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J. Biol. Chem., Vol. 279, Issue 5, 3817-3827, January 30, 2004

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C75, a Fatty Acid Synthase Inhibitor, Modulates AMP-activated Protein Kinase to Alter Neuronal Energy Metabolism^*

Leslie E. Landree, Andrea L. Hanlon, David W. Strong, Gavin Rumbaugh, Ian M. Miller, Jagan N. Thupari¶, Erin C. Connolly, Richard L. Huganir, Christine Richardson||, Lee A. Witters**, Francis P. Kuhajda¶, and Gabriele V. Ronnett¶¶||||

From the Departments of Neuroscience, ^¶¶Neurology, ^¶Pathology, Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine and The Howard Hughes Medical Institute, Baltimore, Maryland 21205 and the ^||Endocrine-Metabolism Division, the Departments of Medicine and Biochemistry, Dartmouth Medical School and the ^**Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755

C75, a synthetic inhibitor of fatty acid synthase (FAS), is hypothesized to alter the metabolism of neurons in the hypothalamus that regulate feeding behavior to contribute to the decreased food intake and profound weight loss seen with C75 treatment. In the present study, we characterize the suitability of primary cultures of cortical neurons for studies designed to investigate the consequences of C75 treatment and the alteration of fatty acid metabolism in neurons. We demonstrate that in primary cortical neurons, C75 inhibits FAS activity and stimulates carnitine palmitoyltransferase-1 (CPT-1), consistent with its effects in peripheral tissues. C75 alters neuronal ATP levels and AMP-activated protein kinase (AMPK) activity. Neuronal ATP levels are affected in a biphasic manner with C75 treatment, decreasing initially, followed by a prolonged increase above control levels. Cerulenin, a FAS inhibitor, causes a similar biphasic change in ATP levels, although levels do not exceed control. C75 and cerulenin modulate AMPK phosphorylation and activity. TOFA, an inhibitor of acetyl-CoA carboxylase, increases ATP levels, but does not affect AMPK activity. Several downstream pathways are affected by C75 treatment, including glucose metabolism and acetyl-CoA carboxylase (ACC) phosphorylation. These data demonstrate that C75 modulates the levels of energy intermediates, thus, affecting the energy sensor AMPK. Similar effects in hypothalamic neurons could form the basis for the effects of C75 on feeding behavior.

Received for publication, October 6, 2003 , and in revised form, November 6, 2003.

^* 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 Building, 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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