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This study is a first of a kind project to investigate circadian arrhythmia as an environmental stress factor and furthermore how such an impact can lead to epigenetically transmitted phenotypes in the offspring. We were successful in showing that circadian arrhythmia via restricted food intake in F0 males led to significant metabolic and behavioral phenotypes in the unexposed F1 generation. We hereby observed that phenotypical alterations such as food intake amounts and corticosterone levels can be influenced by circadian arrhythmia of the fathers. This was especially interesting since the F1 offspring was completely unexposed of any environmental factors. Diese Promotionsarbeit beschäftigt sich mit dem Zusammenhang von väterlichen Störungen der inneren Uhr im Körper und den daraus folgenden körperlichen Auswirkungen auf die Nachkommen. Wir haben hierbei herausgefunden, dass schon kurze Phasen von starken Umwelteinflüssen (wie der Störung der inneren Uhr) Einfluss auf die Kinder haben kann, selbst wenn diese niemals dem Umwelteinfluss selbst ausgesetzt wurden. Dies sieht man im Mausmodell sowohl an einer erhöhter Futterzunahme als auch an veränderten metabolischen Werten wie Glucose- und Cortisolkonzentrationen.

Funder: European Foundation for the Study of Diabetes (EFSD); doi: https://doi.org/10.13039/501100001648, The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.