Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin

Cell Metab. 2008 May;7(5):389-99. doi: 10.1016/j.cmet.2008.03.006.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carnitine O-Palmitoyltransferase / metabolism
  • Fasting / physiology
  • Fatty Acid Synthases / antagonists & inhibitors
  • Fatty Acid Synthases / metabolism
  • Fatty Acids / metabolism*
  • Feeding Behavior
  • Ghrelin / physiology*
  • Hypothalamus / metabolism*
  • Hypothalamus / pathology
  • In Situ Hybridization
  • Leptin / metabolism
  • Male
  • Malonyl Coenzyme A / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Phosphorylation
  • Protein Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • fas Receptor


  • Fas protein, mouse
  • Fatty Acids
  • Ghrelin
  • Leptin
  • fas Receptor
  • Malonyl Coenzyme A
  • Carnitine O-Palmitoyltransferase
  • Fatty Acid Synthases
  • Protein Kinases
  • AMP-activated protein kinase kinase