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

Area of Science:

• Metabolic Regulation
• Adipose Tissue Biology
• Transcriptional Control

Background:

• Glycolysis fuels thermogenesis in brown adipose tissue (BAT), but its transcriptional regulation is unclear.
• Understanding BAT's glycolytic control is crucial for metabolic health and energy balance.

Purpose of the Study:

• To identify key transcriptional regulators of glycolysis in brown adipocytes.
• To elucidate the role of GA binding protein alpha chain (Gabpα) in BAT function.

Main Methods:

• Investigated Gabpα expression and function in mouse BAT models.
• Utilized genetic ablation and overexpression of Gabpα.
• Examined molecular interactions between Gabpα and Pparγ.
• Assessed glycolytic flux, thermogenesis, glucose tolerance, and cold tolerance.

Main Results:

• Gabpα is highly expressed in BAT and is essential for maintaining glycolytic capacity and thermogenesis.
• BAT-specific Gabpα deficiency impairs glucose and cold tolerance.
• Gabpα directly interacts with Pparγ to enhance transcription of the glycolytic gene enolase 1 (Eno1).
• Disrupting the Gabpα-Pparγ interaction suppresses glycolysis, energy expenditure, and thermogenesis (Ucp1 expression).
• Gabpα overexpression enhances BAT activity and protects against diet-induced obesity and cold stress.

Conclusions:

• The Gabpα-Pparγ complex is a critical regulator of glycolysis and thermogenesis in BAT.
• Targeting the Gabpα-Pparγ interaction offers a potential therapeutic strategy for metabolic diseases.