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Articles in PresS, published online ahead of print July 9, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00178.2002
Submitted on April 29, 2002
Accepted on June 26, 2002
1 Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3 Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
4 Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
5 Medicine and Biochemistry, Dartmouth Medical School, Dartmouth, NH, USA
6 Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: gronnett{at}jhmi.edu.
We previously demonstrated that C75, a specific and potent inhibitor of fatty acid synthase (FAS), reduced food intake and decreased body weight in mice. In the present study, we determined that these effects were not due to conditioned taste aversion. To investigate the mechanism of C75 action, we examined FAS brain expression. FAS was expressed in a number of brain regions, including arcuate and paraventricular nuclei (PVN) within regions that comprise the arcuate-PVN pathway in mouse and human. Although C75 and fasting significantly down regulated liver FAS, FAS levels remained high in hypothalamus, indicating that brain FAS levels were regulated differently than in liver. Double fluorescence in situ for FAS and NPY showed that FAS co-localized with NPY in neurons in the arcuate nucleus. NPY immnuoreactivity following C75 treatment was decreased in axon terminals that innervate the PVN and lateral hypothalamus. Collectively, these results demonstrate that FAS is present and active in neurons, and suggests that C75 may alter food intake via interactions within the arcuate-PVN pathway mediated by NPY.
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