Current evidence suggests that the adipocyte-derived hormone resistin (RSTN) regulates both feeding and peripheral metabolism through unclear hypothalamic-mediated mechanisms. Here, we demonstrate by the first time, that the anorectic effect of RSTN is associated to specific changes in the expression of neuropeptides in the arcuate nucleus of the hypothalamus (ARC), namely AgRP, NPY and CART. Very interestingly, RSTN also exerts a deep, nutritional-dependent inhibitory effect on hypothalamic fatty acid metabolism, by increasing the phosphorylation levels of both AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC), as well as decreasing the expression of fatty acid synthase (FAS), specifically in the ventromedial nucleus of the hypothalamus (VMH). In addition, we also demonstrate that chronic RSTN injection markedly reduces body weight and induces major changes in peripheral de novo lipogenesis in a tissue-specific and nutritional dependent fashion. Thus, in fed conditions central RSTN stimulates fatty acid synthesis in liver while in fast condition does so in white adipose tissue (WAT). Overall, our results indicate that hypothalamic actions of RSTN are a physiological mechanism controlling feeding and peripheral lipid metabolism and also that hepatic RSTN-induced insulin resistance may be mediated by central activation of lipogenesis de novo in liver.
03 - 07 May 2008
European Society of Endocrinology