Impairment of the Gβγ-SNAP25 brake on exocytosis enhances insulin action, protects against diet-induced obesity, and promotes adipocyte browning

The Gβγ complex inhibits vesicle exocytosis by two mechanisms: inhibiting calcium entry by binding to voltage gated calcium channels, and binding to SNAP25 in the SNAP Receptor (SNARE) complex. To de-convolute the role of each of these mechanisms in vivo , we have made a mouse with the second mechanism disabled. The SNAP25Δ3 mutation renders the SNARE complex deficient in binding to Gβγ and was used to investigate the importance of the Gβγ-SNAP25 interaction in glucose stimulated insulin secretion (GSIS) and global metabolic homeostasis. GSIS and α 2A adrenergic receptor-mediated inhibition of GSIS were not altered in SNAP25 Δ3/Δ3 mice. Nevertheless, SNAP25 Δ3/Δ3 mice exhibited a marked improvement in insulin sensitivity and were resistant to weight gain when challenged with a high fat diet (HFD). Reduced food consumption in the early stages of HFD feeding were partly responsible for the inability of SNAP25 Δ3/Δ3 mice to gain weight on HFD. Additionally, improved insulin-mediated glucose uptake into white adipose tissue and increased ‘browning’ were observed in SNAP25 Δ3/Δ3 mice, which is consistent with an impaired ability to retain energy stores. These phenotypic changes in SNAP25 Δ3/Δ3 mice are all metabolically protective, indicating that pharmacological targeting of the Gβγ-SNAP25 interaction may have a metabolic benefit.