Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment.
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.
Kim
Eun-Kyoung
EK
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Miller
Ian
I
Landree
Leslie E
LE
Borisy-Rudin
Felice F
FF
Brown
Pierre
P
Tihan
Tarik
T
Townsend
Craig A
CA
Witters
Lee A
LA
Moran
Timothy H
TH
Kuhajda
Francis P
FP
Ronnett
Gabriele V
GV
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
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