title: Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment.
abstract: 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 downregulated liver FAS, FAS levels remained high in hypothalamus, indicating that FAS levels were regulated differently in brain from those in liver. Double fluorescence in situ for FAS and neuropeptide Y (NPY) showed that FAS co-localized with NPY in neurons in the arcuate nucleus. NPY immnuoreactivity after 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.
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Kim
authors.forename: Ian
authors.initials: I
authors.lastname: Miller
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Landree
authors.forename: Felice F
authors.initials: FF
authors.lastname: Borisy-Rudin
authors.forename: Pierre
authors.initials: P
authors.lastname: Brown
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Craig A
authors.initials: CA
authors.lastname: Townsend
authors.forename: Lee A
authors.initials: LA
authors.lastname: Witters
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Francis P
authors.initials: FP
authors.lastname: Kuhajda
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001066:Appetite / Q000187:drug effects / Q000502:physiology; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000502:physiology*; D002262:Carboxy-Lyases / Q000235:genetics; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005215:Fasting / Q000502:physiology; D064429:Fatty Acid Synthases / Q000032:analysis / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000201:enzymology*; D009478:Neuropeptide Y / Q000032:analysis / Q000235:genetics; D009765:Obesity / Q000503:physiopathology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D013649:Taste
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004791:Enzyme Inhibitors; D009478:Neuropeptide Y; D012333:RNA, Messenger; D064429:Fatty Acid Synthases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D000103:Acetyl-CoA Carboxylase; D015107:4-Butyrolactone