SOX4 facilitates brown fat development and maintenance through EBF2-mediated thermogenic gene program in mice

Area of Science:

• Metabolic disease research
• Adipose tissue biology
• Thermogenesis regulation

Background:

• Brown adipose tissue (BAT) is vital for non-shivering thermogenesis and presents a therapeutic target for obesity and metabolic disorders.
• The precise molecular mechanisms governing brown fat development and function are not fully elucidated.

Purpose of the Study:

• To investigate the role of SOX4 in brown adipose tissue development and thermogenic program.
• To elucidate the molecular mechanisms by which SOX4 influences BAT function.

Main Methods:

• Conditional knockout mouse models (Sox4-MKO and Sox4-BKO) were utilized to assess SOX4 function in BAT.
• Overexpression studies were performed to evaluate the effects of increased SOX4 levels on thermogenesis.
• Molecular analyses were conducted to identify downstream targets and regulatory pathways involving SOX4.

Main Results:

• SOX4 depletion in BAT progenitors or mature adipocytes led to "whitened" BAT, hypothermia, and increased susceptibility to diet-induced obesity.
• Overexpression of SOX4 in BAT enhanced thermogenesis and counteracted diet-induced obesity.
• SOX4 was identified as a key transcriptional activator of EBF2, a determinant of brown fat fate.
• PKA-mediated phosphorylation of SOX4 at S235 promotes its nuclear translocation and subsequent EBF2 activation.
• SOX4 and EBF2 cooperate to regulate the expression of genes involved in thermogenesis.

Conclusions:

• SOX4 is indispensable for proper BAT development and the maintenance of its thermogenic program.
• SOX4 acts as an upstream regulator of EBF2, playing a critical role in brown adipocyte differentiation and function.
• Targeting the SOX4-EBF2 axis offers a potential therapeutic strategy for metabolic diseases like obesity.