Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis

Abstract

The central nervous system (CNS) is capable of gathering information on the body's nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus.

Fig. 1

Potential mechanisms of glucose sensing in hypothalamic neurons. a An increase in extracellular glucose and/or lactate raises the ATP/ADP ratio in GE neurons, which leads to the closure of K_ATP channels and thus plasma membrane depolarization. Subsequent Ca²⁺ entry through voltage-gated channels finally increases neuronal activity and neurotransmitter secretion. b In GI neurons, suppression of neurotransmitter secretion at elevated glucose might be caused by an ATP-mediated increase in Na⁺–K⁺-ATPase activity and/or inhibition of AMPK, which in turn opens Cl⁻ or other ion channels. In other GI neurons, glucose-induced hyperpolarization might be due to K⁺ channels opened by an ATP- and AMPK-independent mechanism

Fig. 2

Crosstalk and hormonal regulation of glucose and lipid sensing. This schematic representation of the interrelationship between glucose and lipid-sensing mechanisms and their modulation by hormones underlines the convergence of these signals on three key players: AMPK, malonyl-CoA, and K_ATP channels. LCFA-CoA long-chain fatty acyl-CoA, ACC acetyl-CoA carboxylase, FAS fatty acid synthase, CPT1 carnitine palmitoyltransferase 1