This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takahashi, K. A. Articles by Cone, R. D. Search for Related Content PubMed PubMed Citation Articles by Takahashi, K. A. Articles by Cone, R. D.

The Anorexigenic Fatty Acid Synthase Inhibitor, C75, Is a Nonspecific Neuronal Activator

The Vollum Institute (K.A.T., J.L.S., R.D.C), Oregon Health and Science University, Portland, Oregon 97239; and Howard Hughes Medical Institute (H.L.), The Rockefeller University, New York, New York 10021

Address all correspondence and requests for reprints to: Roger Cone, Vollum Institute L-474, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland Oregon 97239. E-mail: cone{at}ohsu.edu.

C75, a recently derived compound that potently suppresses feeding and induces weight loss, has been proposed to act mainly by inhibiting fatty acid synthase (FAS) in central neurons that control feeding. For example, normal, fasting- associated, hypothalamic increases in neuropeptide Y (NPY)/Agouti-related protein (AGRP) expression and decreases in proopiomelanocortin (POMC)/cocaine and amphetamine regulated transcript (CART) expression were reported to be blocked by C75. Using loose-patch extracellular recording in acute slices, we tested the effect of C75 on anorexigenic POMC neurons and orexigenic NPY neurons of the hypothalamic arcuate nucleus, which were identified by promoter-driven GFP expression, as well as on feeding-unrelated cerebellar Purkinje neurons. We expected C75 to activate POMC neurons, inhibit NPY neurons, and have no effect on Purkinje neurons. Instead, C75 activated all cell types, suggesting that it lacks target specificity. This activation was probably not caused by FAS inhibition, because the classical FAS inhibitor, cerulenin, did not have this effect when tested on POMC and NPY neurons. Nonspecific neuronal activation and resulting neurological effects might contribute to the decreased feeding reported to follow centrally administered C75. Injection, ip, of C75 induced severe loosening or liquefaction of stools, weight loss, and decreased food intake in both wild-type and melanocortin-4 receptor knockout mice. In contrast, cerulenin failed to loosen stools, even at a molar dose over 9-fold greater than C75, and had a much smaller effect on body weight. FAS inhibitory activity, by itself, seems to be insufficient to reproduce all of the effects of ip-injected C75.

This article has been cited by other articles:

				H. Shimizu, K. Inoue, and M. Mori The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure J. Endocrinol., April 1, 2007; 193(1): 1 - 9. [Abstract] [Full Text] [PDF]

				C. D.L. Folmes and G. D. Lopaschuk Role of malonyl-CoA in heart disease and the hypothalamic control of obesity Cardiovasc Res, January 15, 2007; 73(2): 278 - 287. [Abstract] [Full Text] [PDF]

				S. Aja, S. Bi, S. B. Knipp, J. M. McFadden, G. V. Ronnett, F. P. Kuhajda, and T. H. Moran Intracerebroventricular C75 decreases meal frequency and reduces AgRP gene expression in rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2006; 291(1): R148 - R154. [Abstract] [Full Text] [PDF]

				Y.-M. Zhang, J. Hurlbert, S. W. White, and C. O. Rock Roles of the Active Site Water, Histidine 303, and Phenylalanine 396 in the Catalytic Mechanism of the Elongation Condensing Enzyme of Streptococcus pneumoniae J. Biol. Chem., June 23, 2006; 281(25): 17390 - 17399. [Abstract] [Full Text] [PDF]

				R. Wang, C. Cruciani-Guglielmacci, S. Migrenne, C. Magnan, V. E. Cotero, and V. H. Routh Effects of Oleic Acid on Distinct Populations of Neurons in the Hypothalamic Arcuate Nucleus Are Dependent on Extracellular Glucose Levels J Neurophysiol, March 1, 2006; 95(3): 1491 - 1498. [Abstract] [Full Text] [PDF]

				Z. Hu, Y. Dai, M. Prentki, S. Chohnan, and M. D. Lane A Role for Hypothalamic Malonyl-CoA in the Control of Food Intake J. Biol. Chem., December 2, 2005; 280(48): 39681 - 39683. [Abstract] [Full Text] [PDF]

				K. A. Takahashi and R. D. Cone Fasting Induces a Large, Leptin-Dependent Increase in the Intrinsic Action Potential Frequency of Orexigenic Arcuate Nucleus Neuropeptide Y/Agouti-Related Protein Neurons Endocrinology, March 1, 2005; 146(3): 1043 - 1047. [Abstract] [Full Text] [PDF]

				M. W. Schwartz and D. Porte Jr. Diabetes, Obesity, and the Brain Science, January 21, 2005; 307(5708): 375 - 379. [Abstract] [Full Text] [PDF]

				J. N. Thupari, E.-K. Kim, T. H. Moran, G. V. Ronnett, and F. P. Kuhajda Chronic C75 treatment of diet-induced obese mice increases fat oxidation and reduces food intake to reduce adipose mass Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E97 - E104. [Abstract] [Full Text] [PDF]