Morales, P. E.; Tong, W.; Vishvanath, L.; Leander, D. C.; Wade, T. E.; Hallaron, D. S.; El, K.; Hollander, R. A.; Truong, A.; Wothe, D.; Elmquist, G.; Russo, M.; Hamilos, H. K.; Dewyer, G. E.; Crewe, C.; Holland, W. L.; Koves, T. R.; Muoio, D. M.; D'Alessio, D. A.; Campbell, J. E.; Cannavino, J.; Shao, M.; Gupta, R. K.

Pathologic white adipose tissue (WAT) remodeling, characterized by fibrosis, inflammation, and adipocyte dysfunction, is a hallmark and driver of metabolic disease in obesity1. Here, we show that legacy effects of early physiological or pharmacological interventions driving adaptive adipose remodeling can mitigate maladaptive WAT remodeling and metabolic dysfunction when developing obesity later in life. Cold exposure or beta3-adrenergic receptor (beta3AR) agonism (CL316,243) induced thermogenic remodeling of WAT in male mice. After a prolonged recovery at room temperature, trained epididymal WAT reverted to an energy-storing state but retained a population of adipocytes resembling metabolically flexible visceral adipocytes found in human metabolically healthy obesity. The legacy of the antecedent treatment conferred lasting protection against glucose intolerance when later developing high fat diet (HFD)-induced obesity, with insulin sensitivity persisting for at least 20 weeks of overnutrition. This metabolic resilience was accompanied by healthy epididymal WAT expansion with reduced fibrosis and inflammation. Our findings demonstrate that short-term interventions, without genetic manipulation, can train adipose tissue, enhancing its long-term plasticity and conferring durable protection against future obesity-associated insulin resistance.