Reduced content of cholesterol in caveolae of adipocytes from insulin resistant, obese, and diabetic Zucker fa/fa rats

• The Zucker fa/fa rat has a mutation in the leptin receptor and therefore over-eats and becomes grossly obese. The animal develops insulin resistance and tumor necrosis factor a (TNFa) has been implicated in the pathogenesis of the insulin resistance that thls animal model of type 2 diabetes exhibits. We have shown that the insulin receptor is located in caveolae of the plasma membrane and that reduction of caveolar cholesterol content makes adipocytes insulin resistant (Parpal et a., J. Biol. Chem. 276 (2001)9670-9678). Here we show that adipocytes from the Zucker fa/fa rat are insulin resistant and that this can be explained by a 50 % lower content of cholesterol in the caveolae compared to lean rats. Moreover, TNFa treatment reduces the caveolar content of cholesterol in normal rat adipocytes. An enhanced production of TNFa may thus reduce caveolar cholesterol levels and make the Zucker fa/fa rat insulin resistant.

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