Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin.
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.
López
Miguel
M
Department of Physiology, School of Medicine, University of Santiago de Compostela, S. Francisco s/n, 15782 Santiago de Compostela (A Coruña), Spain. miguellp@usc.es
Lage
Ricardo
R
Saha
Asish K
AK
Pérez-Tilve
Diego
D
Vázquez
María J
MJ
Varela
Luis
L
Sangiao-Alvarellos
Susana
S
Tovar
Sulay
S
Raghay
Kawtar
K
Rodríguez-Cuenca
Sergio
S
Deoliveira
Rosangela M
RM
Castañeda
Tamara
T
Datta
Rakesh
R
Dong
Jesse Z
JZ
Culler
Michael
M
Sleeman
Mark W
MW
Alvarez
Clara V
CV
Gallego
Rosalía
R
Lelliott
Christopher J
CJ
Carling
David
D
Tschöp
Matthias H
MH
Diéguez
Carlos
C
Vidal-Puig
Antonio
A
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D005215:Fasting / Q000502:physiology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005247:Feeding Behavior; D054439:Ghrelin / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D017403:In Situ Hybridization; D020738:Leptin / Q000378:metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019014:fas Receptor
C491899:Fas protein, mouse; D005227:Fatty Acids; D054439:Ghrelin; D020738:Leptin; D019014:fas Receptor; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases