Overexpression of Myl2 Inspires Thermogenic Potential of BAT by Enhancing Adipogenic Differentiation of Brown Adipose Derived Stem Cells

Abstract

Obesity arises from a prolonged state of energy intake exceeding energy expenditure, leading to the “whitening” of brown adipose tissue (BAT) and a decline in metabolic function. To investigate factors contributing to BAT whitening in mice, we used microarray analysis to identify genes differentially expressed in brown adipose-derived stem cells (BADSCs) of wild-type (WT) and ob/ob mice. By intersecting differentially expressed genes between BADSCs and white adipose-derived stem cells (WADSCs) in WT mice, we identified Myl2 as a key gene in BAT function. Myl2 expression showed a 120.8-fold change between ob/ob and WT BADSCs, which was validated by in vivo BAT and in vitro BADSC experiments. Downregulation of Myl2 expression by inhibitor administration significantly reduced the differentiation capacity of BADSCs. Furthermore, overexpression of Myl2 in vitro through adeno-associated virus (AAV) transduction promoted the differentiation of obese mouse-derived BADSCs into brown adipocytes. We further demonstrated the therapeutic potential of Myl2 by administering local injections of Myl2-expressing adeno-associated virus specifically for adipose tissue in ob/ob mice, resulting in improved brown adipose activity and energy metabolism. In summary, this study highlighted the crucial role of Myl2 in BADSC differentiation and BAT function, providing a potential therapeutic target for obesity treatment.