Abstract
Whether a pharmacological strategy can replicate the broad improvement of human cardiometabolic health associated with brown fat (BAT) remains an active area of investigation. Here, we show that adipokine Adissp activates both glucose disposal and energy expenditure within white fat, delivering pleiotropic metabolic benefits. Endogenous Adissp is essential for glucose homeostasis. Administration of recombinant Adissp (rAdissp) protein sustainably normalizes hyperglycemia in type 1 and type 2 diabetic mice by activating insulin-independent Akt signaling. Furthermore, rAdissp robustly induces a comprehensive thermogenic program, which not only reduces body weight but also independently ameliorates a wide range of cardiometabolic diseases. Thus, a single adipokine, Adissp, recapitulates the systemic metabolic benefits of BAT and essentially functions as a cold mimetic. These findings reveal an unanticipated insulin-independent glucose uptake pathway and offer mechanistic insights into the cardiometabolic protection linked to human BAT. Adissp and its analogs represent a promising class of therapeutic agents to concurrently and synergistically treat diabetes and cardiometabolic diseases.