Abstract
Pathological states in the early life environment of mammalian offspring, including maternal obesity and intrauterine overnutrition, can induce obesity and metabolic disorder later in life. Leptin resistance caused by upregulation of Socs3 in the hypothalamus of offspring was believed to be the main mechanism of this effect. In this study, obese mother (OM) and lean mother (LM) models were generated by feeding C57BL/6N female mice a high-fat diet or standard lean diet, respectively. Additionally, an obese mother with intervention (OMI) model was generated by injecting the high-fat diet group with Socs3-shRNA lentivirus during early pregnancy. The offspring of the groups was correspondingly named OM-F1 , LM-F1 , and OMI-F1 , representing progeny mouse models of different early life environments. The offspring were fed a high-fat diet to test their propensity for obesity. The body weight, food intake and fat accumulation were higher, while glucose intolerance and insulin resistance were worse in the OM-F1 group than LM-F1 group. By contrast, the obesity phenotype, hyperphagia and metabolic disorder were alleviated in the OMI-F1 group compared with the OM-F1 group. The mechanism was identified that downregulation of hypothalamic SOCS3 resulted in an increased level of p-STAT3 and p-JAK2, which ameliorated the leptin resistance and restored the lean expression of appetite regulatory genes (Pomc and Agrp) in hypothalamus of OMI-F1 group. Taken together, these results indicate that reducing maternal Socs3 expression during pregnancy can attenuate obesity caused by the early life environment in mice, which may inspire therapies that enable obese mothers to bear metabolically healthy children.