Intracerebroventricular C75 decreases meal frequency and reduces AgRP gene expression in rats.
3-Carboxy-4-alkyl-2-methylenebutyrolactone (C75), an inhibitor of fatty acid synthase and stimulator of carnitine palmitoyltransferase-1, reduces food intake and body weight in rodents when given systemically or centrally. Intracellular molecular mechanisms involving changes in cellular energy status are proposed to initiate the feeding and body weight reductions. However, effectors that lie downstream of these initial steps are not yet fully identified. Present experiments characterize the time courses of hypophagia and weight loss after single injections of C75 into the lateral cerebroventicle in rats and go on to identify specific meal pattern changes and coinciding alterations in gene expression for feeding-related hypothalamic neuropeptides. C75 reduced chow intake and body weight dose dependently. Although the principal effects occurred on the first day, weight losses relative to vehicle control were maintained over multiple days. C75 did not affect generalized locomotor activity. C75 began to reduce feeding after a 6-h delay. The hypophagia was due primarily to decreased meal number during 6-12 h without a significant effect on meal size, suggesting that central C75 reduced the drive to initiate meals. C75 prevented the anticipated hypophagia-induced increases in mRNA for AgRP in the arcuate nucleus at 22 h and at 6 h when C75 begins to suppress feeding. Overall, the data suggest that gene expression changes leading to altered melanocortin signaling are important for the hypophagic response to intracerebroventricular C75.
Department of Psychiatry and Behavioural Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. saja1@jhmi.edu
Susan
S
Aja
Sheng
S
Bi
Susan B
SB
Knipp
Jill M
JM
McFadden
Gabriele V
GV
Ronnett
Francis P
FP
Kuhajda
Timothy H
TH
Moran
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D054369:Agouti-Related Protein; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects*; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D036361:Peptide Hormones / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D036361:Peptide Hormones; D012333:RNA, Messenger; D015107:4-Butyrolactone