TY - JOUR A1 - Klaus, Susanne A1 - Igual Gil, Carla A1 - Ost, Mario T1 - Regulation of diurnal energy balance by mitokines JF - Cellular and molecular life sciences : CMLS N2 - The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease. KW - Mitochondria KW - FGF21 KW - GDF15 KW - Circadian rhythm KW - Hormones KW - Nutrition Y1 - 2021 U6 - https://doi.org/10.1007/s00018-020-03748-9 SN - 1420-682X SN - 1420-9071 VL - 78 IS - 7 SP - 3369 EP - 3384 PB - Springer International Publishing AG CY - Cham (ZG) ER - 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 -