title: Chronic C75 treatment of diet-induced obese mice increases fat oxidation and reduces food intake to reduce adipose mass.
abstract: Obesity and its attendant disorders, such as type 2 diabetes, are global health problems. We previously reported that C75, an inhibitor of fatty acid synthase (FAS) and stimulator of carnitine palmitoyltransferase I (CPT I), caused anorexia and profound weight loss in lean and genetically obese mice. To approximate human obesity, we utilized a chronic C75 treatment model for diet-induced obese (DIO) mice. Chronic C75 treatment decreased food consumption and increased energy expenditure due to increased fatty acid oxidation in both DIO and lean mice. There was a substantial loss of adipose tissue and resolution of hepatic steatosis in C75-treated DIO mice. Analysis of changes in the expression of hypothalamic neuropeptides demonstrated that the reduced food consumption in C75-treated DIO mice was accompanied by an increase in cocaine and amphetamine-related transcript expression but not by changes in neuropeptide Y such as seen with acute C75 treatment of lean mice. Inhibition of FAS and stimulation of CPT I provide a means to achieve stable, sustained weight loss in DIO mice.
authors.affiliation: Johns Hopkins Univ. School of Medicine, Bldg. AA, Rm. 154A, 4940 Eastern Ave., Baltimore, MD 21224, USA.
authors.forename: Jagan N
authors.initials: JN
authors.lastname: Thupari
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Kim
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
authors.forename: Francis P
authors.initials: FP
authors.lastname: Kuhajda
mesh_terms: D015107:4-Butyrolactone / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000187:drug effects; D002908:Chronic Disease; D004032:Diet / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D010084:Oxidation-Reduction; D016896:Treatment Outcome
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D005227:Fatty Acids; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D015107:4-Butyrolactone