Gabpα‐Pparγ Complex Determines Glycolytic Capacity and Lactic Acid Homeostasis in Brown Fat

Glycolysis in brown adipose tissue (BAT) plays a critical role in fueling thermogenesis. However, the transcriptional control of glycolysis in brown fat remains poorly understood. Here, GA binding protein alpha chain (Gabpα) is identified as a key transcriptional regulator that sustains the glycolytic capacity of brown adipocytes. Gabpα is preferentially expressed in BAT, yet BAT-specific ablation of Gabpα substantially impairs glycolytic flux and heat production, leading to reduced glucose tolerance and impaired cold tolerance. Mechanistically, the C-terminus of the Gabpα protein directly interacts with peroxisome proliferator-activated receptor-γ (Pparγ) and synergistically promotes transcription of the glycolytic gene enolase 1 (Eno1). Disruption of the Gabpα-Pparγ interaction in BAT significantly suppresses glycolysis, reduces energy expenditure, and induces cold intolerance in mice. Notably, inhibition of Gabpα-Pparγ binding also decreases lactic acid concentration and downregulates lactate dehydrogenase (Ldh) expression, resulting in the suppression of uncoupling protein 1 (Ucp1) expression and thermogenesis. Conversely, adipose-specific overexpression of Gabpα markedly enhances BAT glycolytic and thermogenic activity, protecting against cold challenge and high-fat diet (HFD)-induced obesity. Collectively, these results point to the Gabpα-Pparγ complex as a potent regulator of glycolysis in BAT and may represent a promising therapeutic target for metabolic disease intervention.