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Malonyl-CoA Mediates Leptin Hypothalamic Control of Feeding Independent of Inhibition of CPT-1a
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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.
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GAO, Su, KEUNG, Wendy, SERRA I CUCURULL, Dolors, WANG, Wei, CARRASCO, Patricia, CASALS I FARRÉ, Núria, HEGARDT, Fausto, MORAN, Timothy h., LOPASCHUK, Gary d.. Malonyl-CoA Mediates Leptin Hypothalamic Control of Feeding Independent of Inhibition of CPT-1a. _American Journal of Physiology-Regulatory Integrative and Comparative Physiology_. 2011. Vol. 301, núm. 1, pàgs. R209-17. [consulta: 11 de gener de 2026]. ISSN: 0363-6119. [Disponible a: https://hdl.handle.net/2445/167702]