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

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-α, IL-6, and IL-1ß 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-α, IL-6 and IL-1ß in adult female offspring and decreased plasma IL-6 in neonatal male offspring. Neonatal female offspring of obese dams had decreased TNF-α 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.

Female and male C57BL/6J offspring exposed to maternal obesogenic diet develop altered hypothalamic energy metabolism in adulthood.

Maternal obesity is exceedingly common and strongly linked to offspring obesity and metabolic disease. Hypothalamic function is critical to obesity development. Hypothalamic mechanisms causing obesity following exposure to maternal obesity have not been elucidated. Therefore, we studied a cohort of C57BL/6J dams, treated with a control or high-fat-high-sugar diet, and their adult offspring to explore potential hypothalamic mechanisms to explain the link between maternal and offspring obesity. Dams treated with obesogenic diet were heavier with mild insulin resistance, which is reflective of the most common metabolic disease in pregnancy. Adult offspring exposed to maternal obesogenic diet had no change in body weight but significant increase in fat mass, decreased glucose tolerance, decreased insulin sensitivity, elevated plasma leptin, and elevated plasma thyroid-stimulating hormone. In addition, offspring exposed to maternal obesity had decreased energy intake and activity without change in basal metabolic rate. Hypothalamic neurochemical profile and transcriptome demonstrated decreased neuronal activity and inhibition of oxidative phosphorylation. Collectively, these results indicate that maternal obesity without diabetes is associated with adiposity and decreased hypothalamic energy production in offspring. We hypothesize that altered hypothalamic function significantly contributes to obesity development. Future studies focused on neuroprotective strategies aimed to improve hypothalamic function may decrease obesity development.NEW & NOTEWORTHY Offspring exposed to maternal diet-induced obesity demonstrate a phenotype consistent with energy excess. Contrary to previous studies, the observed energy phenotype was not associated with hyperphagia or decreased basal metabolic rate but rather decreased hypothalamic neuronal activity and energy production. This was supported by neurochemical changes in the hypothalamus as well as inhibition of hypothalamic oxidative phosphorylation pathway. These results highlight the potential for neuroprotective interventions in the prevention of obesity with fetal origins.

Excess sucrose intake during pregnancy programs fetal brain glucocorticoid receptor expression in female but not male C57Bl/6J mice.

BACKGROUND: Sex-specific mechanisms explaining the association between mothers with obesity and the development of obesity in children are poorly characterized. Permanent changes in fetal brain glucocorticoid receptor (GR) expression caused by exposure to overnutrition in utero may program aberrant energy homeostasis, thereby predisposing the offspring to obesity. This study explores sex differences in brain GR expression using an established mouse model of overnutrition during pregnancy. METHODS: Female C57Bl/6J mice were fed control (CON) or high-fat-high-sucrose (HFHS) diets. Dam cholesterol, insulin, and triglycerides were measured by colorimetric assays. Fetal corticosterone exposure was measured by placental Abca1, Hsd11ß1, Hsd11ß2, and brain Nr3c1 (GR); Pomc expression measured by RT-qPCR. RESULTS: Female, but not male, HFHS fetuses had 46% decreased brain GR and twofold increased Pomc expression. There was decreased Abca1 and Hsd11ß1 but not Hsd11ß2 expression in HFHS placentas. Caloric and sucrose intake, but not fat intake, in dams inversely correlated with fetal GR expression in both sexes. Excess sucrose consumption by dams inversely correlated with female fetal GR and directly correlated with female fetal Pomc expression. CONCLUSIONS: Excess sucrose consumption in pregnant dams caused lower GR and higher Pomc expression in the female fetal brain. Clinical investigation of excess sucrose intake during pregnancy and its subsequent effect on hypothalamic-pituitary-adrenal axis activity and appetite in offspring may lead to novel, sex-specific obesity prevention strategies in the development of obesity in children.

Maternal High-Fat-High-Carbohydrate Diet-Induced Obesity Is Associated with Increased Appetite in Peripubertal Male but Not Female C57Bl/6J Mice.

Diet-induced maternal obesity might play a critical role in altering hypothalamic development, predisposing the offspring to obesity and metabolic disease later in life. The objective of this study was to describe both phenotypic and molecular sex differences in peripubertal offspring energy homeostasis, using a mouse model of maternal obesity induced by a high-fat-high-carbohydrate (HFHC) diet. We report that males, not females, exposed to a maternal HFHC diet had increased energy intake. Males exposed to a maternal HFHC diet had a 15% increased meal size and a 46% increased frequency, compared to the control (CON) males, without a change in energy expenditure. CON and HFHC offspring did not differ in body weight, composition, or plasma metabolic profile. HFHC diet caused decreased hypothalamic glucocorticoid expression, which was further decreased in males compared to females. Maternal weight, maternal caloric intake, and male offspring meal frequency were inversely correlated with offspring hypothalamic insulin receptor (IR) expression. There was a significant interaction between maternal-diet exposure and sex in hypothalamic IR. Based on our preclinical data, we suggest that interventions focusing on normalizing maternal nutrition might be considered to attenuate nutritional influences on obesity programming and curb the continuing rise in obesity rates.

Integrative effects of dystrophin loss on metabolic function of the mdx mouse.

Duchenne muscular dystrophy (DMD) is a disease marked by the development of skeletal muscle weakness and wasting. DMD results from mutations in the gene for the cytoskeletal protein dystrophin. The loss of dystrophin expression is not limited to muscle weakness but has multiple systemic consequences. Managing the nutritional requirements is an important aspect of the clinical care of DMD patients and is complicated by the poor understanding of the role of dystrophin, and dystrophic processes, in regulating metabolism. Here, we show that mdx mice, a genetic model of DMD, have significantly reduced fat mass relative to wild type C57BL/10. The alteration in body composition is independent of the presence of skeletal muscle disease, as it is still present in mice with transgenic expression of a fully-functional dystrophin in skeletal muscle. Furthermore, mdx mice do not increase their fat mass or body weight when housed under thermoneutral conditions, in marked contrast to C57BL/10 mice. We also demonstrated that mdx mice have significantly reduced fat metabolism and altered glucose uptake. These significant metabolic changes in dystrophic mice implicate dystrophin as an important regulator of metabolism. Understanding the metabolic functions of dystrophin is important for managing the nutritional needs of DMD patients.