TY  - JOUR
A1  - Ost, Mario
A1  - Igual Gil, Carla
A1  - Coleman, Verena
A1  - Keipert, Susanne
A1  - Efstathiou, Sotirios
A1  - Vidic, Veronika
A1  - Weyers, Miriam
A1  - Klaus, Susanne
T1  - Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress
JF  - EMBO reports
N2  - 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.
KW  - anorexia
KW  - GDF15
KW  - integrated stress response
KW  - mitochondrial dysfunction
KW  - muscle wasting
Y1  - 2020
U6  - https://doi.org/10.15252/embr.201948804
SN  - 1469-221X
SN  - 1469-3178
VL  - 21
IS  - 3
PB  - Wiley
CY  - Hoboken
ER  -