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Am J Physiol Endocrinol Metab (January 21, 2004). doi:10.1152/ajpendo.00261.2003
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Submitted on June 12, 2003
Accepted on January 16, 2004

Chronic C75 Treatment of Diet-Induced Obese Mice Increases Fat Oxidation and Reduces Food Intake to Reduce Adipose Mass

Jagan N. Thupari1, Eun-Kyoung Kim2, Timothy H. Moran3, Gabriele V. Ronnett4, and Francis P. Kuhajda5*

1 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
3 Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
4 Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
5 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, The Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: fkuhajda{at}jhmi.edu.

Obesity and its attendant disorders such as Type II diabetes are global health problems. We previously reported that C75, an inhibitor of fatty acid synthase (FAS) and stimulator of carnitine palmitoyltransferase-1 (CPT-1) caused anorexia and profound weight loss in lean and genetically obese mice. To approximate human obesity, we have 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 (CART) expression, not by changes in neuropeptide Y (NPY) as seen with acute C75 treatment of lean mice. Inhibition of FAS and stimulation of CPT-1 provide a means to achieve stable sustained weight loss in DIO mice.




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