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

Abstract 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.