Gamma-Aminobutyric Acid Signaling in Brown Adipose Tissue Promotes Systemic Metabolic Derangement in Obesity

Summary: Brown adipose tissue (BAT) is a metabolically active organ that contributes to the maintenance of systemic metabolism. The sympathetic nervous system plays important roles in the homeostasis of BAT and promotes its browning and activation. However, the role of other neurotransmitters in BAT homeostasis remains largely unknown. Our metabolomic analyses reveal that gamma-aminobutyric acid (GABA) levels are increased in the interscapular BAT of mice with dietary obesity. We also found a significant increase in GABA-type B receptor subunit 1 (GABA-BR1) in the cell membranes of brown adipocytes of dietary obese mice. When administered to obese mice, GABA induces BAT dysfunction together with systemic metabolic disorder. Conversely, the genetic inactivation or inhibition of GABA-BR1 leads to the re-browning of BAT under conditions of metabolic stress and ameliorated systemic glucose intolerance. These results indicate that the constitutive activation of GABA/GABA-BR1 signaling in obesity promotes BAT dysfunction and systemic metabolic derangement. : Brown adipose tissue (BAT) is a metabolically active organ important for systemic metabolism. Here, Ikegami et al. identify a role for gamma-aminobutyric acid (GABA) in metabolic and BAT dysfunction in obese mice and demonstrate that inhibition of GABA/GABA-BR1-mediated signaling and of mitochondrial calcium overload can restore BAT function in obesity. Keywords: brown adipose tissue, BAT, metabolome, gamma-aminobutyric acid, GABA, obesit