title: Regulation of hypothalamic malonyl-CoA by central glucose and leptin.
abstract: Hypothalamic malonyl-CoA has been shown to function in global energy homeostasis by modulating food intake and energy expenditure. Little is known, however, about the regulation of malonyl-CoA concentration in the central nervous system. To address this issue we investigated the response of putative intermediates in the malonyl-CoA pathway to metabolic and endocrine cues, notably those provoked by glucose and leptin. Hypothalamic malonyl-CoA rises in proportion to the carbohydrate content of the diet consumed after food deprivation. Malonyl-CoA concentration peaks 1 h after refeeding or after peripheral glucose administration. This response depends on the dose of glucose administered and is blocked by the i.c.v. administration of an inhibitor of glucose metabolism, 2-deoxyglucose (2-DG). The kinetics of change in hypothalamic malonyl-CoA after glucose administration is coincident with the suppression of phosphorylation of AMP kinase and acetyl-CoA carboxylase. Blockade of glucose utilization in the CNS by i.c.v. 2-DG prevented the effects of glucose on 5'AMP-activated protein kinase, malonyl-CoA, hypothalamic neuropeptide expression, and food intake. Finally, we showed that leptin can increase hypothalamic malonyl-CoA and that the increase is additive with glucose administration. Leptin-deficient ob/ob mice, however, showed no defect in the glucose- or refeeding-induced rise in hypothalamic malonyl-CoA after food deprivation, demonstrating that leptin was not required for this effect. These studies show that hypothalamic malonyl-CoA responds to the level of circulating glucose and leptin, both of which affect energy homeostasis.
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wolfgang
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Cha
authors.forename: Aniket
authors.initials: A
authors.lastname: Sidhaye
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chohnan
authors.forename: Gary
authors.initials: G
authors.lastname: Cline
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: M Daniel
authors.initials: MD
authors.lastname: Lane
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008316:Malonyl Coenzyme A / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; D000963:Antimetabolites; D001786:Blood Glucose; D004040:Dietary Carbohydrates; D005227:Fatty Acids; D020738:Leptin; D008316:Malonyl Coenzyme A; D011333:Pro-Opiomelanocortin; D003847:Deoxyglucose; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase; D005947:Glucose