Heterozygous caveolin‐3 mice show increased susceptibility to palmitate‐induced insulin resistance

Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin‐3 (CAV3). We further test whether haploinsufficiency for CAV3 increases the susceptibility to high‐fat‐induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of the IR. We show that haploinsufficiency for CAV3 increases susceptibility to palmitate‐induced global insulin resistance and causes cardiomyopathy. On the basis of fluorescence energy transfer (FRET) experiments, we show that CAV3 and IR directly interact in cardiomyocytes. Palmitate impairs insulin signaling by a decrease in insulin‐stimulated phosphorylation of Akt that corresponds to an 87% decrease in insulin‐stimulated glucose uptake in HL‐1 cardiomyocytes. Despite loss of Akt phosphorylation and lower glucose uptake, palmitate increased insulin‐independent serine phosphorylation of IRS‐1 by 35%. In addition, we found lipid induced downregulation of CD36, the fatty acid transporter associated with caveolae. This may explain the problem the diabetic heart is facing with the simultaneous impairment of glucose uptake and lipid transport. Thus, these findings suggest that loss of CAV3 interferes with downstream insulin signaling and lipid uptake, implicating CAV3 as a regulator of the IR and regulator of lipid uptake in the heart.