Abstract 12631: Peripheral Gamma-aminobutyric Acid(gaba) Signaling in Brown Adipose Tissue Induces Metabolic Dysfunction in Obesity

Accumulating evidence suggests that adult humans possess active brown adipose tissue (BAT) that may contribute significantly to systemic metabolism because of its high energy consumption capacity. Recently, we demonstrated that metabolic stress induced BAT hypoxia and impaired mitochondrial function, leading to the development of BAT “whitening” and systemic metabolic dysfunction in murine obese models. Various neurotransmitters are known to be involved in the maintenance of BAT homeostasis. Among them, the gamma-aminobutyric acid (GABA) signaling in the central nervous system is well accepted to have anti-obesity effects through the activation of the sympathetic nervous system. Here we show the previously unknown role of peripheral GABA signaling in the development of systemic metabolic dysfunction in obesity. We generated an obese model by imposing a high fat/high sucrose (HFHS) diet on C57BL/6NCr mice. Mass spectrometry analysis demonstrated a significant increase in GABA level in BAT of the dietary obese model. Addition of GABA into drinking water induced BAT whitening, reduced the thermogenic response upon cold tolerance test, and promoted systemic metabolic dysfunction in the obese mice. Mitochondrial calcium is important for the maintenance of mitochondrial homeostasis, whereas calcium overload is reported to inhibit mitochondrial function. Treatment of BAT cells with GABA markedly increased mitochondrial calcium level, promoted the production of reactive oxygen species (ROS), and inhibited mitochondrial respiration. These results indicate that peripheral GABA contributes to the development of systemic metabolic dysfunction by inhibiting BAT function in obesity. The inhibition of peripheral GABA signaling would become a new therapeutic target for obesity and diabetes.