty acid -oxidation (47, 65). Homozygous knock-out ERR^–/– mice were found to have a significant reduction in fat mass and a commensurate resistance to high fat induced obesity (102). This phenotype was attributable to the altered expression of genes involved in lipid metabolism and adipocyte development. Somewhat paradoxically, a synthetic ERR agonist was found to increase energy expenditure and thus antagonize the development of obesity (71).

ERR regulation of cellular metabolism appears to involve interactions with the PGC1 co-regulator. PGC1 has been shown to be a potent co-activator of ERR with a synthetic inhibitor of ERR significantly attenuating PGC1 mediated regulation of oxidative phosphorylation and mitochondrial respiration in skeletal and cardiac muscle cells (115). ERR has also been found to activate PPAR in skeletal muscle cells subsequently regulating an array of genes involved in fatty acid uptake, fatty acid oxidation, and oxidative phosphorylation (64). Recent evidence that an ERR-dependent PGC1 program mediates the induction of mitofusin-2 helps explain the link between exercise and PGC1/ERR mediated modulation of mitochondrial function (24). Mitofusin-2 is a key regulator of mitochondrial biogenesis and is pivotal to the increase in mitochondrial size, content and oxidative capacity in response to exericse. In light of established links between insulin resistance and impaired mitochondrial function synthetic modulation of ERR function may prove to be an effective therapeutic target in the treatment of metabolic disease.

	RORS AND REV-ERBS

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
RORs and Rev-erbs belong to the NR1F, and NR1D subgroups subgroups of nuclear hormone receptors, respectively. These are closely related families of orphan nuclear receptors that operate in opposing manners. Three ROR genes have been identified; ROR encodes four alternatively spliced isoforms (ROR1, ROR2, ROR3, and ROR), which are predominantly expressed in blood, brain, skeletal muscle, and fat cells. ROR is expressed specifically in the brain and ROR is found at high levels in skeletal muscle and thymocytes (67). Two Rev-erb genes have been identified: Rev-erb and Rev-erb. The Rev-erb gene encodes two alternatively spliced isoforms, Rev-erb1 and Rev-erb2. The mRNAs are expressed in most tissues, although very abundant expression is seen in energy-demanding tissues, including skeletal and cardiac muscle, liver, kidney, and brown fat.

Analysis of the spontaneously generated "staggerer" (sg/sg) mutant mouse, which carries a loss of function mutation in the ROR- gene, has been extremely informative on the role of ROR- in lipid homeostasis and skeletal muscle function. The most obvious staggerer phenotype is ataxia associated with a cerebellar atrophy, aberrant vascular physiology, hypersensitive inflammatory response, dyslipidemia, and enhanced susceptibility to atherosclerosis (104). In the context of lipid homeostasis, the sg/sg mice exhibit a dyslipidemia, characterized by lower circulating plasma levels of HDL-C, ApoA1, AII, and CIII and plasma triglycerides. Notably, ApoAI is a major constituent of HDL, whereas ApoCIII is a component of HDL and VLDL that plays a role in regulation of triglyceride levels and lipoprotein lipase activity (146, 178). This observation is supported by cell culture studies demonstrating that ROR-, and Rev-erb- activate and repress the expression of ApoAI and CIII in cell culture, respectively (18, 66).

Futhermore, sg/sg mice have been shown to have a reduced muscular strength, a finding supported by earlier work conducted in our laboratory, demonstrating that ROR- potentiates skeletal muscle myogenesis, whereas the Rev-erbs antagonize muscle cell differentiation in culture (22, 37, 87). Ectopic expression of a dominant negative form of ROR- in skeletal muscle cells attenuated ROR-dependent gene expression, repressed the endogenous levels of ROR- and ROR- mRNA, and also resulted in attenuated expression of many genes involved in lipogenesis and energy homeostasis, including SREBP-1c, SCD1/2 and FAS, a finding consistent with the lowered TG levels observed in sg/sg mice (88). Furthermore, previous studies have demonstrated that MCPT-1 an established target for PPAR- in cardiac muscle and PPAR- in skeletal muscle cells, is also directly regulated by ROR1 raising the suggesting a potential tissue-specific cross-talk between PPAR- and ROR-. Cell culture studies and analysis of the sg/sg mouse highlights the importance of ROR- in the regulation of lipid homeostasis, and we hypothesize that ROR-₁ in skeletal muscle programs a cascade of gene expression designed to regulate lipid and energy homeostasis in this tissue (88).

Similarly, mice homozygous (–/–) for the Rev-erb- null allele have a dyslipidemic phenotype and a 20% lower body weight. Male Rev-erb--deficient mice show elevated serum VLDL triglyceride levels and increased serum and liver expression of apoCIII mRNA (146). Elevated ApoCIII and VLDL triglycerides in Rev-erb-–/– is in contrast to reduced ApoCIII and triglycerides observed in ROR- mutant sg/sg mice and concurs with the negative regulation of ApoCIII by Rev-erb-. Interestingly, homozygous Rev-erb--null mice display a significant shift from fast (type IIA) to slow (type I) myosin heavy chain expression in the slow twitch, mitochondrial rich oxidative fibres which encodes the thick filament of the sarcomere. This is in concordance with the selective expression of Rev-erb- in type IIB glycolytic and intermediate type IIA oxidative fibers (138). This suggests that this orphan NR regulates muscle fiber type, which will have concomitant effects on insulin sensitivity and aerobic/anaerobic metabolism.

Ectopic expression of a dominant negative mutant Rev-erb-E (lacking the LBD) in skeletal muscle cells attenuated a range of genes involved in fatty acid/lipid absorption including CD36, FABP3, and FABP4 (143). Increased expression of SREBP-1c and SCD1 was also observed and is consistent with elevated TG levels in Rev-erb-–/– mice. Moreover, a dramatic decrease in the myostatin expression and elevated IL-6 expression further highlights a potential role of this orphan receptor in the regulation of muscle mass, adiposity, and inflammation (143). Modulation of these myokines coupled with observed changes in genes controlling muscle lipid absorption and metabolism suggest that Rev-erb- activity plays and important role in muscle growth and lipid homeostasis (143).

These studies underscore the potential therapeutic utility of ROR-₁, and Rev-erb agonists, that is further highlighted by genetic and biochemical studies demonstrating the anti-atherogenic and anti-inflammatory properties of ROR-, and proinflammatory properties of Rev-erb. The mechanism involves the modulation of the NF-B signaling pathway and regulation of p65 translocation, and of IB activity. Moreover, we propose that the atherogenic and dyslipidemic phenotype of the sg/sg mouse is related to aberrant ROR function in skeletal muscle and surmise that ROR₁ agonists may have therapeutic utility in the treatment of hypercholesterolemia and atherosclerosis.

	NR4A FAMILY

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
The NR4A subgroup of orphan nuclear receptors comprises three members Nurr1, Nur77, and NOR-1, which largely function as immediate-early genes, whose expression and activation is regulated in a cell-type specific manner in response to a range of signals, such as mitogenic and apoptotic stimuli. Nur77 is expressed in a range of tissues, including the thymus, muscle, lung, liver, testis, ovary, and prostate, and adrenal, thyroid and pituitary glands (33, 120, 126). NOR-1 is expressed in the pituitary and adrenal glands, cardiac and skeletal muscle, thymus, and kidney (44, 127, 191), whereas Nurr1 is expressed in the central nervous system, thymus, liver, and pituitary gland (89, 117, 118). Crystalographic studies suggest the NR4A subgroup are perhaps true orphan receptors that have little space available for ligand interaction within their respective LBDs, but when expressed, are constitutively active and highly responsive to various signaling pathways. Despite the fact that these genes may not afford agonist (or antagonist) modulation of activity in the classic sense, recent evidence has demonstrated the potential for the identification of small molecule regulators of these orphan nuclear receptors. The finding that the purine anti-metabolite 6-mercaptopurine modulated the activity of NR4A family members in an AF1 dependent manner suggests such molecules may provide a platform for the pharmacological and ultimately therapeutic exploitation of these genes (129, 182).

The Nur77 orphan nuclear receptor has recently been linked to adrenergic control of energy balance/homeostasis. In cultured muscle cells -adrenergic receptor activation by isoprenaline elicited a rapid, striking, and transient upregulation of Nur77 expression (99, 108). Concordantly, it was found that small interfering RNA-mediated knockdown of Nur77 expression in this cell model resulted in attenuation of gene expression pathways associated with preferential lipid utilization and energy balance, such as UCP-3 and AMPK3 (108). Similarly, UCP-3 was found to be downregulated in mouse tibialis muscle after injection and electro-transfer of siNur77 in concordance with decreased expression of UCP-3 in the C2C12 culture model (108). In addition, attenuation of Nur77 expression resulted in decreased expression of genes involved in carbohydrate and lipid homeostasis, such as adiponectin receptor 2, CD36 and GLUT4, which correlated with decreased lypolysis in these cells (108). These data are concordant with the known effects of adrenergic agonists on glucose uptake (123) and the links between UCP3 and AMPK in skeletal muscle cells (170). Increased lipolysis and energy expenditure upon Nur77 activation makes Nur77 a highly attractive potential therapeutic target in the treatment of obesity.

	CHICKEN OVALBUMIN UPSTREAM PROMOTER-TRANSCRIPTION FACTOR

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
The chicken ovalbumin upstream promotor (COUP)-transcription factors (TFs) are most related to the retinoid X receptor/retinoid acid receptor, and are generally considered to be repressors of other nuclear receptors, such as PPARs, retinoic acid, thyroid hormone, and vitamin D receptors (130). COUP-TFs are involved in the regulation of several fundamental biological processes, such as neurogenesis, organogenesis, and metabolic homeostasis. COUP-TFs can modulate the activity of genes that are fundamental in the orchestration of glucose and lipid metabolism, such as bile acid synthesis (CYP7A-cholesterol 7a-hydroxylase) (31), ketogenesis (mitochondrial HMG-CoA synthase) (56), cholesterol transport (cholesterol ester transfer gene and apolipoprotein AI) (46, 121), fatty-acid -oxidation (medium-chain acyl CoA dehydrogenase) (35), and glucose homeostasis and insulin sensitivity (10). Moreover, COUP-TF can inhibit preadipocyte differentiation, and its ortholog in Drosophila (svp) is required for fat cell differentiation (60). Previous studies (7) in muscle cell cultures have demonstrated a role for COUP-TFs in muscle development showing COUP-TFII inhibits the expression and function of MyoD. Despite COUP-TFII involvement in muscle differentiation and its implication in the regulation of carbohydrate and lipid metabolism in other tissues the specific contribution of COUP-TFs in skeletal muscle metabolic homeostasis remains unexplored.

In conclusion, it is increasingly obvious that orphan and adopted nuclear receptors are key regulators of lipid and carbohydrate homeostasis in skeletal muscle. The efficacy of a number of pharmacological agents that target a number of these adopted orphan receptors such as PPAR- (TZD) and PPAR- (fibrates) underscores the immense potential of orphan nuclear receptors as therapeutic targets in the treatment of metabolic and cardiovascular disease. The relative mass and metabolic flexibility of skeletal muscle, and the observed metabolic and biochemical perturbations in diabetic and obese individuals, attests to the importance of this tissue in systemic metabolic homeostasis. For this reason, NRs and skeletal muscle are valid targets in the battle to ameliorate metabolic perturbations associated with metabolic syndrome, obesity, and cardiovascular disease. Despite recent advances in our understanding of NR function in metabolic homeostasis, considerable future effort is required to realise the potential of NR agonists in the battle against cardiovascular disease.

Dyslipidemia, insulin resistance, blood glucose levels (and glucose tolerance), diabetes, inflammation, and obesity are all serious risk factors for cardiovascular and metabolic disease. NRs and skeletal muscle are validated targets in the battle to ameliorate metabolic perturbations; however, the real promise and potential of NR agonists in the battle against cardiovascular disease has not yet been realized.

	FOOTNOTES

 

Address for reprint requests and other correspondence: A. G. Smith, Institute for Molecular Bioscience, Univ. of Queensland, St. Lucia 4072, Queensland, Australia (e-mail: a.smith{at}imb.uq.edu.au)

	REFERENCES

TOP ABSTRACT METABOLIC SYNDROME SKELETAL MUSCLE CARBOHYDRATE AND... SKELETAL MUSCLE AS AN... NUCLEAR RECEPTOR REGULATION OF... NUCLEAR RECEPTOR FUNCTION:... ORPHAN NRs AS THERAPEUTIC... REGULATION OF SKELETAL MUSCLE... PPARs LXRs ESTROGEN-RELATED RECEPTOR RORS AND REV-ERBS NR4A FAMILY CHICKEN OVALBUMIN UPSTREAM... REFERENCES

 
1. Adult Treatment Panel III. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults. JAMA 285: 2486–2497, 2001.[Free Full Text]

2. Agostini M, Gurnell M, Savage DB, Wood EM, Smith AG, Rajanayagam O, Garnes KT, Levinson SH, Xu HE, Schwabe JW, Willson TM, O'Rahilly S, and Chatterjee VK. Tyrosine agonists reverse the molecular defects associated with dominant-negative mutations in human peroxisome proliferator-activated receptor . Endocrinology 145: 1527–1538, 2004.[Abstract/Free Full Text]

3. American Heart Association. Heart Disease and Stroke Statistics–2004 Update, 2004.

4. American Heart Association. International Cardiovascular Disease Statistics, 2005.

5. Arakawa K, Ishihara T, Aoto M, Inamasu M, Saito A, and Ikezawa K. Actions of novel antidiabetic thiazolidinedione, T-174, in animal models of non-insulin-dependent diabetes mellitus (NIDDM) and in cultured muscle cells. Br J Pharmacol 125: 429–436, 1998.[CrossRef][Web of Science][Medline]

6. Aranda A and Pascual A. Nuclear hormone receptors and gene expression. Physiol Rev 81: 1269–1304, 2001.[Abstract/Free Full Text]

7. Bailey P, Sartorelli V, Hamamori Y, and Muscat GE. The orphan nuclear receptor, COUP-TF II, inhibits myogenesis by post-transcriptional regulation of MyoD function: COUP-TF II directly interacts with p300 and myoD. Nucleic Acids Res 26: 5501–5510, 1998.[Abstract/Free Full Text]

8. Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, Boland R, and Evans RM. Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer. Proc Natl Acad Sci USA 99: 303–308, 2002.[Abstract/Free Full Text]

9. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, and Evans RM. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 4: 585–595, 1999.[CrossRef][Web of Science][Medline]

10. Bardoux P, Zhang P, Flamez D, Perilhou A, Lavin TA, Tanti JF, Hellemans K, Gomas E, Godard C, Andreelli F, Buccheri MA, Kahn A, Le Marchand-Brustel Y, Burcelin R, Schuit F, and Vasseur-Cognet M. Essential role of chicken ovalbumin upstream promoter-transcription factor II in insulin secretion and insulin sensitivity revealed by conditional gene knockout. Diabetes 54: 1357–1363, 2005.[Abstract/Free Full Text]

11. Barger PM and Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 10: 238–245, 2000.[CrossRef][Web of Science][Medline]

12. Barish GD and Evans RM. PPARs and LXRs: atherosclerosis goes nuclear. Trends Endocrinol Metab 15: 158–165, 2004.[CrossRef][Web of Science][Medline]

13. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, and O'Rahilly S. Dominant negative mutations in human PPAR associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402: 880–883, 1999.[Medline]

14. Berkenstam A and Gustafsson JA. Nuclear receptors and their relevance to diseases related to lipid metabolism. Curr Opin Pharmacol 5: 171–176, 2005.[CrossRef][Web of Science][Medline]

15. Bierman EL, Dole VP, and Roberts TN. An abnormality of nonesterified fatty acid metabolism in diabetes mellitus. Diabetes 6: 475–479, 1957.[Web of Science][Medline]

16. Bonen A, Parolin ML, Steinberg GR, Calles-Escandon J, Tandon NN, Glatz JF, Luiken JJ, Heigenhauser GJ, and Dyck DJ. Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. FASEB J 18: 1144–1146, 2004.[Abstract/Free Full Text]

17. Boucher A, Lu D, Burgess SC, Telemaque-Potts S, Jensen MV, Mulder H, Wang MY, Unger RH, Sherry AD, and Newgard CB. Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue. J Biol Chem 279: 27263–27271, 2004.[Abstract/Free Full Text]

18. Boukhtouche F, Mariani J, and Tedgui A. The "CholesteROR" protective pathway in the vascular system. Arterioscler Thromb Vasc Biol 24: 637–643, 2004.[Abstract/Free Full Text]

19. Bruce CR and Dyck DJ. Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-. Am J Physiol Endocrinol Metab 287: E616–E621, 2004.[Abstract/Free Full Text]

20. Brun S, Carmona MC, Mampel T, Vinas O, Giralt M, Iglesias R, and Villarroya F. Activators of peroxisome proliferator-activated receptor- induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. Diabetes 48: 1217–1222, 1999.[Abstract]

21. Burant CF, Sreenan S, Hirano K, Tai TA, Lohmiller J, Lukens J, Davidson NO, Ross S, and Graves RA. Troglitazone action is independent of adipose tissue. J Clin Invest 100: 2900–2908, 1997.[Web of Science][Medline]

22. Burke L, Downes M, Carozzi A, Giguere V, and Muscat GE. Transcriptional repression by the orphan steroid receptor RVR/Rev-erb is dependent on the signature motif and helix 5 in the E region: functional evidence for a biological role of RVR in myogenesis. Nucleic Acids Res 24: 3481–3489, 1996.[Abstract/Free Full Text]

23. Carbo N, Lopez-Soriano J, Costelli P, Busquets S, Alvarez B, Baccino FM, Quinn LS, Lopez-Soriano FJ, and Argiles JM. Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats. Br J Cancer 83: 526–531, 2000.[CrossRef][Web of Science][Medline]

24. Cartoni R, Leger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Deriaz O, Zorzano A, Gobelet C, Kralli A, and Russell AP. Mitofusins 1/2 and ERR expression are increased in human skeletal muscle after physical exercise. J Physiol 567: 349–358, 2005.[Abstract/Free Full Text]

25. Cha BS, Ciaraldi TP, Carter L, Nikoulina SE, Mudaliar S, Mukherjee R, Paterniti JR Jr, and Henry RR. Peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) agonists have complementary effects on glucose and lipid metabolism in human skeletal muscle. Diabetologia 44: 444–452, 2001.[CrossRef][Web of Science][Medline]

26. Chan MH, Carey AL, Watt MJ, and Febbraio MA. Cytokine gene expression in human skeletal muscle during concentric contraction: evidence that IL-8, like IL-6, is influenced by glycogen availability. Am J Physiol Regul Integr Comp Physiol 287: R322–R327, 2004.[Abstract/Free Full Text]

27. Chan MH, McGee SL, Watt MJ, Hargreaves M, and Febbraio MA. Altering dietary nutrient intake that reduces glycogen content leads to phosphorylation of nuclear p38 MAP kinase in human skeletal muscle: association with IL-6 gene transcription during contraction. FASEB J 18: 1785–1787, 2004.[Abstract/Free Full Text]

28. Chavez JA, Knotts TA, Wang LP, Li G, Dobrowsky RT, Florant GL, and Summers SA. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem 278: 10297–10303, 2003.[Abstract/Free Full Text]

28a. Chawla A, Repa JJ, Evans RM, and Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science 294: 1866–1870, 2001.[Abstract/Free Full Text]

29. Chawla A, Lee CH, Barak Y, He W, Rosenfeld J, Liao D, Han J, Kang H, and Evans RM. PPAR is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci USA 100: 1268–1273, 2003.[Abstract/Free Full Text]

30. Ciaraldi TP, Cha BS, Park KS, Carter L, Mudaliar SR, and Henry RR. Free fatty acid metabolism in human skeletal muscle is regulated by PPAR and RXR agonists. Ann NY Acad Sci 967: 66–70, 2002.[Web of Science][Medline]

31. Crestani M, Sadeghpour A, Stroup D, Galli G, and Chiang JY. Transcriptional activation of the cholesterol 7-hydroxylase gene (CYP7A) by nuclear hormone receptors. J Lipid Res 39: 2192–2200, 1998.[Free Full Text]

32. Davila-Roman VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, and Gropler RJ. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 40: 271–277, 2002.[Abstract/Free Full Text]

33. Davis IJ and Lau LF. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands. Mol Cell Biol 14: 3469–3483, 1994.[Abstract/Free Full Text]

34. Diradourian C, Girard J, and Pegorier JP. Phosphorylation of PPARs: from molecular characterization to physiological relevance. Biochimie 87: 33–38, 2005.[Medline]

35. Disch DL, Rader TA, Cresci S, Leone TC, Barger PM, Vega R, Wood PA, and Kelly DP. Transcriptional control of a nuclear gene encoding a mitochondrial fatty acid oxidation enzyme in transgenic mice: role for nuclear receptors in cardiac and brown adipose expression. Mol Cell Biol 16: 4043–4051, 1996.[Abstract]

36. Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin J, Gonzalez FJ, and Kelly DP. A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor -deficient mice. J Clin Invest 102: 1083–1091, 1998.[Web of Science][Medline]

37. Downes M, Carozzi AJ, and Muscat GE. Constitutive expression of the orphan receptor, Rev-erbA , inhibits muscle differentiation and abrogates the expression of the myoD gene family. Mol Endocrinol 9: 1666–1678, 1995.[Abstract/Free Full Text]

38. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, and Shulman GI. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103: 253–259, 1999.[Web of Science][Medline]

39. Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, and Muscat GE. The peroxisome proliferator-activated receptor / agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol 17: 2477–2493, 2003.[Abstract/Free Full Text]

40. Eckel RH, Grundy SM, and Zimmet PZ. The metabolic syndrome. Lancet 365: 1415–1428, 2005.[CrossRef][Web of Science][Medline]

41. Evans RM, Barish GD, and Wang YX. PPARs and the complex journey to obesity. Nat Med 10: 355–361, 2004.[CrossRef][Web of Science][Medline]

42. Febbraio MA and Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 33: 114–119, 2005.[CrossRef][Web of Science][Medline]

43. Febbraio MA and Pedersen BK. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J 16: 1335–1347, 2002.[Abstract/Free Full Text]

44. Fernandez PM, Brunel F, Jimenez MA, Saez JM, Cereghini S, and Zakin MM. Nuclear receptors Nor1 and NGFI-B/Nur77 play similar, albeit distinct, roles in the hypothalamo-pituitary-adrenal axis. Endocrinology 141: 2392–2400, 2000.[Abstract/Free Full Text]

45. Francis GA, Fayard E, Picard F, and Auwerx J. Nuclear receptors and the control of metabolism. Annu Rev Physiol 65: 261–311, 2003.[CrossRef][Web of Science][Medline]

46. Gaudet F and Ginsburg GS. Transcriptional regulation of the cholesteryl ester transfer protein gene by the orphan nuclear hormone receptor apolipoprotein AI regulatory protein-1. J Biol Chem 270: 29916–29922, 1995.[Abstract/Free Full Text]

47. Giguere V, Yang N, Segui P, and Evans RM. Identification of a new class of steroid hormone receptors. Nature 331: 91–94, 1988.[CrossRef][Medline]

48. Gilde AJ, van der Lee KA, Willemsen PH, Chinetti G, van der Leij FR, van der Vusse GJ, Staels B, and van Bilsen M. Peroxisome proliferator-activated receptor (PPAR) and PPAR/, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res 92: 518–524, 2003.[Abstract/Free Full Text]

49. Goodpaster BH and Wolf D. Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes. Pediatr Diabetes 5: 219–226, 2004.[CrossRef][Web of Science][Medline]

50. Gronemeyer H, Gustafsson JA, and Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3: 950–964, 2004.[CrossRef][Web of Science][Medline]

51. Gurnell M and Chatterjee VK. Nuclear receptors in disease: thyroid receptor beta, peroxisome-proliferator-activated receptor gamma and orphan receptors. Essays Biochem 40: 169–189, 2004.[Web of Science][Medline]

52. Gurnell M, Savage DB, Chatterjee VK, and O'Rahilly S. The metabolic syndrome: peroxisome proliferator-activated receptor and its therapeutic modulation. J Clin Endocrinol Metab 88: 2412–2421, 2003.[Abstract/Free Full Text]

53. Hammarstedt A and Smith U. Thiazolidinediones (PPAR ligands) increase IRS-1, UCP-2 and C/EBP expression, but not transdifferentiation, in L6 muscle cells. Diabetologia 46: 48–52, 2003.[Web of Science][Medline]

54. He W, Barak Y, Hevener A, Olson P, Liao D, Le J, Nelson M, Ong E, Olefsky JM, and Evans RM. Adipose-specific peroxisome proliferator-activated receptor knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA 100: 15712–15717, 2003.[Abstract/Free Full Text]

55. Hedman A, Byberg L, Reneland R, and Lithell HO. Muscle morphology, self-reported physical activity and insulin resistance syndrome. Acta Physiol Scand 175: 325–332, 2002.[CrossRef][Web of Science][Medline]

56. Hegardt FG. Transcriptional regulation of mitochondrial HMG-CoA synthase in the control of ketogenesis. Biochimie 80: 803–806, 1998.[Medline]

57. Henriksson J. Muscle fuel selection: effect of exercise and training. Proc Nutr Soc 54: 125–138, 1995.[CrossRef][Web of Science][Medline]

58. Hevener AL, He W, Barak Y, Le J, Bandyopadhyay G, Olson P, Wilkes J, Evans RM, and Olefsky J. Muscle-specific Pparg deletion causes insulin resistance. Nat Med 9: 1491–1497, 2003.[CrossRef][Web of Science][Medline]

59. Holst D, Luquet S, Nogueira V, Kristiansen K, Leverve X, and Grimaldi PA. Nutritional regulation and role of peroxisome proliferator-activated receptor delta in fatty acid catabolism in skeletal muscle. Biochim Biophys Acta 1633: 43–50, 2003.[Medline]

60. Hoshizaki DK, Blackburn T, Price C, Ghosh M, Miles K, Ragucci M, and Sweis R. Embryonic fat-cell lineage in Drosophila melanogaster. Development 120: 2489–2499, 1994.[Abstract/Free Full Text]

61. Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 27, Suppl 3: S53–55, 2003.[CrossRef][Web of Science]

62. Hotamisligil GS. The role of TNF and TNF receptors in obesity and insulin resistance. J Intern Med 245: 621–625, 1999.[CrossRef][Web of Science][Medline]

63. Hulver MW, Berggren JR, Carper MJ, Miyazaki M, Ntambi JM, Hoffman EP, Thyfault JP, Stevens R, Dohm GL, Houmard JA, and Muoio DM. Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans. Cell Metab 2: 251–261, 2005.[CrossRef][Web of Science][Medline]

64. Huss JM, Torra IP, Staels B, Giguere V, and Kelly DP. Estrogen-related receptor directs peroxisome proliferator-activated receptor signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol 24: 9079–9091, 2004.[Abstract/Free Full Text]

65. Ichida M, Nemoto S, and Finkel T. Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1). J Biol Chem 277: 50991–50995, 2002.[Abstract/Free Full Text]

66. Jarvis CI, Staels B, Brugg B, Lemaigre-Dubreuil Y, Tedgui A, and Mariani J. Age-related phenotypes in the staggerer mouse expand the ROR nuclear receptor's role beyond the cerebellum. Mol Cell Endocrinol 186: 1–5, 2002.[CrossRef][Web of Science][Medline]

67. Jetten AM, Kurebayashi S, and Ueda E. The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucleic Acid Res Mol Biol 69: 205–247, 2001.[Web of Science][Medline]

68. Jordan VC. Selective estrogen receptor modulation: concept and consequences in cancer. Cancer Cell 5: 207–213, 2004.[CrossRef][Web of Science][Medline]

69. Joseph JW, Koshkin V, Saleh MC, Sivitz WI, Zhang CY, Lowell BB, Chan CB, and Wheeler MB. Free fatty acid-induced -cell defects are dependent on uncoupling protein 2 expression. J Biol Chem 279: 51049–51056, 2004.[Abstract/Free Full Text]

70. Kadowaki T and Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 26: 439–451, 2005.[Abstract/Free Full Text]

71. Kamei Y, Ohizumi H, Fujitani Y, Nemoto T, Tanaka T, Takahashi N, Kawada T, Miyoshi M, Ezaki O, and Kakizuka A. PPARgamma coactivator 1/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci USA 100: 12378–12383, 2003.[Abstract/Free Full Text]

72. Kato S. Estrogen receptor-mediated cross-talk with growth factor signaling pathways. Breast Cancer 8: 3–9, 2001.[Medline]

73. Kausch C, Krutzfeldt J, Witke A, Rettig A, Bachmann O, Rett K, Matthaei S, Machicao F, Haring HU, and Stumvoll M. Effects of troglitazone on cellular differentiation, insulin signaling, and glucose metabolism in cultured human skeletal muscle cells. Biochem Biophys Res Commun 280: 664–674, 2001.[CrossRef][Web of Science][Medline]

74. Kelley DE. Skeletal muscle fat oxidation: timing and flexibility are everything. J Clin Invest 115: 1699–1702, 2005.[CrossRef][Web of Science][Medline]

75. Kelley DE. Skeletal muscle triglycerides: an aspect of regional adiposity and insulin resistance. Ann NY Acad Sci 967: 135–145, 2002.[CrossRef][Web of Science][Medline]

76. Kelley DE, Goodpaster B, Wing RR, and Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol Endocrinol Metab 277: E1130–E1141, 1999.[Abstract/Free Full Text]

77. Kelley DE, He J, Menshikova EV, and Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51: 2944–2950, 2002.[Abstract/Free Full Text]

78. Kelley DE and Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49: 677–683, 2000.[Abstract]

79. Kelly LJ, Vicario PP, Thompson GM, Candelore MR, Doebber TW, Ventre J, Wu MS, Meurer R, Forrest MJ, Conner MW, Cascieri MA, and Moller DE. Peroxisome proliferator-activated receptors and mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression. Endocrinology 139: 4920–4927, 1998.[Abstract/Free Full Text]

80. Kelly M, Keller C, Avilucea PR, Keller P, Luo Z, Xiang X, Giralt M, Hidalgo J, Saha AK, Pedersen BK, and Ruderman NB. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun 320: 449–454, 2004.[CrossRef][Web of Science][Medline]

81. Kim HS, Liang L, Dean RG, Hausman DB, Hartzell DL, and Baile CA. Inhibition of preadipocyte differentiation by myostatin treatment in 3T3-L1 cultures. Biochem Biophys Res Commun 281: 902–906, 2001.[CrossRef][Web of Science][Medline]

82. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, and Shulman GI. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 98: 7522–7527, 2001.[Abstract/Free Full Text]

83. Kim YB, Ciaraldi TP, Kong A, Kim D, Chu N, Mohideen P, Mudaliar S, Henry RR, and Kahn BB. Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110 protein levels in skeletal muscle of type 2 diabetic subjects. Diabetes 51: 443–448, 2002.[Abstract/Free Full Text]

84. Kim YB, Shulman GI, and Kahn BB. Fatty acid infusion selectively impairs insulin action on Akt1 and protein kinase C /zeta but not on glycogen synthase kinase-3. J Biol Chem 277: 32915–32922, 2002.[Abstract/Free Full Text]

85. Kliewer SA, Lehmann JM, and Willson TM. Orphan nuclear receptors: shifting endocrinology into reverse. Science 284: 757–760, 1999.[Abstract/Free Full Text]

86. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, and Shulman GI. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42: 113–116, 1999.[CrossRef][Web of Science][Medline]

87. Lau P, Bailey P, Dowhan DH, and Muscat GE. Exogenous expression of a dominant negative ROR1 vector in muscle cells impairs differentiation: ROR1 directly interacts with p300 and myoD. Nucleic Acids Res 27: 411–420, 1999.[Abstract/Free Full Text]

88. Lau P, Nixon SJ, Parton RG, and Muscat GE. RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. J Biol Chem 279: 36828–36840, 2004.[Abstract/Free Full Text]

89. Law SW, Conneely OM, DeMayo FJ, and O'Malley BW. Identification of a new brain-specific transcription factor, NURR1. Mol Endocrinol 6: 2129–2135, 1992.[Abstract/Free Full Text]

90. Lee CH, Olson P, and Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 144: 2201–2207, 2003.[Abstract/Free Full Text]

91. Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, and Gonzalez FJ. Targeted disruption of the isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15: 3012–3022, 1995.[Abstract]

92. Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, and Unger RH. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte--cell relationships. Proc Natl Acad Sci USA 91: 10878–10882, 1994.[Abstract/Free Full Text]

93. Lee YH and Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep 5: 70–75, 2005.[Medline]

94. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, and Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor (PPAR). J Biol Chem 270: 12953–12956, 1995.[Abstract/Free Full Text]

95. Leibowitz MD, Fievet C, Hennuyer N, Peinado-Onsurbe J, Duez H, Bergera J, Cullinan CA, Sparrow CP, Baffic J, Berger GD, Santini C, Marquis RW, Tolman RL, Smith RG, Moller DE, and Auwerx J. Activation of PPAR alters lipid metabolism in db/db mice. FEBS Lett 473: 333–336, 2000.[CrossRef][Web of Science][Medline]

96. Leone TC, Weinheimer CJ, and Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPAR) in the cellular fasting response: the PPAR-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci USA 96: 7473–7478, 1999.[Abstract/Free Full Text]

97. Lewis GF and Steiner G. Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state. Diabetes Care 19: 390–393, 1996.[Abstract]

98. Lewis GF, Uffelman KD, Szeto LW, Weller B, and Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest 95: 158–166, 1995.[Web of Science][Medline]

99. Lim RW, Yang WL, and Yu H. Signal-transduction-pathway-specific desensitization of expression of orphan nuclear receptor TIS1. Biochem J 308: 785–789, 1995.[Web of Science][Medline]

100. Long SD and Pekala PH. Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3–L1 adipocytes. Biochem J 319: 179–184, 1996.[Medline]

101. Lopez-Solache I, Marie V, Vignault E, Camirand A, and Silva JE. Regulation of uncoupling protein-2 mRNA in L6 myotubules. I: thiazolidinediones stimulate uncoupling protein-2 gene expression by a mechanism requiring ongoing protein synthesis and an active mitogen-activated protein kinase. Endocrinology 19: 197–208, 2002.

102. Luo J, Sladek R, Carrier J, Bader JA, Richard D, and Giguere V. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol Cell Biol 23: 7947–7956, 2003.[Abstract/Free Full Text]

103. Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, Rassoulzadegan M, and Grimaldi PA. Peroxisome proliferator-activated receptor controls muscle development and oxidative capability. FASEB J 17: 2299–2301, 2003.[Abstract/Free Full Text]

104. Mamontova A, Seguret-Mace S, Esposito B, Chaniale C, Bouly M, Delhaye-Bouchaud N, Luc G, Staels B, Duverger N, Mariani J, and Tedgui A. Severe atherosclerosis and hypoalphalipoproteinemia in the staggerer mouse, a mutant of the nuclear receptor ROR. Circulation 98: 2738–2743, 1998.[Abstract/Free Full Text]

105. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, and Evans RM. The nuclear receptor superfamily: the second decade. Cell 83: 835–839, 1995.[CrossRef][Web of Science][Medline]

106. Margetic S, Gazzola C, Pegg GG, and Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 26: 1407–1433, 2002.[CrossRef][Web of Science][Medline]

107. Martini F. Fundamentals of Anatomy and Physiology. Englewood Cliffs, NJ: Prentice-Hall, 1998.

108. Maxwell MA, Cleasby ME, Harding A, Stark A, Cooney GJ, and Muscat GE. Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the -adrenergic and an orphan nuclear hormone receptor pathway. J Biol Chem 280: 12573–12584, 2005.[Abstract/Free Full Text]

109. McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51: 7–18, 2002.[Free Full Text]

110. McPherron AC and Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 94: 12457–12461, 1997.[Abstract/Free Full Text]

111. McPherron AC and Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 109: 595–601, 2002.[CrossRef][Web of Science][Medline]

112. Michalik L, Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, Peters JM, Kaya G, Gonzalez FJ, Zakany J, Metzger D, Chambon P, Duboule D, and Wahli W. Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR) and PPAR mutant mice. J Cell Biol 154: 799–814, 2001.[Abstract/Free Full Text]

113. Minnich A, Tian N, Byan L, and Bilder G. A potent PPAR agonist stimulates mitochondrial fatty acid -oxidation in liver and skeletal muscle. Am J Physiol Endocrinol Metab 280: E270–E279, 2001.[Abstract/Free Full Text]

114. Mohan R and Heyman RA. Orphan nuclear receptor modulators. Curr Top Med Chem 3: 1637–1647, 2003.[CrossRef][Web of Science][Medline]

115. Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, and Spiegelman BM. Erralpha and Gabpa/b specify PGC-1-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci USA 101: 6570–6575, 2004.[Abstract/Free Full Text]

116. Muoio DM, MacLean PS, Lang DB, Li S, Houmard JA, Way JM, Winegar DA, Corton JC, Dohm GL, and Kraus WE. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) knock-out mice. Evidence for compensatory regulation by PPAR. J Biol Chem 277: 26089–26097, 2002.[Abstract/Free Full Text]

117. Murphy EP and Conneely OM. Neuroendocrine regulation of the hypothalamic pituitary adrenal axis by the nurr1/nur77 subfamily of nuclear receptors. Mol Endocrinol 11: 39–47, 1997.[Abstract/Free Full Text]

118. Murphy EP, Dobson AD, Keller C, and Conneely OM. Differential regulation of transcription by the NURR1/NUR77 subfamily of nuclear transcription factors. Gene Expr 5: 169–179, 1996.[Web of Science][Medline]

119. Muscat GE, Wagner BL, Hou J, Tangirala RK, Bischoff ED, Rohde P, Petrowski M, Li J, Shao G, Macondray G, and Schulman IG. Regulation of cholesterol homeostasis and lipid metabolism in skeletal muscle by liver X receptors. J Biol Chem 277: 40722–40728, 2002.[Abstract/Free Full Text]

120. Nakai A, Kartha S, Sakurai A, Toback FG, and DeGroot LJ. A human early response gene homologous to murine nur77 and rat NGFI-B, and related to the nuclear receptor superfamily. Mol Endocrinol 4: 1438–1443, 1990.[Abstract/Free Full Text]

121. Nakamura T, Fox-Robichaud A, Kikkawa R, Kashiwagi A, Kojima H, Fujimiya M, and Wong NC. Transcription factors and age-related decline in apolipoprotein A-I expression. J Lipid Res 40: 1709–1718, 1999.[Abstract/Free Full Text]

122. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, and Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA 290: 1884–1890, 2003.[Abstract/Free Full Text]

123. Nevzorova J, Bengtsson T, Evans BA, and Summers RJ. Characterization of the -adrenoceptor subtype involved in mediation of glucose transport in L6 cells. Br J Pharmacol 137: 9–18, 2002.[CrossRef][Web of Science][Medline]

124. Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, and Kahn CR. Muscle-specific PPAR-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Invest 112: 608–618, 2003.[CrossRef][Web of Science][Medline]

125. Oakes ND, Bell KS, Furler SM, Camilleri S, Saha AK, Ruderman NB, Chisholm DJ, and Kraegen EW. Diet-induced muscle insulin resistance in rats is ameliorated by acute dietary lipid withdrawal or a single bout of exercise: parallel relationship between insulin stimulation of glucose uptake and suppression of long-chain fatty acyl-CoA. Diabetes 46: 2022–2028, 1997.[Abstract]

126. Ohkubo T, Sugawara Y, Sasaki K, Maruyama K, Ohkura N, and Makuuchi M. Early induction of nerve growth factor-induced genes after liver resection-reperfusion injury. J Hepatol 36: 210–217, 2002.[Web of Science][Medline]

127. Ohkura N, Ito M, Tsukada T, Sasaki K, Yamaguchi K, and Miki K. Structure, mapping and expression of a human NOR-1 gene, the third member of the Nur77/NGFI-B family. Biochim Biophys Acta 1308: 205–214, 1996.[Medline]

128. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, and Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 98: 5306–5311, 2001.[Abstract/Free Full Text]

129. Ordentlich P, Yan Y, Zhou S, and Heyman RA. Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1. J Biol Chem 278: 24791–24799, 2003.[Abstract/Free Full Text]

130. Park JI, Tsai SY, and Tsai MJ. Molecular mechanism of chicken ovalbumin upstream promoter-transcription factor (COUP-TF) actions. Keio J Med 52: 174–181, 2003.[Medline]

131. Pearce KH, Iannone MA, Simmons CA, and Gray JG. Discovery of novel nuclear receptor modulating ligands: an integral role for peptide interaction profiling. Drug Discov Today 9: 741–751, 2004.[CrossRef][Web of Science][Medline]

132. Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Wolsk-Petersen E, and Febbraio M. The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? Proc Nutr Soc 63: 263–267, 2004.[CrossRef][Web of Science][Medline]

133. Perseghin G. Muscle lipid metabolism in the metabolic syndrome. Curr Opin Lipidol 16: 416–420, 2005.[Web of Science][Medline]

134. Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, Reitman ML, Hudson LD, and Gonzalez FJ. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor (). Mol Cell Biol 20: 5119–5128, 2000.[Abstract/Free Full Text]

135. Petersen EW, Carey AL, Sacchetti M, Steinberg GR, Macaulay SL, Febbraio MA, and Pedersen BK. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab 288: E155–E162, 2005.[Abstract/Free Full Text]

136. Petersen KF and Shulman GI. Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus. Am J Cardiol 90: 11G-18G, 2002.[Web of Science][Medline]

137. Pickup JC, Mattock MB, Chusney GD, and Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40: 1286–1292, 1997.[CrossRef][Web of Science][Medline]

138. Pircher P, Chomez P, Yu F, Vennström B, and Larsson L. Aberrant expression of myosin isoforms in skeletal muscles from mice lacking the rev-erb orphan receptor gene. Am J Physiol Regul Integr Comp Physiol 288: R482–R490, 2004.[Medline]

139. Pradhan AD, Manson JE, Rifai N, Buring JE, and Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286: 327–334, 2001.[Abstract/Free Full Text]

140. Prentice T. World Health Organization: World Health Report. Overview. 2002.

141. Quinn LS, Haugk KL, and Grabstein KH. Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology 136: 3669–3672, 1995.[Abstract]

142. Quinn LS, Strait-Bodey L, Anderson BG, Argiles JM, and Havel PJ. Interleukin-15 stimulates adiponectin secretion by 3T3–L1 adipocytes: evidence for a skeletal muscle-to-fat signaling pathway. Cell Biol Int 29: 449–457, 2005.[CrossRef][Web of Science][Medline]

143. Ramakrishnan SN, Lau P, Burke LJ, and Muscat GE. Rev-erb regulates the expression of genes involved in lipid absorption in skeletal muscle cells: evidence for cross-talk between orphan nuclear receptors and myokines. J Biol Chem 280: 8651–8659, 2005.[Abstract/Free Full Text]

144. Randle PJ, Garland PB, Hales CN, and Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1: 785–789, 1963.[Web of Science][Medline]

145. Rangwala SM and Lazar MA. Peroxisome proliferator-activated receptor- in diabetes and metabolism. Trends Pharmacol Sci 25: 331–336, 2004.[CrossRef][Medline]

146. Raspe E, Duez H, Gervois P, Fievet C, Fruchart JC, Besnard S, Mariani J, Tedgui A, and Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor ROR. J Biol Chem 276: 2865–2871, 2001.[Abstract/Free Full Text]

147. Roden M, Krssak M, Stingl H, Gruber S, Hofer A, Furnsinn C, Moser E, and Waldhausl W. Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans. Diabetes 48: 358–364, 1999.[Abstract]

148. Romijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, and Wolfe RR. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol Endocrinol Metab 265: E380–E391, 1993.[Abstract/Free Full Text]

149. Romijn JA, Klein S, Coyle EF, Sidossis LS, and Wolfe RR. Strenuous endurance training increases lipolysis and triglyceride-fatty acid cycling at rest. J Appl Physiol 75: 108–113, 1993.[Abstract/Free Full Text]

150. Rosen ED and Spiegelman BM. PPAR: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276: 37731–37734, 2001.[Free Full Text]

151. Rosen ED, Walkey CJ, Puigserver P, and Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev 14: 1293–1307, 2000.[Free Full Text]

152. Rotter V, Nagaev I, and Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3–L1 adipocytes and is, like IL-8 and tumor necrosis factor-, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278: 45777–45784, 2003.[Abstract/Free Full Text]

153. Sack MN, Rader TA, Park S, Bastin J, McCune SA, and Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94: 2837–2842, 1996.[Abstract/Free Full Text]

154. Saladin R, Fajas L, Dana S, Halvorsen YD, Auwerx J, and Briggs M. Differential regulation of peroxisome proliferator activated receptor 1 (PPAR1) and PPAR2 messenger RNA expression in the early stages of adipogenesis. Cell Growth Differ 10: 43–48, 1999.[Abstract/Free Full Text]

155. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, and Shulman GI. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279: 32345–32353, 2004.[Abstract/Free Full Text]

156. Savage DB, Agostini M, Barroso I, Gurnell M, Luan J, Meirhaeghe A, Harding AH, Ihrke G, Rajanayagam O, Soos MA, George S, Berger D, Thomas EL, Bell JD, Meeran K, Ross RJ, Vidal-Puig A, Wareham NJ, O'Rahilly S, Chatterjee VK, and Schafer AJ. Digenic inheritance of severe insulin resistance in a human pedigree. Nat Genet 31: 379–384, 2002.[CrossRef][Web of Science][Medline]

157. Savage DB, Petersen KF, and Shulman GI. Mechanisms of insulin resistance in humans and possible links with inflammation. Hypertension 45: 828–833, 2005.[Abstract/Free Full Text]

158. Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams RL, Umpleby AM, Thomas EL, Bell JD, Dixon AK, Dunne F, Boiani R, Cinti S, Vidal-Puig A, Karpe F, Chatterjee VK, and O'Rahilly S. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-. Diabetes 52: 910–917, 2003.[Abstract/Free Full Text]

159. Schmitz-Peiffer C. Protein kinase C and lipid-induced insulin resistance in skeletal muscle. Ann NY Acad Sci 967: 146–157, 2002.[Web of Science][Medline]

160. Schulman IG and Heyman RA. The flip side: identifying small molecule regulators of nuclear receptors. Chem Biol 11: 639–646, 2004.[CrossRef][Web of Science][Medline]

161. Shao D and Lazar MA. Modulating nuclear receptor function: may the phos be with you. J Clin Invest 103: 1617–1618, 1999.[Web of Science][Medline]

162. Sharma AM and Chetty VT. Obesity, hypertension and insulin resistance. Acta Diabetol 42, Suppl 1: S3–S8, 2005.[CrossRef][Web of Science][Medline]

163. Shimabukuro M, Koyama K, Chen G, Wang MY, Trieu F, Lee Y, Newgard CB, and Unger RH. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci USA 94: 4637–4641, 1997.[Abstract/Free Full Text]

164. Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, and Goldstein JL. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 6: 77–86, 2000.[CrossRef][Web of Science][Medline]

165. Simoneau JA, Colberg SR, Thaete FL, and Kelley DE. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB J 9: 273–278, 1995.[Abstract]

166. Simoneau JA, Veerkamp JH, Turcotte LP, and Kelley DE. Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J 13: 2051–2060, 1999.[Abstract/Free Full Text]

167. Son C, Hosoda K, Matsuda J, Fujikura J, Yonemitsu S, Iwakura H, Masuzaki H, Ogawa Y, Hayashi T, Itoh H, Nishimura H, Inoue G, Yoshimasa Y, Yamori Y, and Nakao K. Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists for PPARs in L6 myotubes. Endocrinology 142: 4189–4194, 2001.[Abstract/Free Full Text]

168. Stavinoha MA, RaySpellicy JW, Essop MF, Graveleau C, Abel ED, Hart-Sailors ML, Mersmann HJ, Bray MS, and Young ME. Evidence for mitochondrial thioesterase 1 as a peroxisome proliferator-activated receptor--regulated gene in cardiac and skeletal muscle. Am J Physiol Endocrinol Metab 287: E888–E895, 2004.[Abstract/Free Full Text]

169. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, and Lazar MA. The hormone resistin links obesity to diabetes. Nature 409: 307–312, 2001.[CrossRef][Medline]

170. Suwa M, Nakano H, and Kumagai S. Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J Appl Physiol 95: 960–968, 2003.[Abstract/Free Full Text]

171. Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, and Sakai J. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci USA 100: 15924–15929, 2003.[Abstract/Free Full Text]

172. Tenbaum S and Baniahmad A. Nuclear receptors: structure, function and involvement in disease. Int J Biochem Cell Biol 29: 1325–1341, 1997.[CrossRef][Web of Science][Medline]

173. Van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, and Pedersen BK. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88: 3005–3010, 2003.[Abstract/Free Full Text]

174. Verma NK, Singh J, and Dey CS. PPAR- expression modulates insulin sensitivity in C2C12 skeletal muscle cells. Br J Pharmacol 143: 1006–1013, 2004.[CrossRef][Web of Science][Medline]

175. Vettor R, Fabris R, Serra R, Lombardi AM, Tonello C, Granzotto M, Marzolo MO, Carruba MO, Ricquier D, Federspil G, and Nisoli E. Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle. Int J Obes Relat Metab Disord 26: 838–847, 2002.[CrossRef][Web of Science][Medline]

176. Vosper H, Khoudoli GA, Graham TL, and Palmer CN. Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis. Pharmacol Ther 95: 47–62, 2002.[CrossRef][Web of Science][Medline]

177. Vosper H, Patel L, Graham TL, Khoudoli GA, Hill A, Macphee CH, Pinto I, Smith SA, Suckling KE, Wolf CR, and Palmer CN. The peroxisome proliferator-activated receptor promotes lipid accumulation in human macrophages. J Biol Chem 276: 44258–44265, 2001.[Abstract/Free Full Text]

178. Vu-Dac N, Gervois P, Grotzinger T, De Vos P, Schoonjans K, Fruchart JC, Auwerx J, Mariani J, Tedgui A, and Staels B. Transcriptional regulation of apolipoprotein A-I gene expression by the nuclear receptor ROR. J Biol Chem 272: 22401–22404, 1997.[Abstract/Free Full Text]

179. Wahl HG, Kausch C, Machicao F, Rett K, Stumvoll M, and Haring HU. Troglitazone downregulates -6 desaturase gene expression in human skeletal muscle cell cultures. Diabetes 51: 1060–1065, 2002.[Abstract/Free Full Text]

180. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, and Jansson JO. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8: 75–79, 2002.[CrossRef][Web of Science][Medline]

181. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, and Evans RM. Regulation of muscle fiber type and running endurance by PPAR. PLoS Biol 2: E294, 2004.[CrossRef][Medline]

182. Wansa KD, Harris JM, Yan G, Ordentlich P, and Muscat GE. The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine. J Biol Chem 278: 24776–24790, 2003.[Abstract/Free Full Text]

183. Wellen KE and Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 112: 1785–1788, 2003.[CrossRef][Web of Science][Medline]

184. White RT, Damm D, Hancock N, Rosen BS, Lowell BB, Usher P, Flier JS, and Spiegelman BM. Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. J Biol Chem 267: 9210–9213, 1992.[Abstract/Free Full Text]

185. WHOIDF. Diabetes Action Now. 2004.

186. Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 15: 2792–2800, 2004.[Abstract/Free Full Text]

187. Wolf G. Tissue-specific knockout defines peroxisome proliferator-activated receptor function in muscle and liver. Nutr Rev 62: 253–255, 2004.[CrossRef][Web of Science][Medline]

188. Yaney GC and Corkey BE. Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia 46: 1297–1312, 2003.[CrossRef][Web of Science][Medline]

189. Yonemitsu S, Nishimura H, Shintani M, Inoue R, Yamamoto Y, Masuzaki H, Ogawa Y, Hosoda K, Inoue G, Hayashi T, and Nakao K. Troglitazone induces GLUT4 translocation in L6 myotubes. Diabetes 50: 1093–1101, 2001.[Abstract/Free Full Text]

190. Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, and Shulman GI. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277: 50230–50236, 2002.[Abstract/Free Full Text]

191. Zetterstrom RH, Solomin L, Mitsiadis T, Olson L, and Perlmann T. Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1. Mol Endocrinol 10: 1656–1666, 1996.[Abstract/Free Full Text]

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