C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase

Eun Kyoung Kim, Ian Miller, Susan M Aja, Leslie E. Landree, Michael Pinn, Jill McFadden, Francis P. Kuhajda, Timothy H Moran, Gabriele V. Ronnett

Research output: Contribution to journalArticle

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-β -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 a subunit (pAMPKα) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKα levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKα levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKα 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.

Original languageEnglish (US)
Pages (from-to)19970-19976
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number19
DOIs
StatePublished - May 7 2004

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Fatty Acid Synthases
AMP-Activated Protein Kinases
Eating
Hypothalamus
Neurology
Anorexia
Energy balance
Central Nervous System
Cyclic AMP Response Element-Binding Protein
Arcuate Nucleus of Hypothalamus
Sensors
Feeding Behavior
Neurons
Weight Loss
Homeostasis
Adenosine Triphosphate
Modulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase. / Kim, Eun Kyoung; Miller, Ian; Aja, Susan M; Landree, Leslie E.; Pinn, Michael; McFadden, Jill; Kuhajda, Francis P.; Moran, Timothy H; Ronnett, Gabriele V.

In: Journal of Biological Chemistry, Vol. 279, No. 19, 07.05.2004, p. 19970-19976.

Research output: Contribution to journalArticle

Kim, EK, Miller, I, Aja, SM, Landree, LE, Pinn, M, McFadden, J, Kuhajda, FP, Moran, TH & Ronnett, GV 2004, 'C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase', Journal of Biological Chemistry, vol. 279, no. 19, pp. 19970-19976. https://doi.org/10.1074/jbc.M402165200
Kim, Eun Kyoung ; Miller, Ian ; Aja, Susan M ; Landree, Leslie E. ; Pinn, Michael ; McFadden, Jill ; Kuhajda, Francis P. ; Moran, Timothy H ; Ronnett, Gabriele V. / C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 19. pp. 19970-19976.
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