Weight gain and metabolism are regulated by the GluN3B subunit of glutamate receptor acting through brain and peripheral fat tissue

Obesity and metabolic disorders are leading causes of mortality and morbidity. Here we report that the GluN3B subunit of glutamate receptor could be a novel drug target to reduce weight and improve metabolic function without affecting appetite or modifying food intake. We found that GluN3B acted through two complementary mechanisms to reduce weight in female mice, regardless of being fed either normal or high fat diets. In brown adipose tissue (BAT), selective knockdown of Grin3b increased sympathetic innervation and thermogenesis. In the brain, inhibition of Grin3b in the excitatory projections from M1 motor cortex to the dorsal medial hypothalamus (DMH) promoted lipolysis and energy consumption. In humans, stimulation of M1 reduced weight in women, and GRIN3B gene variants are associated with female body mass index (BMI). Drugs blocking the GluN3B subunit could be used to promote weight loss through increasing thermogenesis, lipolysis, and energy consumption, regardless of appetite or dietary intake.