Metabolic effects of early life stress and pre‐pregnancy obesity are long lasting and sex specific in mice

Early life stress (ELS) is associated with metabolic, cognitive, and psychiatric diseases and has a very high prevalence, highlighting the urgent need for a better understanding of the versatile physiological changes and identification of predictive biomarkers. In addition to programming the hypothalamic–pituitary–adrenal (HPA) axis, ELS may also affect the gut microbiota and metabolome, opening up a promising research direction for identifying early biomarkers of ELS‐induced (mal)adaptation. Other factors affecting these parameters include maternal metabolic status and diet, with maternal obesity shown to predispose offspring to later metabolic disease. The aim of the present study was to investigate the long‐term effects of ELS and maternal obesity on the metabolic and stress phenotype of rodent offspring. To this end, offspring of both sexes were subjected to an adverse early‐life experience, and their metabolic and stress phenotypes were examined. In addition, we assessed whether a prenatal maternal and an adult high‐fat diet (HFD) stressor further shape observed ELS‐induced phenotypes. We show that ELS has long‐term effects on male body weight (BW) across the lifespan, whereas females more successfully counteract ELS‐induced weight loss, possibly by adapting their microbiota, thereby stabilizing a balanced metabolome. Furthermore, the metabolic effects of a maternal HFD on BW are exclusively triggered by a dietary challenge in adult offspring and are more pronounced in males than in females. Overall, our study suggests that the female microbiota protects against an ELS challenge, rendering them more resilient to additional maternal‐ and adult nutritional stressors than males. Early life stress (ELS) and maternal obesity are associated with metabolic, cognitive, and psychiatric diseases, highlighting the urgent need for a better understanding of the versatile physiological changes and identification of predictive biomarkers, such as changes in the gut microbiota and metabolome. In the current manuscript, we show that ELS and maternal obesity have long‐term effects on male body weight (BW) across the lifespan, whereas females more successfully counteract weight loss by adaptive changes of their microbiota.