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

Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from Gi/o GPCRs by G beta gamma subunit inhibition of 2 mechanisms: decreased calcium entry and direct interaction of G beta gamma 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 (SNAP25 Delta 3) that decreased G beta gamma affinity for the SNARE complex, leaving exocytotic fusion and modulation of calcium entry intact and removing GPCR-G beta gamma inhibition of SNARE-mediated exocytosis. Here, we report substantial metabolic benefit in mice carrying this mutation. Snap25 Delta 3/Delta 3 mice exhibited enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in Snap25 Delta 3/Delta 3 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 Snap25 Delta 3/Delta 3 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 Snap25 Delta 3/Delta 3 inguinal adipose depots resulted in enhanced and prolonged norepinephrine release. Thus, the G beta gamma-SNARE interaction represents a cellular mechanism that deserves further exploration as an additional avenue for combating metabolic disease.