Abstract
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 (< or = 2 h) increases (approximately 5-fold) on refeeding. Intracerebroventricular (i.c.v.) administration of C75 to fasted mice rapidly (< or = 2 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 (< or = 2 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.
Highlights
The hypothalamus monitors global energy status in higher animals [1,2,3,4]
Consistent with the ‘‘malonyl-CoA hypothesis’’ is a recent report of Gilbert et al [10], who found that carotid infusion of obese (Zucker) rats with glucose and insulin suppressed food intake and this effect was prevented by the acetyl-CoA carboxylase (ACC) inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), administered intracerebroventricularly (i.c.v.)
In previous long-term experiments [5] we showed that i.c.v. administration of the ACC inhibitor, TOFA, partially prevented the suppression of food intake caused by C75 administered i.p
Summary
The hypothalamus monitors global energy status in higher animals [1,2,3,4]. Specific regions within the hypothalamus, notably the arcuate nucleus, respond to changes in energy status by altering the expressionsecretion of neuropeptides that affect energy intake and expenditure. Consistent with the ‘‘malonyl-CoA hypothesis’’ is a recent report of Gilbert et al [10], who found that carotid infusion of obese (Zucker) rats with glucose and insulin suppressed food intake and this effect was prevented by the ACC inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), administered intracerebroventricularly (i.c.v.). These indirect lines of evidence support the hypothesis that malonyl-CoA participates in monitoring energy status in the hypothalamus, direct proof is still lacking. Our findings provide compelling evidence that malonyl-CoA is a mediator in the hypothalamic system that monitors global energy status
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