title: C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase.
abstract: Energy homeostasis and feeding are regulated by the central nervous system. C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel central nervous system pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK alpha subunit (pAMPKalpha) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKalpha levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKalpha levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKalpha and phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus.
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Kim
authors.forename: Ian
authors.initials: I
authors.lastname: Miller
authors.forename: Susan
authors.initials: S
authors.lastname: Aja
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Landree
authors.forename: Michael
authors.initials: M
authors.lastname: Pinn
authors.forename: Jill
authors.initials: J
authors.lastname: McFadden
authors.forename: Francis P
authors.initials: FP
authors.lastname: Kuhajda
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D004435:Eating / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D005247:Feeding Behavior / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects* / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology; D013997:Time Factors
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D012313:RNA; D000255:Adenosine Triphosphate; D064429:Fatty Acid Synthases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D015107:4-Butyrolactone