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Central Resistin Regulates Hypothalamic and Peripheral Lipid Metabolism in a Nutritional-Dependent Fashion

Department of Physiology (M.J.V., C.R.G., L.V., R.L., S.T., S.S.-A., R.N., M.L., C.D.), School of Medicine, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) (M.J.V., C.R.G., L.V., R.L., S.T., R.N., M.L., C.D.), Spain; Obesity and Metabolic Health Division (L.M.W.), Rowett Research Institute, Aberdeen AB21 95B, United Kingdom; and Institute of Metabolic Science (A.V.-P.), Metabolic Research Laboratories, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom

Address all correspondence and requests for reprints to: Miguel López, Ph.D., and Professor Carlos Diéguez, M.D., Ph.D., Department of Physiology, School of Medicine, University of Santiago de Compostela and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), S. Francisco s/n, 15782, Santiago de Compostela (A Coruña), Spain. E-mail: miguellp{at}usc.es or m.lopez{at}usc.es (M.L.) and fscadigo{at}usc.es or carlos.dieguez{at}usc.es (C.D.).

Evidence suggests that the adipocyte-derived hormone resistin (RSTN) directly regulates both feeding and peripheral metabolism through, so far, undefined hypothalamic-mediated mechanisms. Here, we demonstrate that the anorectic effect of RSTN is associated with inappropriately decreased mRNA expression of orexigenic (agouti-related protein and neuropeptide Y) and increased mRNA expression of anorexigenic (cocaine and amphetamine-regulated transcript) neuropeptides in the arcuate nucleus of the hypothalamus. Of interest, RSTN also exerts a profound nutrition-dependent inhibitory effect on hypothalamic fatty acid metabolism, as indicated by increased phosphorylation levels of both AMP-activated protein kinase and its downstream target acetyl-coenzyme A carboxylase, associated with decreased expression of fatty acid synthase in the ventromedial nucleus of the hypothalamus. In addition, we also demonstrate that chronic central RSTN infusion results in decreased body weight and major changes in peripheral expression of lipogenic enzymes, in a tissue-specific and nutrition-dependent manner. Thus, in the fed state central RSTN is associated with induced expression of fatty acid synthesis enzymes and proinflammatory cytokines in liver, whereas its administration in the fasted state does so in white adipose tissue. Overall, our results indicate that RSTN controls feeding and peripheral lipid metabolism and suggest that hepatic RSTN-induced insulin resistance may be mediated by central activation of de novo lipogenesis in liver.

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