Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin

Miguel Lopez, Ricardo Lage, Asish K Saha, Diego Perez-Tilve, Maria Vazquez, Luis Varela, Susana Sangiao-Alvarellos, Sulay Tovar, Kawtar Raghay, Sergio Rodriguez-Cuenca, Rosangela M Deoliveira, Tamara R Castaneda, Rakesh Datta, Jesse Z Dong, Michael D Culler, Mark W Sleeman, Clara V Alvarez, Rosalia Gallego, Christopher J Lelliott, David CarlingMatthias H Tschop, Carlos Dieguez, Antonio Vidal-Puig

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Abstract

Current evidence suggests that hypothalamic fatty acid metabolism may play a role in regulating food intake; however, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Here, we use pharmacological and genetic approaches to demonstrate that the physiological orexigenic response to ghrelin involves specific inhibition of fatty acid biosynthesis induced by AMP-activated protein kinase (AMPK) resulting in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. In addition, we also demonstrate that fasting downregulates fatty acid synthase (FAS) in a region-specific manner and that this effect is mediated by an AMPK and ghrelin-dependent mechanisms. Thus, decreasing AMPK activity in the ventromedial nucleus of the hypothalamus (VMH) is sufficient to inhibit ghrelin s effects on FAS expression and feeding. Overall, our results indicate that modulation of hypothalamic fatty acid metabolism specifically in the VMH in response to ghrelin is a physiological mechanism that controls feeding.
Original languageEnglish
Pages (from-to)389 - 399
Number of pages11
JournalCell Metabolism
Volume7
Issue number5
DOIs
Publication statusPublished - 2008
Externally publishedYes

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