FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis

TLDR

White adipose tissue can convert to a brown‑like state under prolonged cold or β‑adrenergic stimulation, forming UCP1‑positive, multilocular adipocytes that boost thermogenic capacity. The study demonstrates that fibroblast growth factor 21 (FGF21) physiologically drives this thermogenic recruitment of white adipose depots. Adipose‑derived FGF21 acts in an autocrine/paracrine manner to upregulate UCP1 and other thermogenic genes, partly by increasing PGC‑1α protein levels independently of its mRNA. FGF21‑deficient mice exhibit impaired cold adaptation and reduced WAT browning, confirming that FGF21 activates and expands the thermogenic machinery to protect against hypothermia.

Abstract

Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to β-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing adipose tissue PGC-1α protein levels independently of mRNA expression. We conclude that FGF21 acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.