Combined loss of GLP-1R and Y2R does not alter progression of high-fat diet-induced obesity or response to RYGB surgery in mice
| Autor: | Christopher J. Rhodes, R. Leigh Townsend, Sangho Yu, Hans-Rudolf Berthoud, James L. Trevaskis, Michael B. Mumphrey, Stephanie Oldham, Brandon B. Boland, Zheng Hao, Sarah Will, Heike Münzberg, Benji Gill, Christopher D. Morrison |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Blood Glucose
Male 0301 basic medicine Bariatric Surgery medicine.disease_cause Receptors G-Protein-Coupled Mice 0302 clinical medicine Insulin Glucose homeostasis Medicine Mice Knockout 2. Zero hunger Diabetes Glucose tolerance Insulin tolerance 3. Good health Original Article Signal transduction medicine.medical_specialty lcsh:Internal medicine Gastric Bypass 030209 endocrinology & metabolism Diet High-Fat Glucagon-Like Peptide-1 Receptor 03 medical and health sciences Metabolic Diseases Diabetes mellitus Animals Peptide YY Obesity lcsh:RC31-1245 Molecular Biology PYY business.industry Gastric bypass surgery Body Weight Wild type Cell Biology medicine.disease Blockade Surgery Mice Inbred C57BL 030104 developmental biology Gene Expression Regulation Insulin Resistance Energy Metabolism Transcriptome GLP-1 business Hormone |
| Zdroj: | Molecular Metabolism, Vol 25, Iss, Pp 64-72 (2019) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective Understanding the mechanisms underlying the remarkable beneficial effects of gastric bypass surgery is important for the development of non-surgical therapies or less invasive surgeries in the fight against obesity and metabolic disease. Although the intestinal L-cell hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine–tyrosine (PYY) have attracted the most attention, direct tests in humans and rodents with pharmacological blockade or genetic deletion of either the GLP1-receptor (GLP1R) or the Y2-receptor (Y2R) were unable to confirm their critical roles in the beneficial effects gastric bypass surgery on body weight and glucose homeostasis. However, new awareness of the power of combinatorial therapies in the treatment of metabolic disease would suggest that combined blockade of more than one signaling pathway may be necessary to reverse the beneficial effects of bariatric surgery. Methods The metabolic effects of high-fat diet and the ability of Roux-en-Y gastric bypass surgery to lower food intake and body weight, as well as improve glucose handling, was tested in GLP1R and Y2R-double knockout (GLP1RKO/Y2RKO) and C57BL6J wildtype (WT) mice. Results GLP1RKO/Y2RKO and WT mice responded similarly for up to 20 weeks on high-fat diet and 16 weeks after RYGB. There were no significant differences in loss of body and liver weight, fat mass, reduced food intake, relative increase in energy expenditure, improved fasting insulin, glucose tolerance, and insulin tolerance between WT and GLP1RKO/Y2RKO mice after RYGB. Conclusions Combined loss of GLP1R and Y2R-signaling was not able to negate or attenuate the beneficial effects of RYGB on body weight and glucose homeostasis in mice, suggesting that a larger number of signaling pathways is involved or that the critical pathway has not yet been identified. Graphical abstract Image 1 Highlights • Mice with combined deletion of GLP1R and PYY receptor Y2R gain weight normally on chow or high-fat diet. • GLP1RKO/Y2RKO double knockout mice also respond normally to RYGB. • Compensatory mechanisms such as GLP2R up-regulation may be responsible for the negative outcomes. |
| Databáze: | OpenAIRE |
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