@article{OstIgualGilColemanetal.2020,
  author    = {Ost, Mario and Igual Gil, Carla and Coleman, Verena and Keipert, Susanne and Efstathiou, Sotirios and Vidic, Veronika and Weyers, Miriam and Klaus, Susanne},
  title     = {Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress},
  series = {EMBO reports},
  volume    = {21},
  journal   = {EMBO reports},
  number    = {3},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {1469-221X},
  doi       = {10.15252/embr.201948804},
  pages     = {14},
  year      = {2020},
  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.},
  language  = {en}
}
@article{IgualGilJariusvonKriesetal.2017,
  author    = {Igual Gil, Carla and Jarius, Mirko and von Kries, Jens P. and Rohlfing, Anne-Kartin},
  title     = {Neuronal Chemosensation and Osmotic Stress Response Converge in the Regulation of aqp-8 in C. elegans},
  series = {Frontiers in physiology},
  volume    = {8},
  journal   = {Frontiers in physiology},
  publisher = {Frontiers Research Foundation},
  address   = {Lausanne},
  issn      = {1664-042X},
  doi       = {10.3389/fphys.2017.00380},
  pages     = {12},
  year      = {2017},
  abstract  = {Aquaporins occupy an essential role in sustaining the salt/water balance in various cells types and tissues. Here, we present new insights into aqp-8 expression and regulation in Caenorhabditis elegans. We show, that upon exposure to osmotic stress, aqp-8 exhibits a distinct expression pattern within the excretory cell compared to other C. elegans aquaporins expressed. This expression is correlated to the osmolarity of the surrounding medium and can be activated physiologically by osmotic stress or genetically in mutants with constitutively active osmotic stress response. In addition, we found aqp-8 expression to be constitutively active in the TRPV channel mutant osm-9(ok1677). In a genome-wide RNAi screen we identified additional regulators of aqp-8. Many of these regulators are connected to chemosensation by the amphid neurons, e.g., odr-10 and gpa-6, and act as suppressors of aqp-8 expression. We postulate from our results, that aqp-8 plays an important role in sustaining the salt/water balance during a secondary response to hyper-osmotic stress. Upon its activation aqp-8 promotes vesicle docking to the lumen of the excretory cell and thereby enhances the ability to secrete water and transport osmotic active substances or waste products caused by protein damage. In summary, aqp-8 expression and function is tightly regulated by a network consisting of the osmotic stress response, neuronal chemosensation as well as the response to protein damage. These new insights in maintaining the salt/water balance in C. elegans will help to reveal the complex homeostasis network preserved throughout species.},
  language  = {en}
}
@article{KlausIgualGilOst2021,
  author    = {Klaus, Susanne and Igual Gil, Carla and Ost, Mario},
  title     = {Regulation of diurnal energy balance by mitokines},
  series = {Cellular and molecular life sciences : CMLS},
  volume    = {78},
  journal   = {Cellular and molecular life sciences : CMLS},
  number    = {7},
  publisher = {Springer International Publishing AG},
  address   = {Cham (ZG)},
  issn      = {1420-682X},
  doi       = {10.1007/s00018-020-03748-9},
  pages     = {3369 -- 3384},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{IgualGilOstKaschetal.2019,
  author    = {Igual Gil, Carla and Ost, Mario and Kasch, Juliane and Schumann, Sara and Heider, Sarah and Klaus, Susanne},
  title     = {Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice},
  series = {Scientific reports},
  volume    = {9},
  journal   = {Scientific reports},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/s41598-019-56922-w},
  pages     = {9},
  year      = {2019},
  abstract  = {Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57BI/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.},
  language  = {en}
}
@article{OttenKnoxBouldayetal.2018,
  author    = {Otten, Cecile and Knox, Jessica and Boulday, Gwenola and Eymery, Mathias and Haniszewski, Marta and Neuenschwander, Martin and Radetzki, Silke and Vogt, Ingo and Haehn, Kristina and De Luca, Coralie and Cardoso, Cecile and Hamad, Sabri and Igual Gil, Carla and Roy, Peter and Albiges-Rizo, Corinne and Faurobert, Eva and von Kries, Jens P. and Campillos, Monica and Tournier-Lasserve, Elisabeth and Derry, William Brent and Abdelilah-Seyfried, Salim},
  title     = {Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations},
  series = {EMBO molecular medicine},
  volume    = {10},
  journal   = {EMBO molecular medicine},
  number    = {10},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {1757-4676},
  doi       = {10.15252/emmm.201809155},
  pages     = {17},
  year      = {2018},
  abstract  = {Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.},
  language  = {en}
}