Gα12/13 deficiency attenuates obesity-associated adipose tissue inflammation and promotes energy expenditure

G protein–coupled receptor signaling via Gα12/13 regulates diverse physiological processes, but its role in adipose tissue metabolism remains largely unknown. Here, we identify Gα12/13 as inhibitory modulators of β-adrenergic Gαs signaling in adipocytes. Obesity is associated with increased Gα12/13 expression in adipose tissue of mice and humans. Using adipocyte-specific Gα13 knockout, global Gα12 knockout, and double knockout mice lacking both adipocyte-specific Gα13 and global Gα12, we demonstrate that loss of Gα12/13 protects against HFD-induced metabolic dysfunction. Deletion of either Gα12 or Gα13 attenuates Rho/ROCK–JNK–mediated inflammatory signaling, suppresses pyroptosis, promotes anti-inflammatory polarization of macrophages and improves insulin sensitivity. Combined deletion of both Gα12 and Gα13 retains these anti-inflammatory effects while further reducing T lymphocyte infiltration and enhancing β-adrenergic Gαs–cAMP–PKA signaling, mitochondrial biogenesis, thermogenic gene expression, and whole-body energy expenditure in HFD-fed mice. Collectively, our findings establish Gα12/13 as brakes on β-adrenergic Gαs signaling and key mediators of HFD-induced adipose tissue inflammation. Targeting the Gα12/13 pathway may therefore potentiate beneficial adipose remodeling and represent a promising therapeutic avenue for obesity-associated metabolic disease. Obesity impairs adipose function and drives metabolic disease. Here, the authors show that obesity-induced Gα12/13 restrains β-adrenergic signaling; its loss raises energy expenditure and protects mice from diet-induced metabolic dysfunction.