FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes

IF 4.7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Obesity Pub Date : 2025-09-02 DOI:10.1002/oby.70004

Joshua Peterson, Jayashree Jena, Ayushi Sood, Shelly Roitershtein, David Smith, Renata O. Pereira

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引用次数: 0

Abstract

Objective

Our previous studies showed that mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have high metabolic rates and are resistant to diet-induced obesity (DIO) via effects partially mediated by independent actions of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) secretion from BAT. We examined whether FGF21 and GDF15 act synergistically, contributing to the systemic metabolic adaptations reported in OPA1 BKO mice.

Methods

We generated mice simultaneously lacking the Opa1, Fgf21, and Gdf15 genes in thermogenic adipocytes (TKO) and assessed energy homeostasis and glucose metabolism after regular chow or high-fat diet feeding.

Results

Young TKO mice fed regular chow had impaired glucose tolerance, while insulin sensitivity was unchanged. Notably, combined Fgf21 and Gdf15 deletion in OPA1 BKO significantly blunted the resistance to DIO and insulin resistance observed in OPA1 BKO mice.

Conclusions

FGF21 and GDF15 act synergistically to maintain glucose homeostasis and promote resistance to DIO in mice lacking OPA1 in BAT, highlighting the potential of combined therapies using FGF21 and GDF15 for the treatment of metabolic disorders.

Abstract Image

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FGF21和GDF15协同调节产热脂肪细胞中缺乏OPA1的小鼠全身代谢稳态。

目的：我们之前的研究表明，在棕色脂肪组织（BAT）中缺乏线粒体融合蛋白optic atrophy 1 （OPA1 BKO）的小鼠具有高代谢率，并通过部分由BAT分泌的成纤维细胞生长因子21 （FGF21）和生长分化因子15 （GDF15）的独立作用介导的作用对饮食性肥胖（DIO）产生抗性。我们研究了FGF21和GDF15是否协同作用，有助于在OPA1 BKO小鼠中报道的全身代谢适应。方法：我们在产热脂肪细胞（TKO）中培养同时缺乏Opa1、Fgf21和Gdf15基因的小鼠，并在常规食物或高脂肪饮食喂养后评估能量稳态和葡萄糖代谢。结果：正常喂养的幼龄TKO小鼠葡萄糖耐量受损，而胰岛素敏感性不变。值得注意的是，在OPA1 BKO中，Fgf21和Gdf15的联合缺失显著减弱了OPA1 BKO小鼠对DIO的抵抗和胰岛素抵抗。结论：FGF21和GDF15协同作用，维持葡萄糖稳态，促进BAT中缺乏OPA1的小鼠对DIO的抵抗，突出了FGF21和GDF15联合治疗代谢紊乱的潜力。

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来源期刊

Obesity 医学-内分泌学与代谢

CiteScore

11.70

自引率

1.40%

发文量

261

审稿时长

2-4 weeks

期刊介绍： Obesity is the official journal of The Obesity Society and is the premier source of information for increasing knowledge, fostering translational research from basic to population science, and promoting better treatment for people with obesity. Obesity publishes important peer-reviewed research and cutting-edge reviews, commentaries, and public health and medical developments.