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

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

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 8

Lower net caloric accumulation upon transition to a HFD is associated with less food intake without alterations in energy expenditure in Snap25Δ3/Δ3 mice.

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Lower net caloric accumulation upon transition to a HFD is associated wi...
(A) Chow-fed 12-week-old male Snap25+/+ and Snap25Δ3/Δ3 mice were acclimated in the Promethion System for 1 week prior to transitioning to a HFD. Graph shows the energy balance (P = 0.0006 genotype × time during the light cycle). (B) Energy expenditure (EE). (C) Cumulative food intake (P = 0.0556 genotype; P = 0.0023 genotype × time during the light cycle) and daily caloric intake. (D) Respiratory exchange ratio (RER). VO2, oxygen consumption volume; VCO2, CO2 production volume. (E) Body weights and composition before (day –7) and after (day 12) these energy balance studies. For all figures, n = 6 Snap25+/+ mice; n = 6 Snap25Δ3/Δ3 mice. *P < 0.05 and ***P < 0.001. Light and dark cycles were analyzed separately. Analyses were performed by 2-way ANOVA with repeated measures, and post hoc analyses were performed using Bonferroni’s multiple-comparison test for the Snap25 genotype only. Energy expenditure was assessed using ANCOVA.