The Glucagon Receptor Is Required for the Adaptive Metabolic Response to Fasting

SummaryGlucagon receptor (Gcgr) signaling maintains hepatic glucose production during the fasting state; however, the importance of the Gcgr for lipid metabolism is unclear. We show here that fasted Gcgr−/− mice exhibit a significant increase in hepatic triglyceride secretion and fasting increases fatty acid oxidation (FAO) in wild-type (WT) but not in Gcgr−/− mice. Moreover fasting upregulated the expression of FAO-related hepatic mRNA transcripts in Gcgr+/+ but not in Gcgr−/− mice. Exogenous glucagon administration reduced plasma triglycerides in WT mice, inhibited TG synthesis and secretion, and stimulated FA beta oxidation in Gcgr+/+ hepatocytes. The actions of glucagon on TG synthesis and FAO were abolished in PPARα−/− hepatocytes. These findings demonstrate that the Gcgr receptor is required for control of lipid metabolism during the adaptive metabolic response to fasting

The endogenous preproglucagon system is not essential for gut growth homeostasis in mice

Objective: The prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice. Methods: We used in situ hybridization to provide a detailed and comparative anatomical map of the local distribution of GLP-1 receptor (Glp1r), GLP-2 receptor (Glp2r), and preproglucagon (Gcg) mRNA expression throughout the mouse gastrointestinal tract. Gut development in GLP-1R-, GLP-2R-, or GCG-deficient mice was compared to their corresponding wild-type controls, and intestinotrophic effects of GLP-1 and GLP-2 analogs were assessed in wild-type mice. Lastly, gut volume was determined in a mouse model of vertical sleeve gastrectomy (VSG). Results: Comparison of Glp1r, Glp2r, and Gcg mRNA expression indicated a widespread, but distinct, distribution of these three transcripts throughout all compartments of the mouse gastrointestinal tract. While mice null for Glp1r or Gcg showed normal intestinal morphology, Glp2r−/− mice exhibited a slight reduction in small intestinal mucosa volume. Pharmacological treatment with GLP-1 and GLP-2 analogs significantly increased gut volume. In contrast, VSG surgery had no effect on intestinal morphology. Conclusion: The present study indicates that the endogenous preproglucagon system, exemplified by the entire GCG gene and the receptors for GLP-1 and GLP-2, does not play a major role in normal gut development in the mouse. Furthermore, elevation in local intestinal and circulating levels of GLP-1 and GLP-2 achieved after VSG has limited impact on intestinal morphometry. Hence, although exogenous treatment with GLP-1 and GLP-2 analogs enhances gut growth, the contributions of endogenously-secreted GLP-1 and GLP-2 to gut growth may be more modest and highly context-dependent

The role of incretin hormones in glucose homeostasis

grantor: University of TorontoIncretins are hormones that are released from the gut in response to nutrient ingestion and act to enhance glucose-stimulated insulin secretion. The two major peptides which have been identified as incretin hormones are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Previous glucoregulatory studies using receptor knockout mice models suggest that the role of GIP is restricted to that of an incretin, whereas GLP-1 also exhibits non-incretin effects. However, studies with genetically-modified mice can be complicated by compensatory adaptive changes. To avoid this possibility, we assessed the incretin and nonincretin actions of GIP and GLP-1 in wild-type mice using the GLP-1 receptor antagonist exendin(9-39) and immunopurified anti-GIP receptor antisera to antagonize GLP-1 and GIP action, respectively. Our results indicate that GLP-1, but not GIP, plays an important role in regulating blood glucose levels in mice in a manner independent of oral nutrient ingestion. In addition to its role as an incretin, GLP-1 contributes to blood glucose lowering through several different mechanisms and thus its therapeutic value as a treatment for diabetes is currently under investigation. However, GLP-1 is rapidly catabolized by dipeptidylpeptidase IV (DPP-IV) and therefore has a short plasma half-life, which may, in turn, limit its therapeutic potential. Inhibition of DPP-IV activity could thus provide a means to extend the half-life of GLP-1. However, DPP-IV may also act upon other substrates important for glucoregulation. To investigate this possibility, we examined the effects of DPP-IV inhibition in GLP-1 receptor knockout mice. Our results suggest that in addition to GLP-1, other substrates are involved in the DPP-IV-mediated regulation of blood glucose control. Exendin-4 is a potent GLP-1 receptor agonist that was originally purified from lizard venom and is currently being evaluated in clinical trials as a treatment for diabetes. Limited information is available regarding the long-term effects of exendin-4 treatment 'in vivo'. To assess the physiological effects of chronic exendin-4 expression 'in vivo', we have generated transgenic mice in which exendin-4 expression is under the control of an inducible promoter. Our data indicate that sustained elevation of circulating exendin-4 has both predicted and unanticipated effects on GLP-1 receptor-dependent physiological end points.Ph.D