PGC-1α mediates differentiation of mesenchymal stem cells to brown adipose cells.

AIM: Mesenchymal stem cells (MSCs) are a multipotent cell type that can differentiate into non-hematopoietic cells, such as adipocytes. Adipocyte tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals. White adipose tissue is the primary site for triglyceride storage, while brown adipose tissue is specialized in energy expenditure. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) controls several aspects of mitochondrial biogenesis. In this study, we hypothesized that PGC-1α plays a role in brown fat differentiation of MSCs.

METHODS: Immortalized human MSCs were infected with adenovirus carrying PGC-1α cDNA to create PGC-1α-expressing MSCs.

RESULTS: The genetic profiling of PGC-1α-expressing MSCs shows the significant increase of genes related to mitochondrial functions and lipid metabolism compared to that of MSCs. When expressed in MSCs, PGC-1α activates robust mitochondrial biogenesis and respiration. The increase of oxygen consumption and reactive oxygen species represents a cellular readout of increased activity of the respiratory chain. The expression of thermogenic markers, such as cytochrome C and complex II, was significantly increased in MSCs with treatment of adenovirus expressing PGC-1α. Moreover, PGC-1α markedly inhibited the osteogenesis of MSCs under osteogenic induction. During adipogenesis, PGC-1α-expressing MSCs showed a significant increase in brown fat markers and a decrease in white fat markers. Notably, PGC-1α knockdown inhibited adipocyte differentiation of MSCs.

CONCLUSIONS: In summary, our data reveal an important role of PGC-1α in promoting brown fat differentiation of MSCs, and provide a new therapeutic approach for the treatment of obesity.