Levels of β-klotho determine the thermogenic responsiveness of adipose tissues: involvement of the autocrine action of FGF21

Fibroblast growth factor-21 (FGF21) is a hormonal regulator of metabolism; it promotes glucose oxidation and the thermogenic capacity of adipose tissues. The levels of β-klotho (KLB), the co-receptor required for FGF21 action, are decreased in brown (BAT) and white (WAT) adipose tissues during obesity, diabetes, and lipodystrophy. Reduced β-klotho levels have been proposed to account for FGF21 resistance in these conditions. In this study, we explored whether downregulation of β-klotho affects metabolic regulation and the thermogenic responsiveness of adipose tissues using mice with total (KLB-KO) or partial (KLB-heterozygotes) ablation of β-klotho. We herein show that KLB gene dosage was inversely associated with adiposity in mice. Upon cold exposure, impaired browning of subcutaneous WAT and milder alterations in BAT were associated with reduced KLB gene dosage in mice. Cultured brown and beige adipocytes from mice with total or partial ablation of the KLB gene showed reduced thermogenic responsiveness to β3-adrenergic activation by treatment with CL316,243, indicating that these effects were cell-autonomous. Deficiency in FGF21 mimicked the KLB-reduction-induced impairment of thermogenic responsiveness in brown and beige adipocytes. These results indicate that the levels of KLB in adipose tissues determine their thermogenic capacity to respond to cold and/or adrenergic stimuli. Moreover, an autocrine action of FGF21 in brown and beige adipocytes may account for the ability of the KLB level to influence thermogenic responsiveness.NEW & NOTEWORTHY Reduced levels of KLB (the obligatory FGF21 co-receptor), as occurring in obesity and type 2 diabetes, reduce the thermogenic responsiveness of adipose tissues in cold-exposed mice. Impaired response to β3-adrenergic activation in brown and beige adipocytes with reduced KLB occurs in a cell-autonomous manner involving an autocrine action of FGF21.