GLP‐2 receptor deficiency in the mouse brain impairs glucose homeostasis

Abstract

In response to food intake, glucagon-like peptide-2 (GLP-2) with GLP-1 is co-secreted from enteroendocrine L cells in the gut. GLP-2 receptor (GLP-2R) is expressed in the hypothalamus, a key tissue to integrate energy signals to regulate energy balance and glucose homeostasis. However, the physiological role of brain GLP-2R has not been defined. Our objective was to critically test if brain GLP-2R activation is essential for glucose homeostasis. [1] We found that icv infusion of GLP-2 increased glucose tolerance with increased expression of POMC gene in the hypothalamus. [2] We showed that GLP-2 (100 nM) increased firing rate by 79%, but decreased membrane potential (Control: −38.4 ± 2.2 vs GLP-2: −32.1 ± 1.9 mV) of POMC neurons on hypothalamic slices using the whole-cell patch clamp. [3] Using our newly generated POMC-specific glp2r knockout (CKO) mice, we demonstrated that glucose intolerance increased by 42% in the CKO mice. Moreover, glucose infusion rate decreased in the CKO mice during hyperinsulinemic euglycemic clamp (WT: 6.46 ± 0.27 vs CKO: 4.54 ± 0.24 mmol/kg/h). During the clamp, hepatic glucose production increased (WT: 3.54 ± 0.34 vs CKO: 4.30 ± 0.35 mmol/kg/h) with increased fraction of gluconeogenesis by 47% and mRNA abundance of G6Pase & PEPCK by 200% in the CKO mice. We conclude that GLP-2R deficiency in POMC neurons impairs glucose homeostasis by decreasing insulin sensitivity, suggesting that brain GLP-2R activation is important for maintenance of glucose homeostasis at high postprandial insulin.