Malonyl-CoA Signaling in the CNS: Hypothalamic Control of Feeding Behavior and Energy Expenditure

Abstract

Whole body energy status is monitored by specialized hypothalamic neurons using a signaling system that responds to peripheral inputs, notably blood glucose, circulating hormone levels, and afferent neuronal signals. Recent evidence indicates that these inputs converge on a 5′-AMP kinase/malonyl-CoA signaling pathway, which regulates feeding behavior and energy expenditure. Malonyl-CoA is a metabolic intermediate in the pathway of fatty acid synthesis that responds to changes in energy status. Formation of malonyl-CoA is catalyzed by acetyl-CoA carboxylase (ACC) – a highly regulated enzyme expressed both in lipogenic tissues, muscle, and hypothalamic feeding centers. Only recently has the importance of malonyl-CoA been recognized as a signaling intermediate in the central nervous system. Hypothalamic malonyl-CoA level has been implicated in the regulation of feeding behavior. Hence, the administration (systemically or centrally) of inhibitors of fatty acid synthase (FAS) – the enzyme that succeeds ACC in the fatty acid synthetic pathway – increases hypothalamic malonyl-CoA and suppresses food intake. Lowering malonyl-CoA with an ACC inhibitor or ectopic expression of malonyl-CoA decarboxylase in the hypothalamus increases food intake and reverses blockade by FAS inhibitors. ACC is targeted by 5′-AMP kinase, phosphorylation provoking inhibition and leading to a lower malonyl-CoA level. Physiologically, hypothalamic malonyl-CoA is subject to regulation by fasting and refeeding and conditions that alter blood glucose level. As the level of glucose entering the hypothalamus increases, food intake is suppressed, and as glucose level falls, food intake is restored. The central metabolism of glucose is linked to the 5′-AMP kinase signaling system through changes in the [AMP]/[ATP] ratio. Thus, glucose metabolism provokes a rise in [ATP] which produces compensatory decreases in [AMP] level and 5′-AMP kinase activity, dephosphorylation of ACC, increased ACC activity and its reaction product, malonyl-CoA. The “malonyl-CoA signal” is relayed to the orexigenic/anorexigenic neuropeptide systems that determine hunger and energy expenditure. In contrast to centrally administered glucose, which produces satiety, centrally administered fructose has an inverse effect on feeding behavior having reciprocal effects on the intermediaries in the 5′-AMP kinase/malonyl-CoA signaling pathway. Elevated hypothalamic malonyl-CoA also rapidly triggers energy expenditure via the sympathetic nervous system connection to skeletal muscle. This gives rise to increased expression of fatty acid-oxidizing enzymes and regulators and a delayed, but significant increase in mtovhondrial biogenesis and number.