Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress
- 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-dependentMitochondrial 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.…
Author details: | Mario OstORCiD, Carla Igual GilORCiDGND, Verena Coleman, Susanne KeipertORCiD, Sotirios Efstathiou, Veronika Vidic, Miriam Weyers, Susanne KlausORCiDGND |
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DOI: | https://doi.org/10.15252/embr.201948804 |
ISSN: | 1469-221X |
ISSN: | 1469-3178 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/32026535 |
Title of parent work (English): | EMBO reports |
Publisher: | Wiley |
Place of publishing: | Hoboken |
Publication type: | Article |
Language: | English |
Date of first publication: | 2020/02/06 |
Publication year: | 2020 |
Release date: | 2023/11/10 |
Tag: | GDF15; anorexia; integrated stress response; mitochondrial dysfunction; muscle wasting |
Volume: | 21 |
Issue: | 3 |
Article number: | e48804 |
Number of pages: | 14 |
Funding institution: | German Research Foundation (DFG)German Research Foundation (DFG); [KL613/23-1]; COST (European Cooperation in Science and; Technology)European Cooperation in Science and Technology (COST); [CA15203 MitoEAGLE] |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
DDC classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Peer review: | Referiert |
Publishing method: | Open Access / Hybrid Open-Access |
License (German): | CC-BY - Namensnennung 4.0 International |