Muscle‐derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress. (6th February 2020)

• Record Type: Journal Article
• Authors: Ost, Mario; Igual Gil, Carla; Coleman, Verena; Keipert, Susanne; Efstathiou, Sotirios; Vidic, Veronika; Weyers, Miriam; Klaus, Susanne
• Is Part Of: EMBO reports. Volume 21:Number 3(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-06
• Subjects: anorexia -- GDF15 -- integrated stress response -- mitochondrial dysfunction -- muscle wasting; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201948804
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Mitochondrial dysfunction promotes metabolic stress responses in a cell‐autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice ( Ucp1 ‐TG) with compromised muscle‐specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1 ‐TG mice show a skeletal muscle‐specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1 ‐TG mice does not affect muscle wasting or transcriptional cell‐autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress‐induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15‐dependent daytime‐restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress‐induced GDF15 in the regulation of systemic energy metabolism. Synopsis: Growth differentiation factor 15 (GDF15) is highly induced during mitochondrial dysfunction, which in turn promotes a diurnal anorectic response that controls systemic metabolic adaptation. Mitochondrial stress promotes GDF15 secretion from skeletal muscle in mice. Local GDF15 action is dispensable for muscle wasting during mitochondrial stress. Mitochondrial stress‐induced GDF15 promotes daytime‐restricted anorectic action. GDF15 ablation abolishes mitochondrial stress induced metabolic flexibility, WAT browning and improved insulin sensitivity. Abstract : Growth differentiation factor 15 (GDF15) is highly induced during mitochondrial dysfunction, which in turn promotes a diurnal anorectic response that controls systemic metabolic adaptation.