Maternal High-Fat Diet-Induced Obesity in Offspring: Unraveling Adipose Tissue Dysfunction Mediated by Increased Heat Shock Proteins

Objectives: Maternal weight and diet prior to and during pregnancy significantly affect offspring metabolic health. This study aimed to assess the sex-specific impact of maternal HFD-induced obesity on offspring adiposity, glucose metabolism, and lipid profiles. Methods: Female C57BL6/J mice were fed low or high-fat diets (10% or 45% calories) for 12 weeks. After mating, dams had access to low-fat or HFD during pregnancy and lactation. Post-weaning, offspring had control diet and HFD for 6 weeks. Assessments included body composition, weight, glucose homeostasis, and indirect calorimetry. Adipose tissue (AT) depots were analyzed via histology and RT-PCR. In a separate experiment, brown (wild-type mouse) and white (3T3L1) cell lines underwent adipogenic differentiation and bioenergetics assays. Umbilical cord-derived mesenchymal stem cells (UCMSC) from overweight/obese mothers (n=60) were used to assess gene expression associations with maternal BMI. Results: Male offspring born to HFD fed dams, displayed greater weight gain than females (maternal diet x sex (MD x S), p < 0.05)). Male offspring of HFD-fed dams exhibited elevated fat mass (MD, p< 0.05) and glucose intolerance (MD x S, p < 0.05), while maternal HFD induced differential cholesterol and lipoprotein profiles in males (MD x S, p < 0.05). Adipogenic gene expression and hypertrophy in inguinal white AT were more prominent in males, while heat shock protein (HSP) expression varied with maternal diet and sex (MD x S, p < 0.05). In vitro, brown adipocytes (BA) displayed lower expression of HSPs as differentiation progressed vs higher expression of HSPs in white adipocytes (WA) (p < 0.05). Induction of HSPs increased oxygen consumption rate in WA but not in brown adipocytes (p < 0.05). Additionally, HSP90ab1 gene expression tended to positively correlate with UCMSC of male infant origin (r = 0.34, p < 0.07) whereas no correlations were observed in female infant. Conclusions: In summary, maternal HFD induces sex-specific effects in offspring. Male offspring born to HFD-fed dams show differential HSP expression in adipose tissue. Differentiated UCMSCs suggest an association between HSP90ab1 expression and maternal body mass index, indicating a potential link between maternal diet, HSPs, and adipose tissue. Funding Sources: USDA-ARS Project 6026-51000-012-06 S.