Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity
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
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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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 7

The initial hyperphagic response to a HFD is attenuated without differences in fasting-induced hyperphagia or dietary preference in Snap25Δ3/Δ3 mice.

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The initial hyperphagic response to a HFD is attenuated without differen...
(A) Body weight (P < 0.001, genotype; P < 0.001, genotype × time interaction) and food consumption (P < 0.001, genotype; P = 0.2466, genotype × time interaction) during the first 5 weeks of HFD feeding in a separate cohort of male Snap25+/+ and Snap25Δ3/Δ3 mice. n = 23 Snap25+/+ mice; n = 18 Snap25Δ3/Δ3 mice. (B) Consumption of a HFD by male Snap25+/+ and Snap25Δ3/Δ3 mice following a 12-hour fast. n = 5 Snap25+/+ mice; n = 5 Snap25Δ3/Δ3 mice. (C) Cumulative food intake from chow-adapted male Snap25+/+ and Snap25Δ3/Δ3 mice given ad libitum access to both chow and a HFD. n = 5 Snap25+/+ mice; n = 6 Snap25Δ3/Δ3 mice. *P < 0.05, **P < 0.01, and ***P < 0.001. Values are the mean ± SEM. Analyses were performed using 2-way ANOVA, and post hoc analyses were performed using Bonferroni’s multiple-comparison test for the Snap25 genotype only.