tailieunhanh - Báo cáo khoa học: Hypothalamic malonyl-CoA and CPT1c in the treatment of obesity

Metabolic integration of nutrient sensing in the central nervous system has been shown to be an important regulator of adiposity by affecting food intake and peripheral energy expenditure. Modulation of de novofatty acid synthetic flux by cytokines and nutrient availability plays an important role in this process. | IFEBS Journal MINIREVIEW Hypothalamic malonyl-CoA and CPT1c in the treatment of obesity Michael J. Wolfgang and M. Daniel Lane Department of BiologicalChemistry The Johns Hopkins University Schoolof Medicine Baltimore MD USA Keywords acetyl-CoA carboxylase AMPK carnitine palmitoyl-transferase-1c diabetes fatty acid fatty acid synthase malonyl-CoA neurometabolism nutrient sensing obesity Correspondence M. J. Wolfgang Department of Biological Chemistry Johns Hopkins University School of Medicine Center for Metabolism and Obesity Research 475 Rangos Building 725 N. Wolfe St. Baltimore MD 21205 USA Fax 1 410 614 8033 Tel 1 443 287 7680 E-mail mwolfga1@ Received 10 August 2010 revised 29 October 2010 accepted 3 December 2010 doi Metabolic integration of nutrient sensing in the central nervous system has been shown to be an important regulator of adiposity by affecting food intake and peripheral energy expenditure. Modulation of de novo fatty acid synthetic flux by cytokines and nutrient availability plays an important role in this process. Inhibition of hypothalamic fatty acid synthase by pharmacologic or genetic means leads to an increased malonyl-CoA level and suppression of food intake and adiposity. Conversely the ectopic expression of malonyl-CoA decarboxylase in the hypothalamus is sufficient to promote feeding and adiposity. Based on these and other findings metabolic intermediates in fatty acid biogenesis including malonyl-CoA and long-chain acyl-CoAs have been implicated as signaling mediators in the central control of body weight. Malonyl-CoA has been hypothesized to mediate its effects in part through an allosteric interaction with an atypical and brainspecific carnitine palmitoyltransferase-1 CPT1c . CPT1c is expressed in neurons and binds malonyl-CoA however it does not perform the same biochemical function as the prototypical CPT1 enzymes. Mouse knockout models of CPT1c exhibit suppressed food intake and smaller .