Prenatal exposure to high-energy diets (HED) increases the susceptibility to behavioral alterations in the male offspring. We addressed whether prenatal HED primes the transgenerational inheritance of structural brain changes impacting anxiety/depression-like behavior in the offspring. For this, we used female Wistar rats exposed to a HED [cafeteria (CAF) diet,n = 6] or chow [control (CON)n = 6] during development. Anxiety and depression-like behavior were evaluated in filial 1 (F1), filial 2 (F2), and filial 3 (F3) male offspring using the open field (OFT), elevated plus maze, novelty suppressed feeding (NSFT), tail suspension (TST), and forced swimming tests. Structural brain changes were identified by deformation-based morphometry (DBM) and diffusion tensor imaging using ex vivo MRI. We found that the F1, F2, and F3 offspring exposed to CAF diet displayed higher anxious scores including longer feeding latency during the NSFT, and in the closed arms, only F1 offspring showed longer stay on edges during the OFT versus control offspring. DBM analysis revealed that CAF offspring exhibited altered volume in the cerebellum, hypothalamus, amygdala, and hippocampus preserved up to the F3 generation of anxious individuals. Also, F3 CAF anxious exhibited greater fractional anisotropy and axial diffusivity (AD) in the amygdala, greater apparent diffusion coefficient in the corpus callosum, and greater AD in the hippocampus with respect to the control. Our results suggest that prenatal and lactation exposure to HED programs the transgenerational inheritance of structural brain changes related to anxiety-like behavior in the male offspring.

Early life stress (ELS) increases the risk of metabolic disorders such as obesity, as well as neuropsychiatric conditions including depression. Adolescence represents a critical window for metabolic programming, particularly under the influence of ELS and poor dietary habits. Animal models of ELS, such as maternal separation (MS180), induce long-term alterations in hypothalamic-pituitary-adrenal (HPA) axis function, glucose metabolism, and emotionality; however, it remains unclear whether this paradigm increases vulnerability to a chronic metabolic challenge. The aim of this study was to evaluate the effects of MS180 on male rats provided with mild fructose in drinking water starting at postnatal day (P) 21. Control and MS180 (3 h daily, from postnatal day 1 to day 14) rats were given a choice of normal water or a 10% fructose solution for 10 weeks, with standard animal facility-reared (STD) animals serving as controls. Innate emotionality was assessed using the forced swimming test. Animals were implanted with a jugular vein catheter and we evaluated fasting glucose, glucose tolerance, and baseline corticosterone (CORT) levels after one week. Our findings showed that only MS180 + Fructose rats showed a decrease in swimming and increased immobility in the forced swimming test, and previously reported effects of MS180 were only observed when performing simple comparisons. MS180 also increased body weight gain, caloric intake, impaired glucose tolerance, and elevated baseline CORT levels; however, these effects were not exacerbated by fructose. These findings suggest that even low-level fructose exposure during periadolescence may exacerbate behavioral, but not metabolic, vulnerabilities induced by ELS.

Background/Objectives: Human milk contains hormonal and immune bioactives that may vary with maternal, infant and perinatal characteristics including maternal body mass index (BMI), infant sex and birth mode. However, evidence linking these factors remains inconsistent. This exploratory study evaluated if maternal, infant and perinatal characteristics were associated with milk composition. Secondarily, hypothesis-generating analyses examined if milk hormones and cytokines were associated with infant anthropometric Z-scores. Methods: This cross-sectional study included 47 healthy term, exclusively breastfed mother–infant dyads with ages ranging from 0.39 to 6.01 months. Milk hormones (ghrelin, leptin, insulin and glucagon) and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-7, MCP-1, IFN-γ and TNF-α) were quantified using multiplex assays and infant anthropometry was evaluated using WHO Z-scores. Adjusted models included infant age, postpartum maternal BMI, infant sex, and birth mode. Analyte-specific complete-case samples ranged from 37 to 44. All p values were nominal, and false-discovery-rate-adjusted q values assessed multiplicity. Results: Postpartum maternal BMI was positively associated with milk leptin (β = 0.152; p < 0.001; n = 39) and cesarean delivery, relative to vaginal delivery, was associated with lower milk glucagon (β = −0.579; p < 0.001; n = 37). Milk IFN-γ showed nominal exploratory positive associations with weight-for-length Z-score (β = 0.188; p = 0.017; n = 39) and BMI-for-age Z-score (β = 0.211; p = 0.032; n = 39). Conclusions: Postpartum maternal BMI and birth mode showed robust adjusted associations with leptin and glucagon, respectively. The cross-sectional design does not establish temporal direction or clinical relevance. The IFN-γ findings require longitudinal evaluation.