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

doi:10.1172/JCI160617

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

Ryan P. Ceddia,¹ Zack Zurawski,² Analisa Thompson Gray,³ Feyisayo Adegboye,³ Ainsley McDonald-Boyer,⁴ Fubiao Shi,¹ Dianxin Liu,¹ Jose Maldonado,⁵ Jiesi Feng,⁶ Yulong Li,⁶ Simon Alford,² Julio E. Ayala,⁵ Owen P. McGuinness,⁵ Sheila Collins,¹ and Heidi E. Hamm³

Published August 10, 2023 - More info

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Abstract

Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from G_i/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. SNAP25^Δ3/Δ3 mice exhibit enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in SNAP25^Δ3/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 SNAP25^Δ3/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 SNAP25^Δ3/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.

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

Ryan P. Ceddia,¹ Zack Zurawski,² Analisa Thompson Gray,³ Feyisayo Adegboye,³ Ainsley McDonald-Boyer,⁴ Fubiao Shi,¹ Dianxin Liu,¹ Jose Maldonado,⁵ Jiesi Feng,⁶ Yulong Li,⁶ Simon Alford,² Julio E. Ayala,⁵ Owen P. McGuinness,⁵ Sheila Collins,¹ and Heidi E. Hamm³

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

Ryan P. Ceddia,1 Zack Zurawski,2 Analisa Thompson Gray,3 Feyisayo Adegboye,3 Ainsley McDonald-Boyer,4 Fubiao Shi,1 Dianxin Liu,1 Jose Maldonado,5 Jiesi Feng,6 Yulong Li,6 Simon Alford,2 Julio E. Ayala,5 Owen P. McGuinness,5 Sheila Collins,1 and Heidi E. Hamm3

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Ryan P. Ceddia,¹ Zack Zurawski,² Analisa Thompson Gray,³ Feyisayo Adegboye,³ Ainsley McDonald-Boyer,⁴ Fubiao Shi,¹ Dianxin Liu,¹ Jose Maldonado,⁵ Jiesi Feng,⁶ Yulong Li,⁶ Simon Alford,² Julio E. Ayala,⁵ Owen P. McGuinness,⁵ Sheila Collins,¹ and Heidi E. Hamm³