Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice.
C75 is a potent inhibitor of fatty acid synthase that acts centrally to reduce food intake and body weight in mice; a single dose causes a rapid (>90%) decrease of food intake. These effects are associated with inhibition of fasting-induced up-regulation and down-regulation, respectively, of the expression of orexigenic (NPY and AgRP) and anorexigenic (POMC and CART) neuropeptide messages in the hypothalamus. Repeated administration of C75 at a submaximal level, however, differentially affected food intake of lean and obese mice. With lean mice, C75 suppressed food intake by approximately 50% and, with obese mice (ob/ob and dietary-induced obesity), by 85-95% during the first day of treatment. Lean mice, however, became tolerant/resistant to C75 over the next 2-5 days of treatment, with food intake returning to near normal and rebound hyperphagia occurring on cessation of treatment. In contrast, ob/ob obese mice responded to C75 with a >90% suppression of food intake throughout the same period with incipient tolerance becoming evident only after substantial weight loss had occurred. Dietary-induced obese mice exhibited intermediate behavior. In all cases, a substantial loss of body weight resulted. Pair-fed controls lost 24-50% less body weight than C75-treated mice, indicating that, in addition to suppressing food intake, C75 may increase energy expenditure. The decrease in body weight by ob/ob mice was due primarily to loss of body fat. In contrast to the short-term effects of C75 on "fasting-induced" changes of hypothalamic orexigenic and anorexigenic neuropeptide mRNAs, repeated administration of C75 either had the inverse or no effect as tolerance developed.
Kumar
Monica V
MV
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shimokawa
Teruhiko
T
Nagy
Tim R
TR
Lane
M Daniel
MD
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D007031:Hypothalamus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D064429:Fatty Acid Synthases; D012260:Ribonucleases; D015107:4-Butyrolactone