Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, Catalonia, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Barcelona, Spain.
Am J Physiol Endocrinol Metab. 2021 Apr 1;320(4):E822-E834. doi: 10.1152/ajpendo.00270.2020. Epub 2021 Feb 22.
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. 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.
成纤维细胞生长因子 21（FGF21）是代谢的激素调节剂；它促进葡萄糖氧化和脂肪组织的产热能力。在肥胖、糖尿病和脂肪营养不良期间，β-klotho（KLB）的水平（FGF21 作用所需的共受体）在棕色（BAT）和白色（WAT）脂肪组织中降低。有人提出，在这些情况下，降低β-klotho 水平是 FGF21 抵抗的原因。在这项研究中，我们使用完全（KLB-KO）或部分（KLB 杂合子）消融β-klotho 的小鼠探索了β-klotho 的下调是否会影响代谢调节和脂肪组织的产热反应。我们在此表明，KLB 基因剂量与小鼠的肥胖程度呈负相关。在冷暴露下，皮下 WAT 棕色化受损和 BAT 改变较轻与小鼠 KLB 基因剂量降低有关。用 CL316,243 处理时，来自完全或部分消融 KLB 基因的小鼠的培养棕色和米色脂肪细胞显示出对β3-肾上腺素能激活的产热反应性降低，表明这些作用是细胞自主的。FGF21 缺乏模拟了 KLB 减少诱导的棕色和米色脂肪细胞产热反应性受损。这些结果表明，脂肪组织中 KLB 的水平决定了它们对冷和/或肾上腺素刺激的产热能力。此外，FGF21 在棕色和米色脂肪细胞中的自分泌作用可能解释了 KLB 水平影响产热反应性的能力。肥胖和 2 型糖尿病中发生的 KLB 水平降低（必需的 FGF21 共受体）会降低冷暴露小鼠脂肪组织的产热反应性。棕色和米色脂肪细胞中 KLB 减少导致对β3-肾上腺素能激活的反应受损，以细胞自主的方式发生，涉及 FGF21 的自分泌作用。
