Brown adipose tissue (BAT), acts as a thermoregulator by uncoupling oxidative phosphorylation through uncoupling protein 1 (UCP1) and holds the promise of enhancing energy expenditure for the treatment of metabolic diseases. Adrenergic signaling is viewed as a key regulator of thermogenesis and UCP1 expression in BAT, while also operating as a potent contractile stimulator in muscle. The muscle-like gene expression patterns in BAT have not been attributed to any functional role in thermoregulation. However, we have demonstrated that upon adrenergic stimulation, BAT utilizes key components of muscular contractile machinery, specifically the actomyosin network, to generate tensional responses. Furthermore, we have found that during differentiation, brown and beige adipocytes have a unique type II myosin (Myh) expression pattern. Disruption of the actomyosin network using type II myosin inhibitors such as blebbistatin or 2,3BDM results in a decrease in brown adipose function. Conversely, we are interested in determining if we can stimulate brown and beige adipose tissue by increasing myosin activity. Atomwise uses artificial intelligence for structure-based drug discovery and through the AIMS award program we are screening a library of several million compounds targeted at type Myh4 and Myh11.From our screen we will determine if increasing the ATPase activity of the myosin isoforms results in an increase in brown and beige adipose function as a result of increased UCP1 expression and cellular respiration.

Activating brown and beige adipose tissue with type II myosin small molecule activators

2019 Fall National Meeting

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