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ResearchIn-Press PreviewEndocrinologyMetabolism
Open Access | 10.1172/JCI160617
1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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Ceddia, R.
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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McDonald-Boyer, A.
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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Feng, J.
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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Li, Y.
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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Alford, S.
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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Ayala, J.
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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McGuinness, O.
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America
2Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States of America
3Department of Pharmacology, Vanderbilt University, Nashville, United States of America
4Program in Chemical & Physical Biology, Vanderbilt University, Nashville, United States of America
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States of America
6School of Life Sciences, Peking University, Beijing, China
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Published August 10, 2023 - More info
Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from Gi/o G-protein-coupled-receptors by Gβγ subunit inhibition of two mechanisms: decreased calcium entry and direct interaction of Gβγ with Soluble N-ethylmaleimide-sensitive factor Attachment Protein (SNAP) Receptor (SNARE) plasma membrane fusion machinery. Previously, we disabled the second mechanism with a SNAP25 truncation (SNAP25Δ3) decreasing Gβγ affinity for the SNARE complex, leaving exocytotic fusion and modulation of calcium entry intact, and removing GPCR-Gβγ inhibition of SNARE-mediated exocytosis. Here, we report substantial metabolic benefit in mice carrying this mutation. SNAP25Δ3/Δ3 mice exhibit enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in SNAP25Δ3/Δ3 mice challenged with high fat diet. Glucose homeostasis, whole body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. 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 neuron exocytosis from SNAP25Δ3/Δ3 inguinal adipose depots resulted in enhanced and prolonged norepinephrine release. Thus, the Gβγ-SNARE interaction represents a cellular mechanism that deserves further exploration as an additional avenue for combatting metabolic disease.