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Submitted on March 18, 2003
Accepted on September 15, 2003
1 The Vollum Institute (K.A.T., J.L.S., R.D.C), Oregon Health & Science University, Portland, OR 97239; and Howard Hughes Medical Institute (H.L.), The Rockefeller University, 1230 York Avenue, New York, NY 10021.
* To whom correspondence should be addressed. 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 NPY/AGRP expression and decreases in POMC/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 since the classical FAS inhibitor, cerulenin, did not have this effect when tested on POMC and NPY neurons. Non-specific neuronal activation and resulting neurological effects might contribute to the decreased feeding reported to follow centrally administered C75. Intraperitoneal (IP) injection 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, appears to be insufficient to reproduce all of the effects of IP-injected C75.
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