Malonyl-CoA mediates leptin hypothalamic control of feeding independent of inhibition of CPT-1a

Su Gao, Wendy Keung, Dolors Serra, Wei Wang, Patricia Carrasco, Nuria Casals, Fausto G. Hegardt, Timothy H. Moran, Gary D. Lopaschuk

Research output: Contribution to journalArticlepeer-review

Abstract

Hypothalamic fatty acid metabolism is involved in central nervous system controls of feeding and energy balance. Malonyl-CoA, an intermediate of fatty acid biosynthesis, is emerging as a significant player in these processes. Notably, hypothalamic malonyl-CoA has been implicated in leptin's feeding effect. Leptin treatment increases malonyl- CoA level in the hypothalamic arcuate nucleus (Arc), and this increase is required for leptin-induced decrease in food intake. However, the intracellular downstream mediators of malonyl-CoA's feeding effect have not been identified. A primary biochemical action of malonyl- CoA is the inhibition of the acyltransferase activity of carnitine palmitoyltransferase-1 (CPT-1). In the hypothalamus, the predominant isoform of CPT-1 that possesses the acyltransferase activity is CPT-1 liver type (CPT-1a). To address the role of CPT-1a in malonyl- CoA's anorectic action, we used a recombinant adenovirus expressing a mutant CPT-1a that is insensitive to malonyl-CoA inhibition. We show that Arc overexpression of the mutant CPT-1a blocked the malonyl-CoA-mediated inhibition of CPT-1 activity. However, the overexpression of this mutant did not affect the anorectic actions of leptin or central cerulenin for which an increase in Arc malonyl-CoA level is also required. Thus, CPT-1a does not appear to be involved inthe malonyl-CoA's anorectic actions induced by leptin. Furthermore, long-chain fatty acyl-CoAs, substrates of CPT-1a, dissociate from malonyl-CoA's actions in the Arc under different feeding states. Together, our results suggest that Arc intracellular mechanisms of malonyl-CoA's anorectic actions induced by leptin are independent of CPT-1a. The data suggest that target(s), rather than CPT-1a, mediates malonyl-CoA action on feeding.

Original languageEnglish (US)
Pages (from-to)R209-R217
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume301
Issue number1
DOIs
StatePublished - Jul 2011

Keywords

  • Carnitine palmitoyltransferase
  • Food intake
  • Hypothalamus

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Malonyl-CoA mediates leptin hypothalamic control of feeding independent of inhibition of CPT-1a'. Together they form a unique fingerprint.

Cite this