Our research used glucocorticoids as a medically relevant molecular probe to identify a previously unrecognized ADAMTS1-PTN-Wnt pathway. We elucidated the role of this pathway in regulating adipose precursor cell (APC) behavior to either proliferate or differentiate in response to systemic cues, such as elevated caloric intake. Further, our studies identified the non-muscle myosin protein MYH9 as a key target of this pathway to modulate adipogenesis in vivo. These findings enable strategies toward developing novel therapeutics for obesity and related metabolic disorders.