Prenatal stress induces sex- and tissue-specific alterations in insulin pathway of Wistar rats offspring

Prenatal stress may lead to tissue- and sex-specific cardiometabolic disorders in the offspring through imbalances in the insulin signaling pathway. Therefore, we aimed to determine the sex-specific adaptations of prenatal stress on the insulin signaling pathway of cardiac and hepatic tissue of adult offspring Wistar rats. Wistar pregnant rats were divided into control and stress groups. Unpredictable stress protocol was performed from the 14th to the 21st day of pregnancy. After lactation, the dams were euthanized, and blood was collected for corticosterone measurement and the offspring were separated into four groups according to sex and intervention (n = 8/group). At 90 days old, the offspring were submitted to an oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT). After euthanasia, blood collection was used for biochemical analysis and the left ventricle and liver were used for protein expression and histological analysis. Stress increased maternal corticosterone levels. It also increased glucose concentration in both OGTT and ITT and reduced insulin receptor (Ir beta) and insulin receptor substrate-1 (IRS1) activation, while reducing the insulin receptor inhibition [protein tyrosine phosphatase 1B (PTP1B)] in the liver of male offspring at 90 days old, without repercussions in cardiac tissue. Moreover, female offspring submitted to prenatal stress exhibited reduced fatty acid uptake, with lower hepatic CD36 expression, reduced high-density lipoprotein cholesterol (cHDL), and increased Castelli risk indexes I and II. Unpredictable prenatal stress evoked reduced insulin sensitivity and liver-specific impairment in insulin signaling activation in male while increasing markers of cardiovascular risk in females. NEW & NOTEWORTHY Prenatal stress may contribute to tissue-specific programming, especially in the liver. Our results showed that, although there were no repercussions to stress in cardiac tissue at 90 days old, prenatal stress induces a glucose intolerance phenotype with insulin signaling pathway alterations in the liver of male offspring at 90 days old. Furthermore, the prenatal stress altered lipid profile and increased cardiovascular risk in female offspring.