Central GLP-2 Enhances Hepatic Insulin Sensitivity via Activating PI3K Signaling in POMC Neurons

Abstract

Glucagon-like peptides (GLP-1/2) are co-produced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We show that mice lacking GLP-2 receptor (GLP-2R) in POMC neurons display glucose intolerance and hepatic insulin resistance. GLP-2R activation in POMC neurons is required for GLP-2 to enhance insulin-mediated suppression of hepatic glucose production (HGP) and gluconeogenesis. GLP-2 directly modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners. GLP-2 initiates GLP-2R-p85α interaction and facilitates PI3K-Akt-dependent FoxO1 nuclear exclusion in POMC neurons. Central GLP-2 suppresses basal HGP and enhances insulin sensitivity, which are abolished in POMC-p110α KO mice. Thus, CNS GLP-2 plays a key physiological role in the control of hepatic glucose production through activating PI3K-dependent modulation of membrane excitability and nuclear transcription of POMC neurons in the brain.

Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

“…The clamp results are noteworthy, however, because they indicate that hepatic insulin resistance is the primary glucoregulatory defect in 2C flox × POMC-cre mice and suggest that glucagon contributes to, but does fully account for, this phenotype. Interestingly, the current estimation that the maximum glucagon-stimulated contribution to elevated clamp endo R a in postabsorptive 2C flox × POMC-cre mice is approximately 20% is on par with recent work assessing the role(s) of relative hyperglucagonemia in clamp data (27,36). The relevance of these data in mice is bolstered by work showing that failed suppression of glucagon contributes to postprandial hyperglycemia in humans with T2D (40, 41).…”

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…New evidence obtained from GLP2R tissue-specific KO mice indicates that GLP2R in POMC neurons is essential for suppressing hepatic glucose production (Shi et al 2013). Indeed, mice lacking GLP2R selectively in POMC neurons display impaired postprandial glucose tolerance and hepatic insulin resistance (by increased gluconeogenesis), suggesting a physiological significance of GLP2 neural action in glycaemic control.…”

“…In fact, GLP2 is able to modulate the excitability of POMC neurons in GLP2R-and PI3K-dependent manner (Shi et al 2013). Hypothesis has been advanced that GLP2 activates POMC neurons to release α-melanocyte-stimulating hormone.…”

“…Indeed, mice lacking GLP2R selectively in POMC neurons display impaired postprandial glucose tolerance and hepatic insulin resistance (by increased gluconeogenesis), suggesting a physiological significance of GLP2 neural action in glycaemic control. Moreover, intracerebroventricular infusion of GLP2 increases glucose tolerance and insulin sensitivity and suppresses basal hepatic glucose production through GLP2R activation in POMC neurons (Shi et al 2013). Therefore, GLP2 has been proposed as a crucial neuroendocrine signal for glucose homeostasis (Guan 2014).…”

“…However, the overwhelming interest attracted by GLP1 analogues as potent incretins has somewhat clouded the efforts to understand the importance of other proglucagon-derived peptides. In fact, unlike GLP1, initially, GLP2 was not reported to modulate insulin secretion or glucose homeostasis (Schmidt et al 1985(Schmidt et al , Ørskov et al 1988; however, recent experimental data suggest that GLP2 exerts beneficial effects on glucose metabolism, especially in conditions related to increased uptake of energy, such as obesity, at least in the animal model (Cani et al 2009, Bahrami et al 2010, Shi et al 2013, Guan 2014.…”