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Title: Malonyl-CoA Mediates Leptin Hypothalamic Control of Feeding Independent of Inhibition of CPT-1a
Author: Gao, Su
Keung, Wendy
Serra i Cucurull, Dolors
Wang, Wei
Carrasco, Patricia
Casals, Núria
Hegardt, Fausto
Moran, Timothy H.
Lopaschuk, Gary D.
Keywords: Fisiologia
Mutació (Biologia)
Mutation (Biology)
Issue Date: 20-Apr-2011
Publisher: American Physiological Society
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 in the 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.
Note: Versió postprint del document publicat a:
It is part of: American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 2011, vol. 301, num. 1, p. R209-17
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ISSN: 0363-6119
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Bioquímica i Fisiologia)

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