Sex-specific effects of maternal metformin intervention during glucose-intolerant obese pregnancy on body composition and metabolic health in aged mouse offspring.

AIMS/HYPOTHESIS: Metformin is increasingly used to treat gestational diabetes (GDM) and pregnancies complicated by pregestational type 2 diabetes or polycystic ovary syndrome but data regarding long-term offspring outcome are lacking in both human studies and animal models. Using a mouse model, this study investigated the effects of maternal metformin intervention during obese glucose-intolerant pregnancy on adiposity, hepatic steatosis and markers of metabolic health of male and female offspring up to the age of 12 months. METHODS: C57BL/6J female mice were weaned onto either a control diet (Con) or, to induce pre-conception obesity, an obesogenic diet (Ob). The respective diets were maintained throughout pregnancy and lactation. These obese dams were then randomised to the untreated group or to receive 300 mg/kg oral metformin hydrochloride treatment (Ob-Met) daily during pregnancy. In male and female offspring, body weights and body composition were measured from 1 month until 12 months of age, when serum and tissues were collected for investigation of adipocyte cellularity (histology), adipose tissue inflammation (histology and quantitative RT-PCR), and hepatic steatosis and fibrosis (histochemistry and modified Folch assay). RESULTS: At 12 months of age, male Ob and Ob-Met offspring showed increased adiposity, adipocyte hypertrophy, elevated expression of proinflammatory genes, hyperleptinaemia and hepatic lipid accumulation compared with Con offspring. Male Ob-Met offspring failed to show hyperplasia between 8 weeks and 12 months, indicative of restricted adipose tissue expansion, resulting in increased immune cell infiltration and ectopic lipid deposition. Female Ob offspring were relatively protected from these phenotypes but Ob-Met female offspring showed increased adiposity, adipose tissue inflammation, hepatic lipid accumulation, hyperleptinaemia and hyperinsulinaemia compared with Con female offspring. CONCLUSIONS/INTERPRETATION: Maternal metformin treatment of obese dams increased offspring metabolic risk factors in a sex- and age-dependent manner. These observations highlight the importance of following up offspring of both sexes beyond early adulthood after interventions during pregnancy. Our findings illustrate the complexity of balancing short-term benefits to mother and child vs any potential long-term metabolic effects on the offspring when prescribing therapeutic agents that cross the placenta.

Obesity in Survivors of Childhood Cancer: a Review.

Obesity is a late effect of antineoplastic treatment in childhood cancer survivors and this correlates with chronic complications. This review examines the data currently available to health professionals, for increasing awareness and identifying strategies to address the treatment and prevention of late effects. The mechanism involved in the pathophysiology of obesity remains unclear. However, damage to the hypothalamus and endocrine disorders (e.g. insulin and leptin resistance) and a positive energetic balance may play a role in increasing obesity rates. A patient's diet during, and after treatment may also influence the weight of survivors. Implementation of an effective educational program by professionals during all stages of treatment enables children to obtain basic knowledge regarding food and nutrition, thereby encouraging them to take responsibility for developing healthy eating behaviors.

The influence of parental high-fat high-sugar diet on the gut-brain axis in male offspring.

PURPOSE: The gut-brain axis (GBA) is implicated in the development of obesity, and its role in developmental programming needs to be explored. This study uncovers the effects of a parental high-fat, high-sugar diet (HFS) on the gut (colon) and brain (hypothalamus) GBA of male Wistar rat offspring at weaning until adulthood. METHODS: For ten weeks before mating, male progenitors were fed a control diet (CD) or HFS, whereas dams were fed CD or HFS during pregnancy and lactation. Male offspring aged 21-and 90-day old were assessed for: Gene expression of toll-like receptor 4 (TLR4) pathway and zonula occludens 1 (ZO1) in the colon and hypothalamus; hypothalamic gene expression of orexigenic neuropeptides and Leptin receptor; serum levels of lipopolysaccharide (LPS), glucagon like peptide 1 (GLP-1), Ghrelin and neuropeptide Y (NPY); colonic cytokine levels; FaecalBifidobacterium spp.andLactobacillus spp. DNA. RESULTS: Paternal HFS showed increased endotoxaemia, reduced colonic gene expression of ZO1 and reduced colonic TNF-α at weaning. In the adult offspring, paternal HFS showed increased NPY, reduced serum Ghrelin, colonic pro-inflammatory cytokines, and lower faecalBifidobacteriumspp. DNA. Maternal diet showed increased hypothalamic gene expression of myeloid differentiation primary response 88 (MYD88) at weaning. The maternal HFS diet showed increased NPY and reduced faecalBifidobacteriumspp. andLactobacillusspp. DNA in the adult offspring. The combined effect of parental diet showed increased NPY at weaning, and lowerBifidobacteriumspp. andLactobacillus spp.in the adult offspring. CONCLUSION: Maternal and paternal HFS diet seem to influence the programming of the gut-brain axis, leading to increased visceral adiposity and weight of male offspring at weaning, the effect that lasted until adulthood.

Role of vitamin D in pregnancy and Toll-like receptor pathway.

There is a growing concern about the impacts of hypovitaminosis D on the health of pregnant woman, fetal development, childhood, and adult life. Variations in maternal nutrition during gestation and/or lactation play a critical role in the physiological and metabolic development of the fetus and neonate, which can induce phenotypic changes and trigger important consequences throughout life, such as type 2 diabetes, cardiovascular disease, obesity, and hypertension. Vitamin D plays a role in regulating cell proliferation and differentiation and in modulating the innate and adaptive immune response. Also, vitamin D correlates with changes in cytokines, anti and proinflammatory, as well as prevents inflammation induced by changes in myometrial cells mediated by the nuclear factor kappa B pathway. Further investigation is required regarding these relationship.