PT  - JOURNAL ARTICLE
AU  - Ryan P. Ceddia
AU  - Zack Zurawski
AU  - Analisa Thompson Gray
AU  - Feyisayo Adegboye
AU  - Fubiao Shi
AU  - Dianxin Liu
AU  - Jose Maldonado
AU  - Julio E. Ayala
AU  - Owen P. McGuinness
AU  - Sheila Collins
AU  - Heidi E. Hamm
TI  - Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity
AID  - 10.1101/2020.04.29.069138
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2020.04.29.069138
4099  - http://biorxiv.org/content/early/2022/06/14/2020.04.29.069138.short
4100  - http://biorxiv.org/content/early/2022/06/14/2020.04.29.069138.full
AB  - Negative regulation of exocytosis from secretory cells throughout the body is accomplished through inhibitory signals from Gi/o G protein-coupled receptors by Gβγ subunit inhibition of two common mechanisms: (i) decreased calcium entry and (ii) direct interaction of Gβγ with the Soluble N-ethylmaleimide-sensitive factor Attachment Protein (SNAP) Receptor (SNARE) plasma membrane fusion machinery. We have previously shown that disabling the second mechanism with a truncation of SNAP25 (SNAP25Δ3/Δ3) decreases the affinity of Gβγ for the SNARE complex, leaving exocytotic fusion as well as modulation of calcium entry intact. Here we report significant beneficial metabolic remodeling in mice carrying this mutation. Chow-fed SNAP25Δ3/Δ3 mice exhibit enhanced insulin sensitivity and increased beiging of white fat. In response to a high fat diet, the metabolic protection was amplified in SNAP25Δ3/Δ3 mice. Glucose homeostasis, whole body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. This 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 tone is required. Thus, the Gβγ-SNARE interaction represents a cellular mechanism that deserves further exploration as a new avenue for combatting metabolic disease.GRAPHICAL ABSTRACTCompeting Interest StatementThe authors have declared no competing interest.