White adipose tissue is a major energy reservoir and its unhealthy expansion often results in severe fat tissue dysfunction and induces undesirable ectopic fat deposition. Since brown/beige adipocytes can consume excess energy for thermogenesis, strategies for beige fat biogenesis have attracted much attention.

Hypothermia, exercise and fasting are well known to induce beige fat generation in mammals. These mechanisms could induce white adipocyte trans-differentiation into brown adipocytes, a process called “beiging”. It has been reported that white and beige adipocytes are from common precursor cells (adipose tissue derived mesenchymal stem cells, ADSCs). However, to specifically promote the generation of beige adipocytes has been a long-lasting goal of the scientific community.

In a study published online in PNAS on Jan. 17, Dr. LIU Keli from Drs. SHI Yufang and WANG Ying's group at the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences and the collaborators discovered a critical role of stearoyl-coenzyme A desaturase 1 (Scd1) and succinate in promoting beige adipogenesis of adipose precursor cells, providing a new potential target for the treatment of obesity and related metabolic diseases.

This finding was originated from the analysis of various mice with deficiency of Scd1, a rate-limiting enzyme for the synthesis of monounsaturated fatty acids.

By generating a series of Scd1-related transgenic mice and performing various in vitro differentiation experiments, the researchers found a key role of mitochondrial complex II activity in dictating the beige adipogenesis of Scd1 deficient ADSCs. Specific deletion of Scd1 only in ADSCs was able to provide resistance to obesity and type 2 diabetes.

Furthermore, using metabolomics and transcriptomics analysis, the researchers demonstrated that it was succinate that sharpened the activity of mitochondrial complex II and promoted the beige adipogenesis of adipose precursor cells. More importantly, the addition of succinate in drinking water can augment the formation of beige fat in vivo, and thus protect mice from high-fat diet induced obesity.

This study highlighted a new negative regulatory relationship between Scd1 and succinate during adipogenesis, holding great potentials for combating obesity.

In mammals, adipose tissue has a crucial role in regulating systemic energy homeostasis. In addition to the disruption of the balance between food intake and energy expenditure, the disturbance of the balance between white adipose tissue and brown/beige adipose tissue can also cause obesity and subsequent metabolic diseases.

Succinate promotes beige adipogenesis of ADSCs. (Image by Drs. SHI Yufang and WANG Ying's group)