Loss of Protein Kinase Cβ Function Protects Mice Against Diet-induced Obesity and Development of Hepatic Steatosis and Insulin Resistance

Obesity is an energy balance disorder in which intake is greater than expenditure, with most excess calories stored as triglyceride (TG). We previously reported that mice lacking the beta-isoform of protein kinase C (PKC beta), a diacylglycerol- and phospholipid-dependent kinase, exhibit marked reduction in the whole body TG content, including white adipose tissue (WAT) mass. To investigate the role of this signaling kinase in metabolic adaptations to severe dietary stress, we studied the impact of a high-fat diet (HFD) on PKC beta expression and the effect of PKC beta deficiency on profound weight gain. We report herein that HFD selectively increased PKC beta expression in obesity-prone C57BL/6J mice, specifically in WAT; the expression levels were little or unchanged in the liver, muscle, kidney, and heart. Basal PKC beta expression was also found to be elevated in WAT of obese ob/ob mice. Remarkably, mice lacking PKC beta were resistant to HFD-induced obesity, showing significantly reduced WAT and slightly higher core body temperatures. Unlike lean lipodystrophic mouse models, these mice did not have fatty livers, nor did they exhibit insulin resistance. Moreover, PKC beta(-/-) mice exhibited changes in lipid metabolism gene expression, and such alterations were accompanied by significant changes in serum adipokines. These observations suggest that PKC beta deficiency induced a unique metabolic state congruous with obesity resistance, thus raising the possibility that dysregulation of PKC beta expression could contribute to dietary fat-induced obesity and related disorders. (HEPATOLOGY 2009;49:1525-1536.)