The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

Abstract

The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiota-derived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance. GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3K-dependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85α interaction. Intracerebroventricular GLP-2 augments glucose tolerance, suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110α) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies.

Keywords: central nervous system; food intake; gastric emptying; glucagon-like peptides; glucose homeostasis; gut-brain axis; insulin sensitivity.

Fig. 1.

Glucagon-like peptide 2 receptor (Glp2r)-induced intracellular signaling in hypothalamic proopiomelanocortin (POMC) neurons. In hypothalamic POMC neurons, GLP-2 induces Glp2r-p85α protein interaction, activating the PI3K-Akt-FoxO1 signaling pathway to derepress POMC transcription. GLP-2-activated PI3K signaling depolarizes one subgroup of POMC neurons (expressing leptin receptor) via activating putative transient receptor potential canonical (TRPC) channels; and hyperpolarizes another subgroup of POMC neurons (expressing insulin receptor) via activating K_ATP channels. This paradox action on membrane excitability may be synchronized with leptin and insulin signaling in segregated POMC neurons. GLP-2-activated POMC neurons are integrated with central autonomic control by enhancing vagal outflows: decelerating gastric emptying or suppressing hepatic glucose production. [Modified from Cell Metabolism, 18(1), Shi X, Zhou F, Li X, Chang B, Li D, Wang Y, Tong Q, Xu Y, Fukuda M, Zhao JJ, Li D, Burrin DJ, Chan L, and Guan X. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neuron, p. 86–98, 2013, with permission from Elsevier (118)].

Fig. 2.

Glucagon-like peptide-2 receptor (Glp2r)-activated neural circuits in the hypothalamus and brain stem. GLP-2 [secreted from endocrine L cells and preproglucagonergic (PPG) neurons] may fine-tune autonomic outputs via the proposed neural circuits. In addition to sympathetic outflow, Glp2r activation in proopiomelanocortin (POMC) neurons in the hypothalamus and brain stem → α-melanocyte stimulating hormone (α-MSH) release → melanocortin receptor 4 (Mc4r) activation in the brain stem dorsal vagal complex (DVC) → vagal outflow. Moreover, Glp2r activation on vagal afferents may influence neural inputs to 1) PPG neurons in the brain stem nucleus of the solitary tract (NTS) → GLP-2 release → Glp2r activation in the hypothalamic arcuate nucleus (ARC)/paraventricular nucleus of the hypothalamus (PVH) and the brain stem dorsal motor nucleus of the vagus (DMV) →→ vagal outflows; and 2) POMC neurons in the brain stem NTS → α-MSH release → melanocortin 4 receptor (Mc4r) activation in the hypothalamic ARC/ventromedial hypothalamus (VMH) and the brain stem DMV →→ vagal outflows. However, GLP-2-modulated neural circuitries have not been fully defined. BBB, blood-brain barrier; GI, gastrointestinal; HGP, hepatic glucose production; 3V, third ventricle; DMH, dorsomedial hypothalamus; ChAT, choline acetyltransferase; LHA, lateral hypothalamic area.