A recent study from researchers in Japan has unveiled a female-specific mechanism that enhances energy expenditure in brown adipose tissue (BAT). The findings, published in Nature Communications on July 14, 2025, indicate that higher activity of the protein PGC-1α in female mice promotes thermogenic activity, yielding significant implications for obesity and diabetes prevention.
Obesity is a pressing global health issue, often leading to diabetes and various metabolic disorders. Notably, while obesity affects both men and women, studies indicate that women tend to be less susceptible to obesity-related diabetes and cardiovascular diseases. Although the biological reasons for this discrepancy remain largely unexplored, the role of BAT—a specialized fat tissue that dissipates energy as heat—has garnered attention. Previous research has suggested that BAT is more metabolically active in females than in males, yet the precise molecular mechanisms driving this difference were not well understood.
To investigate this, a team from the Institute of Science Tokyo, led by Assistant Professor Kazutaka Tsujimoto and collaborators including Professor Tetsuya Yamada, conducted a comprehensive study on the sex-specific activity of BAT. The research team utilized genetically modified mice that lacked PGC-1α specifically in their BAT cells, comparing male and female responses using a variety of analytical methods.
The study revealed that the absence of PGC-1α significantly impaired thermogenic capacity in female mice, evidenced by lower body temperatures during cold exposure. In addition, these mice exhibited decreased oxygen consumption and showed mitochondria with a disorganized internal structure crucial for energy production.
According to the research, PGC-1α plays a pivotal role in activating genes related to de novo lipogenesis (DNL). This is partially mediated by the transcription factor ChREBPβ, which regulates the expression of DNL-related genes. The activation of this pathway leads to increased production of specific phospholipids essential for mitochondrial structure and function, including ether-linked phosphatidylethanolamine and cardiolipin. Without these lipids, mitochondrial efficiency declines, thereby reducing the tissue’s heat-generating capacity.
The research also highlighted the synergistic effect of estrogen on this mechanism. Estrogen signaling was found to enhance the expression of lipid metabolism-related genes in female BAT. As explained by Yamada and Tsujimoto, “This coordination between PGC-1α and estrogen explains why female BAT outperforms male BAT in energy expenditure.”
To further validate their findings, the research team demonstrated that inhibiting ChREBPβ in female BAT reproduced the mitochondrial dysfunction and thermogenic impairment seen with PGC-1α deletion. This phenomenon was not observed in male mice, underscoring the sex-specific nature of the observed mechanisms.
Overall, the study offers fresh insights into how biological sex influences energy metabolism, pinpointing PGC-1α-mediated phospholipid synthesis as a crucial regulator of BAT thermogenesis. These findings could pave the way for new therapeutic interventions aimed at enhancing lipid metabolism to combat obesity and type 2 diabetes. The research sets a promising foundation for exploring metabolic pathways that could improve public health outcomes and lead to innovative treatments.
