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Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity
Ryan P. Ceddia, … , Sheila Collins, Heidi E. Hamm
Ryan P. Ceddia, … , Sheila Collins, Heidi E. Hamm
Published August 10, 2023
Citation Information: J Clin Invest. 2023;133(19):e160617. https://doi.org/10.1172/JCI160617.
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Research Article Endocrinology Metabolism Article has an altmetric score of 33

Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

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Abstract

Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from Gi/o GPCRs by Gβγ subunit inhibition of 2 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) that decreased 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 exhibited enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in Snap25Δ3/Δ3 mice challenged with a 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 that basal autonomic activity was 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 combating metabolic disease.

Authors

Ryan P. Ceddia, Zack Zurawski, Analisa Thompson Gray, Feyisayo Adegboye, Ainsley McDonald-Boyer, Fubiao Shi, Dianxin Liu, Jose Maldonado, Jiesi Feng, Yulong Li, Simon Alford, Julio E. Ayala, Owen P. McGuinness, Sheila Collins, Heidi E. Hamm

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Figure 12

Summary of how removing the Gβγ-SNAP25 brake on exocytosis promotes adipocyte browning and glucose clearance.

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Summary of how removing the Gβγ-SNAP25 brake on exocytosis promotes adip...
During cold stress, sympathetic regulation of adipocyte beiging/browning occurs through release of NE from sympathetic neurons and thereby induces the adipocyte β-adrenergic program. This increases mitochondrial biogenesis (browning) and expression of UCP1, generating heat by expending energy through uncoupled respiration. Housing mice at room temperature (normal housing is around 22°C) evokes a mild cold stress that is generally unnoticed. Normally there is an α2-adrenergic brake on neurotransmitter vesicle fusion that works through the Gβγ-SNARE interaction to limit NE release. We removed this brake on NE release by creating a mutant SNAP25 that decreases Gβγ binding, leading to enhanced and prolonged NE release from sympathetic neurons and, thereby, greater induction of the adipocyte thermogenic program. This enhanced browning increases glucose uptake into beige adipocytes, resulting in enhanced insulin sensitivity, particularly in these white adipose depots. We posit that this global genetic alteration enhances and prolongs synaptic vesicle exocytosis from SNAP25-expressing neurons associated other organ systems, such as those responsible for food intake. A result of these adaptations, Snap25Δ3/Δ3 mice are resistant to diet-induced obesity. Removal of cold-induced sympathetic activity by placing animals under thermoneutral conditions (~30°C) reverses all of these changes, allowing us to conclude that the inability of Gβγ to act as a negative regulator of NE release is the main driver of the beneficial metabolic phenotype.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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