title: Hypothalamic malonyl-CoA and CPT1c in the treatment of obesity.
abstract: 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 brain-specific 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 body weight, but are highly susceptible to weight gain when fed a high-fat diet. Thus, the brain can directly sense and respond to changes in nutrient availability and composition to affect body weight and adiposity.
authors.affiliation: Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. mwolfga1@jhmi.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wolfgang
authors.forename: M Daniel
authors.initials: MD
authors.lastname: Lane
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D019440:Anti-Obesity Agents; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase