Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 22, Pages 12624-12629Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1834402100
Keywords
C75; acetyl-CoA carboxylase; fatty acid synthase; neuropeptides; obesity
Categories
Ask authors/readers for more resources
Previous studies showed that i.p. administration of C75, a potent inhibitor of fatty acid synthase (FAS), blocked fasting-induced up-regulation of orexigenic neuropeptides and down-regulation of anorexigenic neuropeptides in the hypothalami of mice. As a result, food intake and body weight were drastically reduced. Here we provide evidence supporting the hypothesis that hypothalamic malonyl-CoA, a substrate of FAS, is an indicator of global energy status and mediates the feeding behavior of mice. We use a sensitive recycling assay to quantify malonyl-CoA to show that the hypothalamic malonyl-CoA level is low in fasted mice and rapidly (less than or equal to2 h) increases (approximate to5-fold) on refeeding. Intracerebroventricular (i.c.v.) administration of C75 to fasted mice rapidly (less than or equal to2 h) increased (by 4-fold) hypothalamic malonyl-CoA and blocked feeding when the mice were presented with food. Moreover, prior i.c.v. administration of an acetyl-CoA carboxylase inhibitor, 5-(tetradecyloxy)-2-furoic acid, rapidly (although only partially) prevented the C75-induced rise of hypothalamic malonyl-CoA and prevented the C75-induced decrease of food intake. These effects correlated closely with the rapid (less than or equal to2 h) and reciprocal effects of i.c.v. C75 on the expression of hypothalamic orexigenic (NPY and AgRP) and anorexigenic (proopiomelanocortin) neuropeptide mRNAs. Previous results showing that C75 administered i.c.v. rapidly activates hypothalamic neurons of the arcuate and paraventricular nuclei are consistent with the results reported in this paper. Together these findings suggest that level of hypothalamic malonyl-CoA, which depends on the relative activities of acetyl-CoA carboxylase and FAS, is an indicator of energy status and mediates feeding behavior.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available