Calcitonin Gene-Related Peptide-Induced Phosphorylation of STAT3 in Arcuate Neurons Is a Link in the Metabolic Benefits of Portal Glucose

Introduction: Intestinal gluconeogenesis (IGN) exerts metabolic benefits in energy homeostasis via the neural sensing of portal glucose. Objective: The aim of this work was to determine central mechanisms involved in the effects of IGN on the control of energy homeostasis. Methods: We investigated the effects of glucose infusion into the portal vein, at a rate that mimics IGN, in conscious wild-type, leptin-deficient Ob/Ob and calcitonin gene-related peptide (CGRP)-deficient mice. Results: We report that portal glucose infusion decreases food intake and plasma glucose and induces in the hypothalamic arcuate nucleus (ARC) the phosphorylation of STAT3, the classic intracellular messenger of leptin signaling. This notably takes place in POMC-expressing neurons. STAT3 phosphorylation does not require leptin, since portal glucose effects are observed in leptin-deficient Ob/Ob mice. We hypothesized that the portal glucose effects could require CGRP, a neuromediator previously suggested to suppress hunger. In line with this hypothesis, neither the metabolic benefits nor the phosphorylation of STAT3 in the ARC take place upon portal glucose infusion in CGRP-deficient mice. Moreover, intracerebroventricular injection of CGRP activates hypothalamic phosphorylation of STAT3 in mice, and CGRP does the same in hypothalamic cells. Finally, no metabolic benefit of dietary fibers (known to depend on the induction of IGN), takes place in CGRP-deficient mice. Conclusions: CGRP-induced phosphorylation of STAT3 in the ARC is part of the neural chain determining the hunger-modulating and glucose-lowering effects of IGN/portal glucose.

Automated summary

Portal glucose infusion through intestinal gluconeogenesis activates a neural signal in the hypothalamic arcuate nucleus, leading to decreased food intake and plasma glucose levels. The activation of STAT3 phosphorylation in response to portal glucose appears to be independent of leptin but dependent on calcitonin gene-related peptide (CGRP), suggesting a key role for CGRP in mediating the metabolic and hunger-modulating effects of IGN.