Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity
Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity
Abstract Negative regulation of exocytosis from secretory cells throughout the body is accomplished through inhibitory signals from Gi/o G protein-coupled receptors by Gβγ subunit inhibition of two common mechanisms: (i) decreased calcium entry and (ii) direct interaction of Gβγ with the Soluble N-ethylmaleimide-sensitive factor Attachment Protein (SNAP) Receptor (SNARE) plasma membrane fusion machinery. We have previously shown that disabling the second mechanism with a truncation of SNAP25 (SNAP25Δ3/Δ3) decreases the affinity of Gβγ for the SNARE complex, leaving exocytotic fusion as well as modulation of calcium entry intact but disabling GPCR inhibition of exocytosis. Here we report significant beneficial metabolic remodeling in mice carrying this mutation. Chow-fed SNAP25Δ3/Δ3 mice exhibit enhanced insulin sensitivity and increased beiging of white fat. In response to a high fat diet, the metabolic protection was amplified in SNAP25Δ3/Δ3 mice. Glucose homeostasis, whole body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. This metabolic protection in SNAP25Δ3/Δ3 mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting basal autonomic activity is required. Direct electrode stimulation of sympathetic neurons exocytosis from SNAP25Δ3/Δ3 inguinal adipose depot resulted in enhanced and prolonged norepinephrine release. Thus, the Gβγ-SNARE interaction represents a cellular mechanism that deserves further exploration as a new avenue for combatting metabolic disease. GRAPHICAL ABSTRACTbiorxiv;2020.04.29.069138v4/UFIG1F1ufig1
Collins Sheila、Hamm Heidi E.、Adegboye Feyisayo、Maldonado Jose、Feng Jiesi、Alford Simon、Ayala Julio E.、Zurawski Zack、Gray Analisa Thompson、McGuinness Owen P.、McDonald-Boyer Ainsley、Li Yulong、Liu Dianxin、Ceddia Ryan P.、Shi Fubiao
Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center||Department of Molecular Physiology and Biophysics, Vanderbilt UniversityDepartment of Pharmacology, Vanderbilt UniversityDepartment of Pharmacology, Vanderbilt UniversityDepartment of Molecular Physiology and Biophysics, Vanderbilt UniversityState Key Laboratory of Membrane Biology, Peking University School of Life Sciences||PKU-IDG/McGovern Institute for Brain Research||Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking UniversityDepartment of Anatomy and Cell Biology, University of Illinois at ChicagoDepartment of Molecular Physiology and Biophysics, Vanderbilt UniversityDepartment of Pharmacology, Vanderbilt University||Department of Anatomy and Cell Biology, University of Illinois at ChicagoDepartment of Pharmacology, Vanderbilt UniversityDepartment of Molecular Physiology and Biophysics, Vanderbilt UniversityProgram in Chemical & Physical Biology, Vanderbilt UniversityState Key Laboratory of Membrane Biology, Peking University School of Life Sciences||PKU-IDG/McGovern Institute for Brain Research||Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University||Chinese Institute for Brain ResearchDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical CenterDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical CenterDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center
基础医学生理学分子生物学
Collins Sheila,Hamm Heidi E.,Adegboye Feyisayo,Maldonado Jose,Feng Jiesi,Alford Simon,Ayala Julio E.,Zurawski Zack,Gray Analisa Thompson,McGuinness Owen P.,McDonald-Boyer Ainsley,Li Yulong,Liu Dianxin,Ceddia Ryan P.,Shi Fubiao.Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity[EB/OL].(2025-03-28)[2025-05-02].https://www.biorxiv.org/content/10.1101/2020.04.29.069138.点此复制
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