Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors.
| Title: | Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors. |
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| Authors: | Ruohonen ST; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finlandsuvi.ruohonen@utu.fi.; Turku Center for Disease Modeling, University of Turku, Turku, Finlandsuvi.ruohonen@utu.fi.; Valve L; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Tuomainen K; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Ailanen L; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Drug Research Doctoral Program, University of Turku, Turku, Finland.; Röyttä M; Institute of Biomedicine, University of Turku and Unit of Neuropathology, Turku University Hospital, Turku, Finland.; Manz G; LDN Labor Diagnostika Nord, Nordhorn, Germany.; Baur N; NMI Natural and Medical Sciences Institute, University of Tuebingen, Reutlingen, Germany.; Joos TO; NMI Natural and Medical Sciences Institute, University of Tuebingen, Reutlingen, Germany.; Savontaus E; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.; Scheinin M; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland. |
| Source: | Neuroendocrinology [Neuroendocrinology] 2018; Vol. 107 (4), pp. 324-339. Date of Electronic Publication: 2018 Jul 24. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Karger Country of Publication: Switzerland NLM ID: 0035665 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1423-0194 (Electronic) Linking ISSN: 00283835 NLM ISO Abbreviation: Neuroendocrinology Subsets: MEDLINE |
| Imprint Name(s): | Publication: Basel : Karger; Original Publication: Basel. |
| MeSH Terms: | Diabetes Mellitus, Type 2/*genetics ; Energy Metabolism/*genetics ; Hyperinsulinism/*genetics ; Lipolysis/*genetics ; Obesity, Abdominal/*genetics ; Receptors, Adrenergic, alpha-2/*genetics; Adiposity/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diet, High-Fat/adverse effects ; Disease Resistance/genetics ; Hyperinsulinism/metabolism ; Obesity, Abdominal/metabolism ; Up-Regulation/genetics ; Weight Loss/genetics ; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout |
| Abstract: | The alpha2A-adrenoceptors (α2A-ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally inhibit insulin secretion and lipolysis. We have earlier shown that α2A-/- mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α2A-/- mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α2A-ARs protects from diet-induced obesity and type 2 diabetes (T2D). In addition, a high-caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α2A-/- mice accumulated less visceral fat than the wild-type controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α2A-ARs is associated with an increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α2A-/- mice displayed enhanced lipolytic responses to Epi, and increased faecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α2A-/- mice, and brown fat showed an increased response to NE. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α2A-AR signalling promoted weight loss more efficiently than exercise with normal α2A-AR function. These results suggest that blockade of α2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion.; (© 2018 S. Karger AG, Basel.) |
| Contributed Indexing: | Keywords: Alpha2A-adrenoceptor; Diet-induced obesity; Gene-modified mouse; Glucose homeostasis; Knock-out; Physical exercise |
| Substance Nomenclature: | 0 (Adra2a protein, mouse); 0 (Receptors, Adrenergic, alpha-2) |
| Entry Date(s): | Date Created: 20180725 Date Completed: 20190926 Latest Revision: 20190926 |
| Update Code: | 20260130 |
| DOI: | 10.1159/000492387 |
| PMID: | 30041171 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't