"Browning," the appearance and activation of brown-in-white (brite) adipose cells within inguinal white adipose tissue (iWAT), and induction of uncoupling protein 1 (UCP1) correlate with fibroblast growth factor-21 (FGF21)-induced weight loss and glucose homeostasis improvements. Therefore, antiobesity therapies targeting browning and brite adipocyte activation are currently being sought. To test the dependence of weight loss on browning, we examined whether this event was responsible for FGF21-Fc's beneficial effects. Lean and diet-induced obese mice housed at 21°C or 30°C that received FGF21-Fc exhibited similar degrees of body weight reduction and glucose homeostasis improvement. Substantial browning of iWAT occurred only in FGF21-Fc-treated lean mice housed at 21°C. Further, FGF21-Fc-treated Ucp1(-/-) mice showed robust improvements in body weight, glucose homeostasis, and plasma lipids, associated with increased energy expenditure and FGF21-Fc-induced Ppargc1 expression in iWAT. We conclude that FGF21 requires neither UCP1 nor brite adipocytes to elicit weight loss and improve glucose homeostasis.
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