Inflammation as a Sex-Specific Mediator in the Relationship between Maternal and Offspring Obesity in C57Bl/6J Mice

Simple Summary The developmental origins of health and disease (DOHaD) hypothesis posits that stressful exposures during early development alter biological processes and increase the risk for chronic disease later in life. A widely accepted example of the DOHaD hypothesis is the strong link between exposure to maternal obesity and the development of obesity in offspring. Mechanisms explaining this relationship are not fully understood. Therefore, this study investigates both the hypothalamus and inflammation as important variables in the relationship between maternal and offspring obesity. The hypothalamus is the master regulator of energy homeostasis in the body. Inflammation in the hypothalamus is associated with the development of obesity. We used an established mouse model of maternal obesity to study body composition, energy homeostasis, and inflammation in male and female offspring. Like in our previous work, both male and female offspring exposed to maternal obesity had a phenotype consistent with energy excess. We found decreased markers of inflammation in the body and hypothalamus of offspring exposed to maternal obesity compared with offspring exposed to a control pregnancy. Inflammation was different between male and female offspring. Future studies focused on understanding how inflammation affects hypothalamic development in males and females may provide neuroprotective strategies to improve hypothalamic function thereby decreasing obesity risk.Abstract Maternal obesity is a well-established risk factor for offspring obesity development. The relationship between maternal and offspring obesity is mediated in part by developmental programming of offspring metabolic circuitry, including hypothalamic signaling. Dysregulated hypothalamic inflammation has also been linked to development of obesity. We utilized an established C57Bl/6J mouse model of high-fat, high-sugar diet induced maternal obesity to evaluate the effect of maternal obesity on systemic and hypothalamic TNF-alpha, IL-6, and IL-1 beta levels in neonatal and adult offspring. The offspring of dams with obesity demonstrated increased adiposity and decreased activity compared to control offspring. Maternal obesity was associated with decreased plasma TNF-alpha, IL-6 and IL-1 beta in adult female offspring and decreased plasma IL-6 in neonatal male offspring. Neonatal female offspring of obese dams had decreased TNF-alpha gene expression in the hypothalamus compared to control females, while neonatal and adult male offspring of obese dams had decreased IL-6 gene expression in the hypothalamus compared to control males. In summary, our results highlight important sex differences in the inflammatory phenotype of offspring exposed to maternal obesity. Sex-specific immunomodulatory mechanisms should be considered in future efforts to develop therapeutic interventions for obesity prevention and treatment.