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) Protein Expression in Adipose Tissue
1 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA; Division of Hormone-dependent Tumor Biology, Albert Einstein College of Medicine, Bronx, NY, USA
2 Division of Hormone-dependent Tumor Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
3 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
* To whom correspondence should be addressed. E-mail: lisanti{at}aecom.yu.edu.
Several lines of evidence suggest that a functional relationship exists between caveolin-1 and insulin signaling. In vitro studies have shown that caveolin-1 can function as a positive regulator of insulin receptor activation. The scaffolding domain of caveolin-1 (residues 82–101) binds to a specific motif within the kinase domain of the insulin receptor (IR-
) (1193WSFGVVLW1200). Interestingly, mutations within the caveolin binding motif of the human insulin receptor (W1193L and W1200S) result in a syndrome of severe insulin-resistance. Furthermore, recombinant expression of an insulin receptor containing a disrupted caveolin binding motif (W1193G/F1195G/W1200G) reveals that this insulin receptor mutant is unstable, rapidly degraded, and fails to undergo auto-hosphorylation. These studies indirectly suggest
that the Cav-1/IR- interaction may serve to functionally stabilize the insulin receptor. However,
it remains unknown whether caveolin-1 is normally required for proper insulin receptor signaling in vivo.
To directly address this issue, we examined the status of insulin receptor signaling in caveolin-1 (-/-) deficient mice. Here, we show that Cav-1 null mice placed on a high fat diet for 9 months develop post-prandial hyper-insulinemia. An insulin tolerance test (ITT) revealed that
young Cav-1 null mice on a normal chow diet are significantly unresponsive to insulin, as compared to their wild-type counterparts. This insulin resistance is due to a primary a defect in adipose tissue, as evidenced by drastically reduced insulin receptor protein levels (> 90%),
without any changes in insulin receptor mRNA levels. These data suggest that caveolin-1 is necessary for the proper stabilization of the insulin receptor in adipocytes in vivo. In direct support of this notion, we demonstrate that recombinant expression of caveolin-1 in Cav-1 (-/-) null mouse embryo fibroblasts (MEFs) dramatically rescues insulin receptor protein expression.
Using the well-established inhibitor MG-132, we show that in the absence of caveolin-1 the insulin receptor undergoes proteasomal degradation. Finally, we demonstrate that the caveolinscaffolding domain is required to stabilize the insulin receptor, as the Cav-1 (
61-100) mutant fails to rescue insulin receptor expression in Cav-1 null MEFs. Taken together, these data provide evidence that the lean body phenotype observed in the Cav-1 knockout mice is due, at least in part, to a defect in insulin-regulated lipogenesis.
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