Stress-induced FGF21 and GDF15 in obesity and obesity resistance. (November 2021)

• Record Type: Journal Article
• Authors: Keipert, Susanne; Ost, Mario
• Is Part Of: Trends in endocrinology and metabolism. Volume 32:Number 11(2021)
• Page Start: 904
• Page End: 915
• Publication Date: 2021-11
• Subjects: energy balance -- mitochondrial integrated stress response -- obesity resistance -- FGF21 -- GDF15 -- muscle -- adipose tissue; Endocrinology -- Periodicals; Metabolism -- Periodicals; Metabolism; 616.4
• DOI: 10.1016/j.tem.2021.08.008
• Languages: English
• ISSNs: 1043-2760

Abstract

Abstract : Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are established as stress-responsive cytokines that can modulate energy balance by increasing energy expenditure or suppressing food intake, respectively. Despite their pharmacologically induced beneficial effects on obesity and comorbidities, circulating levels of both cytokines are elevated during obesity and related metabolic complications. On the other hand, endocrine crosstalk via FGF21 and GDF15 was also reported to play a crucial role in genetically modified mouse models of mitochondrial perturbations leading to diet-induced obesity (DIO) resistance. This review aims to dissect the complexities of endogenous FGF21 and GDF15 action in obesity versus DIO resistance for the regulation of energy balance in metabolic health and disease. Highlights: Supraphysiological levels of circulating fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) induced by overexpression or pharmacological administration protect against obesity and promote metabolic health. Endogenous FGF21 and GDF15 are simultaneously induced in several tissues and in the circulation of obese mice and humans due to elevated cellular stress. Despite high circulating FGF21 and GDF15 levels, obese mice and humans remain responsive to high doses of exogenous FGF21 and GDF15, supporting the notion that obesity is neither an FGF21 nor a GDF15 resistance state. GDF15 and FGF21 expression is highly induced by chronic mild mitochondrial dysfunction that was shown to promote beneficial effects on metabolism in mutant mouse models, including resistance to diet-induced obesity. Dysregulation of mitochondrial efficiency, no matter which protein or pathway is affected, is able to protect from diet-induced obesity and insulin resistance.