Regulation of hypothalamic malonyl-CoA by central glucose and leptin

Abstract

Hypothalamic malonyl-CoA has been shown to function in global energy homeostasis by modulating food intake and energy expenditure. Little is known, however, about the regulation of malonyl-CoA concentration in the central nervous system. To address this issue we investigated the response of putative intermediates in the malonyl-CoA pathway to metabolic and endocrine cues, notably those provoked by glucose and leptin. Hypothalamic malonyl-CoA rises in proportion to the carbohydrate content of the diet consumed after food deprivation. Malonyl-CoA concentration peaks 1 h after refeeding or after peripheral glucose administration. This response depends on the dose of glucose administered and is blocked by the i.c.v. administration of an inhibitor of glucose metabolism, 2-deoxyglucose (2-DG). The kinetics of change in hypothalamic malonyl-CoA after glucose administration is coincident with the suppression of phosphorylation of AMP kinase and acetyl-CoA carboxylase. Blockade of glucose utilization in the CNS by i.c.v. 2-DG prevented the effects of glucose on 5AMP-activated protein kinase, malonyl-CoA, hypothalamic neuropeptide expression, and food intake. Finally, we showed that leptin can increase hypothalamic malonyl-CoA and that the increase is additive with glucose administration. Leptin-deficient ob/ob mice, however, showed no defect in the glucose-or refeeding-induced rise in hypothalamic malonyl-CoA after food deprivation, demonstrating that leptin was not required for this effect. These studies show that hypothalamic malonyl-CoA responds to the level of circulating glucose and leptin, both of which affect energy homeostasis.acetyl-CoA carboxylase ͉ AMP kinase ͉ carnitine palmitoyl-transferase 1c ͉ fatty acid synthase A n interconnected endocrine and neuroendocrine system controls food intake and energy expenditure (1). Recently, a new pathway for maintaining energy homeostasis has become evident that relies on an ancient nutrient-sensing pathway whereby the CNS directly monitors energy needs by sampling cellular adenine nucleotide levels and responds by directing hunger and peripheral energy expenditure (2, 3). Neural cellular energy status is monitored through AMPK, which directly senses the [AMP]/[ATP] ratio. The AMPK system provides a rapid means of detecting energy status not reliant directly on endocrine signals. The activation of AMPK leads to the inhibition of the key regulatory enzyme of fatty acid synthesis, acetyl-CoA carboxylase (ACC). The activity of this enzyme is an indicator of energy surplus and is thought to be one of the mechanisms by which energy homeostasis is mediated. Several enzymes that are involved in fatty acid metabolism have been implicated in the CNS control of energy homeostasis including AMPK (4-7), ACC (8, 9), fatty acid synthase (FAS) (8, 10), carnitine palmitoyltransferase 1 (CPT1) (11, 12), and stearoyl-CoA desaturase 1 (13). Because fatty acid synthesis is a process that occurs primarily during energy surplus, it is not surprising that this system has evolved as a means to r...

Differential effects of central fructose and glucose on hypothalamic malonyl–CoA and food intake

“…Because AMPK catalyzes the phosphorylation/activation of acetyl-CoA carboxylase (ACC), it follows that a decrease in AMPK activity leads to dephosphorylation and activation of hypothalamic ACC. Consistent with this scenario we found that the central administration of glucose increases hypothalamic malonyl-CoA, decreases orexigenic neuropeptide expression, increases anorexigenic neuropeptide expression and suppresses food intake (9). Similar effects were elicited by feeding a high-carbohydrate diet after food deprivation.…”

“…2-DG blocked this effect, responses characteristic of glucose (ref. 9 and Fig. 1B) rather than fructose.…”

“…8 and findings reported herein) that centrally-administered fructose provokes feeding. In contrast, the central administration of glucose causes satiety (8,9). In this article, we provide a molecular basis for these differences.…”

“…It is not surprising, therefore, that the central metabolism of glucose produces satiety. It does so by inactivating AMPK and depressing ACC activity, which in turn increases hypothalamic malonyl-CoA to produce an anorectic effect (9). A recent seemingly counterintuitive finding (8) revealed that fructose has the inverse effect, i.e., when administered centrally fructose increased food intake.…”

Obesity and energy balance: is the tail wagging the dog?

“…In rats, for example, central administration of fructose increases appe-tite and energy intake (Cha et al, 2008). The rapid decrease in ATP levels associated with fructose metabolism is assumed to activate AMP kinase and inhibit the down-stream production of malonyl-co-A, a known appetite suppressant (Wolfgang et al, 2007). This in turn leads to stimulation of the anorexigenic neurocircuitry (decreased levels of cocaine and amphetamine-regulated transcript and proopiomelanocortin) in the hippocampus, and increased activity of the orexigenic pathway (reduced levels of neuropeptide Y and agouti-related peptide) (Cha et al, 2008).…”