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J. Biol. Chem., Vol. 279, Issue 19, 19970-19976, May 7, 2004

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

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

From the Departments of Neuroscience, Psychiatry, ^¶Pathology, ^**Oncology, Biological Chemistry, and Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and ^||FASgen, Inc., Baltimore, Maryland 21224

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

Received for publication, February 26, 2004

^* This work was supported by grants from the National Institutes of Health, NINDS and NIDDK (to G. V. R.), NIDDK (to T. H. M.), NCI (to F. P. K.), and an NINDS F32 fellowship (to L. E. L.). Funding for the study described in this article was also provided by FASgen, LLC. Under a licensing agreement between FASgen and the Johns Hopkins University, G. V. R. and F. P. K. are entitled to a share of royalty received by the University on sales of products described in this article. F. P. K. owns, and G. V. R. and T. H. M. have an interest in, FASgen stock, which is subject to certain restrictions under University policy. F. P. K., G. V. R., and T. H. M. are consultants to FASgen. The Johns Hopkins University, in accordance with its conflict of interest policies, is managing the terms of this arrangement. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶¶ To whom correspondence should be addressed: Dept. of Neuroscience, 1006B Preclinical Teaching Bldg., Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205. Tel.: 410-614-6482; Fax: 410-614-8033; E-mail: gronnett{at}jhmi.edu.

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