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Chronic C75 treatment of diet-induced obese mice increases fat oxidation and reduces food intake to reduce adipose mass

Departments of ¹Pathology, ²Neuroscience, ³Psychiatry, ⁴Neurology, ⁵Oncology, and ⁶Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Submitted 12 June 2003 ; accepted in final form 16 January 2004

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.

fatty acid synthase; carnitine palmitoyltransferase I; neuropeptide Y

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