Regulation of hypothalamic malonyl-CoA by central glucose and leptin

Michael J. Wolfgang, Hun Cha Seung, Aniket Sidhaye, Shigeru Chohnan, Gary Cline, Gerald I. Shulman, M. Daniel Lane

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)19285-19290
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - Dec 4 2007


  • AMP kinase
  • Acetyl-CoA carboxylase
  • Carnitine palmitoyl-transferase 1c
  • Fatty acid synthase

ASJC Scopus subject areas

  • General


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