Hypothalamic malonyl-CoA as a mediator of feeding behavior

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 (<2 h) increases (Ϸ5-fold) on refeeding. Intracerebroventricular C75 ͉ acetyl-CoA carboxylase ͉ fatty acid synthase ͉ neuropeptides ͉ obesity T he hypothalamus monitors global energy status in higher animals (1-4). Specific regions within the hypothalamus, notably the arcuate nucleus, respond to changes in energy status by altering the expression͞secretion of neuropeptides that affect energy intake and expenditure. Thus, when energy intake exceeds expenditure expression of the orexigenic neuropeptides, i.e., NPY and AgRP, decreases whereas the expression of anorexigenic neuropeptides, i.e., proopiomelanocortin (POMC) and CART, increases (1). Signals triggered by these changes are transmitted to higher brain centers through second-order neurons that affect behavior leading to decreased food intake. Conversely, when energy expenditure exceeds intake, the inverse response occurs. Despite considerable progress in identifying many of the neuropeptides and circuits involved (1-4), the signaling mechanisms by which energy status is initially monitored by neurons of the hypothalamus are incompletely understood.Recent evidence (5, 6) has implicated malonyl-CoA, an intermediate in fatty acid biosynthesis, as a possible mediator in the hypothalamic signaling pathway that monitors energy status. We and others have detected both acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (6, 7), enzymes that catalyze the formation and utilization of malonyl-CoA, respectively, in a subset of hypothalamic neurons. A potent inhibitor of FAS, i.e., C75 (8), that would be expected to increase cellular malonyl-CoA, suppresses food intake and appropriately alters expression of the hypothalamic neuropeptide mRNAs described above (9). Also 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.). Although these indirect lines of evidence support the hypothesis that malonyl-CoA participates in monitoring energy status in the hypothalamus, direct proof is still lacking.Most previous studies (5-7, 9, 11) compared the effects of C75 administered by i.p. injection to mice that had been fasted to increase appetite when presented with food....

Lack of starvation-induced activation of AMP-activated protein kinase in the hypothalamus of the Lou/C rats resistant to obesity

“…[39][40][41][42][43] ACC controls fatty acid partitioning between lipid synthesis and oxidation by its product malonyl-CoA, which inhibits the entry of long-chain fatty acids into the mitochondria via the carnitine palmitoyl transferase 1 (CPT-1). Accordingly, inactivation of ACC by AMPK decreases malonyl-CoA concentration and eventually favors fatty acid oxidation.…”

Regulation of lipid stores and metabolism by lipophagy

“…32,33 Hypothalamic lipid metabolism serves as a sensor of nutrient levels by altering intracellular malonyl-CoA and long-chain fatty-acid levels. [34][35][36] The importance of intracellular lipid metabolism in hypothalamic nutrient sensing, together with the ability of nutrient levels to regulate autophagy and of autophagy to degrade lipids, suggested that lipophagy may mediate hypothalamic regulation of food intake. Two recent studies have confirmed an important function for autophagy in hypothalamic neurons in the control of food intake, 10,37 however, opposing effects have been reported and the function of autophagy in these cells remains unclear (Figure 2).…”

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

“…The role of inhibitors is not limited to the disease treatment only; they also facilitate studies on ACCases roles in physiology or regulatory processes as it was demonstrated in studies on hypothalamic regulation of food intake (Hu et al 2003). Also, RNA interference is used for discriminating between the functions of particular ACCases isoforms (Savage et al, 2006).…”