Translocation of PKC theta by fatty acids causes hypothalamic insulin resistance.

Abstract

Diets high in saturated fats (HFS) promote obesity and attenuate insulin-induced glucose uptake in peripheral tissues. Several potential mechanisms for this disruption have been proposed including altered intracellular signaling, gene expression and protein trafficking. Numerous recent studies have demonstrated that protein-kinase-C isoforms theta, delta and epsilon attenuate insulin and metabolic signaling in peripheral tissues. Because the product of fatty acid metabolism, diacylglyceride (DAG) can directly induce translocation of PKCs and thereby activate them, DAG and activated PKCs may represent a mechanism by which dietary fatty acids induce insulin resistance. Importantly, here we report that obesity and high-fat diets attenuate insulin signaling in the brain. Here we assessed the hypothesis that CNS PKC isoforms mediated the deleterious effects of HFS on CNS function. We found that consumption of HFS increased membrane localization of PKC theta and delta in rat hypothalamus. This was associated with impaired hypothalamic insulin signaling, including a reduction in activation of intracellular insulin signaling cascades, increased food intake, and the development of obesity. This effect was recapitulated both in vivo and in vitro by the addition of the phorbol-ester PMA, which induces PKC membrane-translocation. Collectively, these results suggest that saturated-fats can attenuate CNS insulin signaling, similar to peripheral insulin resistance, by directly influencing the trafficking of hypothalamic PKC isoforms. Therefore, PKC may represent a novel unifying mechanism by which diets high in saturated fats promote both peripheral and central metabolic disease.