Modulating Gbg -SNARE interaction for adipose tissue metabolism and energy expenditure

Obesity is now an epidemic in the United States – more than 40% of the population obese or severely obese (2016 data from CDC). The associated risk for type 2 diabetes, cardiovascular disease, hypertension, and certain cancers continue to escalate. Given that this epidemic is driven by an overall positive energy balance, and since current pharmacological treatments for obesity are largely ineffective, agents acting through peripheral mechanisms to increase energy expenditure (EE) should be particularly valuable. We have discovered a mechanism that is unexpectedly effective at increasing energy expenditure (EE) and improving glucose homeostasis. Disabling the GBy-mediated inhibition of hormone and neurotransmitter secretion through its interaction with the exocytotic fusion machinery has led to metabolic phenotypes of enhanced insulin action, protection against diet-induced obesity (DIO) despite similar food intake, and increased brown adipose tissue (BAT) thermogenesis and ‘beiging’/’browning’ in adipose tissue. Our long- term goal is to understand the signaling mechanisms that control body fat metabolism and its consequences for glucose/insulin homeostasis and cardiovascular disease.