A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS

Pleiotropic effects of prokineticin 2 in the control of energy metabolism

International audienceProkineticins are family of small proteins involved in many important biological processes including food intake and control of energy balance. The prokineticin 2 (PROK2) is expressed in several peripheral tissues and areas in the central nervous system. PROK2 activates G protein-coupled receptors, namely, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). Preclinical models exhibiting disturbances of the PROK2 pathway (at the level of PROK2 or its receptors) are characterized by changes in food intake, feeding behavior and insulin sensitivity related to a dysfunction of the energy balance control. In Humans, mutations of PROK2 and PROKR2 genes are associated to the Kallmann syndrome (KS) that affects both the hormonal reproductive axis and the sense of smell and may also lead to obesity. Moreover, plasma PROK2 concentration has been correlated with various cardiometabolic risk factors and type 2 diabetes (T2D). The present review summarizes knowledge on PROK2 structure, signaling and function focusing on its role in control of food intake and energy homeostasis. (c) 2021 Elsevier B.V. and Soci & eacute;t & eacute; Fran & ccedil;aise de Biochimie et Biologie Mol & eacute;culaire (SFBBM). All rights reserved

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases

International audienc

A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion.

Acknowledgements: We thank Dr Serge Luquet, Giuseppe Gangarossa, Nicolas Thiebaud and Claire Martin for their advice and helpful discussions. The help of Zahra Boudra is also acknowledged. We thank the technical platform Functional and Physiological Exploration platform (FPE) of the Université Paris CIté (BFA-UMR 8251), the animal core facility Buffon of the Université Paris Cité for animal experiments. We would also like to thank Eric Marty for the design of the cannulas used for intrabulbar injections. We thank the core imaging facility of Institut Jacques Monod (ImagoSeine facility) for help in image acquisition and processing. The microscopy for LH cFos analysis was done in the Bordeaux Imaging Center, a service unit of the CNRS-INSERM and Bordeaux University, member of the national infrastructure France BioImaging supported by the French National Research Agency (ANR-10-INBS-04). The help of Sébastien Marais is acknowledged. This work was supported by Research grant of the French Society for Study of Diabetes (SFD-017-2019 to C.M. and H.G., the Medical Research Council UK (MR/N02589X/1 to S.T.), a British Heart Foundation Postdoctoral Fellowship (FS/IPBSRF/20/27001 to M.K.H.), a Wellcome Trust Sir Henry Dale Fellowship (223279/Z/21/Z to D.B.), and a grant from the European Foundation for the Study of Diabetes Germany (Merck Sharpe Dohme grant to S.T. and D.B.). F.R. and F.M.G.’s work was funded by Wellcome (220271/Z/20/Z) and the MRC (MRC_MC_UU_12012/3). Additional support was obtained from the Cities Partnership program UCL to S.T., C.M. and H.G.; M.M. was supported by a “Université Paris Cité IdEx” PhD Fellowship and a “EUR GENE, G.E.N.E. Graduate School” Fellowship. WJ was supported by a UCL ORS Scholarship and a CSC Scholarship from the Chinese Government. L.V.O. is a research professor of the KU Leuven Special Research Fund (Bijzonder Onderzoeksfonds, BOF). We also acknowledge INSERM (to DC) and Agence Nationale de la Recherche (ANR-21-CE14-0018 to D.C.). D.J.H. was supported by MRC (MR/S025618/1) and Diabetes UK (17/0005681) Project Grants, as well as a UKRI ERC Frontier Research Guarantee Grant (EP/X026833/1).Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS

Diabetologia

AIMS/HYPOTHESIS: Per-Arnt-Sim kinase (PASK) is a nutrient-regulated domain-containing protein kinase previously implicated in the control of insulin gene expression and glucagon secretion. Here, we explore the roles of PASK in the control of islet hormone release, by generating mice with selective deletion of the Pask gene in pancreatic beta or alpha cells. METHODS: Floxed alleles of Pask were produced by homologous recombination and animals bred with mice bearing beta (Ins1 Cre; PaskBKO) or alpha (Ppg Cre [also known as Gcg]; PaskAKO) cell-selective Cre recombinase alleles. Glucose homeostasis and hormone secretion in vivo and in vitro, gene expression and islet cell mass were measured using standard techniques. RESULTS: Ins1 Cre-based recombination led to efficient beta cell-targeted deletion of Pask. Beta cell mass was reduced by 36.5% (p < 0.05) compared with controls in PaskBKO mice, as well as in global Pask-null mice (38%, p < 0.05). PaskBKO mice displayed normal body weight and fasting glycaemia, but slightly impaired glucose tolerance, and beta cell proliferation, after maintenance on a high-fat diet. Whilst glucose tolerance was unaffected in PaskAKO mice, glucose infusion rates were increased, and glucagon secretion tended to be lower, during hypoglycaemic clamps. Although alpha cell mass was increased (21.9%, p < 0.05), glucagon release at low glucose was impaired (p < 0.05) in PaskAKO islets. CONCLUSIONS/INTERPRETATION: The findings demonstrate cell-autonomous roles for PASK in the control of pancreatic endocrine hormone secretion. Differences between the glycaemic phenotype of global vs cell type-specific null mice suggest important roles for tissue interactions in the control of glycaemia by PASK