Starvation-induced changes in somatic Insulin/IGF-1R signaling drive metabolic programming across generations

Exposure to adverse nutritional and metabolic environments during critical periods of development can exert long-lasting effects on health outcomes of an individual and its descendants. Although such metabolic programming has been observed in multiple species and in response to distinct nutritional stressors, conclusive insights into signaling pathways and mechanisms responsible for initiating, mediating and manifesting changes to metabolism and behavior across generations remain scarce. By employing a multigenerational starvation paradigm in C. elegans, we show that starvation-induced changes in DAF-16/FoxO activity, the main downstream target of insulin/IGF-1 receptor signaling, are responsible for metabolic programming phenotypes. Tissue-specific depletion of DAF-16/FoxO during distinct developmental time points further demonstrates that DAF-16/FoxO acts in somatic tissues, but not directly in the germline, to both initiate and manifest metabolic programming. In conclusion, our study deciphers multifaceted and critical roles of highly conserved insulin/IGF-1 receptor signaling in determining health outcomes and behavior across generations. Differential gene expression analysis of effects of L1 starvation on adult transcriptome (F4), as well as on the transcriptome of great-grandchilden (F4+3)