Mechanisms mediating the impact of maternal obesity on offspring hypothalamic development and later function

Abstract

As obesity rates have risen around the world, so to have pregnancies complicated by maternal obesity. Obesity during pregnancy is not only associated with negative health outcomes for the mother and the baby during pregnancy and birth, there is also strong evidence that exposure to maternal obesity causes an increased risk to develop obesity, diabetes and cardiovascular disease later in life. Animal models have demonstrated that increased weight gain in offspring exposed to maternal obesity is usually preceded by increased food intake, implicating altered neuronal control of food intake as a likely area of change. The hypothalamus is the primary site in the brain for maintaining energy homeostasis, which it coordinates by sensing whole body nutrient status and appropriately adjusting parameters including food intake. The development of the hypothalamus is plastic and regulated by metabolic hormones such as leptin, ghrelin and insulin, making it vulnerable to disruption in an obese in utero environment. This review will summarise how the hypothalamus develops, how maternal obesity impacts on structure and function of the hypothalamus in the offspring, and the factors that are altered in an obese in utero environment that may mediate the permanent changes to hypothalamic function in exposed individuals.

Pathophysiological Insight into Fatty Acid-Binding Protein-4: Multifaced Roles in Reproduction, Pregnancy, and Offspring Health

“…It is closely associated with the occurrence of gestational disorders, including PE and GDM [ 82 ]. Importantly, maternal obesity poses deleterious impacts on the offspring’s metabolic health later in life [ 83 ]. Extensive studies have proven that fetuses exposed to maternal obesity have a significantly elevated risk to develop obesity, hypertension, hyperglycemia, insulin resistance, hyperlipidemia, and non-alcoholic fatty-liver disease in their progeny including [ 84 , 85 ].…”

Leptin receptor expression in blood mononuclear cells of lactating women is associated with infant body weight: Potential role as a molecular biomarker

“…These hormones can act as biomarkers of the metabolic and nutritional status of the mother and directly impact on the child, with an outstanding role in early life programming 2,22 . Leptin's action in early life programs metabolism by controlling the development of hypothalamic neurocircuits, 2 and insulin plays a neurotrophic role in numerous brain regions 23 . However, the impact of these hormones on childhood obesity is not well understood.…”

“…2,22 Leptin's action in early life programs metabolism by controlling the development of hypothalamic neurocircuits, 2 and insulin plays a neurotrophic role in numerous brain regions. 23 However, the impact of these hormones on childhood obesity is not well understood. Receptors for these hormones are expressed in the infant gastrointestinal tract, 24,25 suggesting they may act locally to elicit endocrine effects or be absorbed into circulation.…”

Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food

“…Numerous studies in humans and animal models have highlighted the association between maternal obesity and several long-term adverse health outcomes in the offspring, including the risk of obesity and type 2 diabetes (3). Growing evidence from animal models shows that exposure to maternal obesity can disrupt the hypothalamic circuits responsible for maintaining energy homeostasis, which may contribute to increased offspring susceptibility to obesity later in life (4). The hypothalamus is the crucial region of the brain responsible for maintaining energy homeostasis in the body and contains specialised neurons that sense circulating nutrients and hormones.…”

“…The hypothalamus is the crucial region of the brain responsible for maintaining energy homeostasis in the body and contains specialised neurons that sense circulating nutrients and hormones. Exposure to over-nutrition during critical windows of development has been shown to program increased food intake in animal models (4), including increased preference for high-fat foods in rats and non-human primates (5)(6)(7). Studies in mouse models report that maternal obesity alters hypothalamic neuronal projections (8)(9)(10), but aside from this little is known about the molecular mechanisms by which maternal overnutrition programs permanent changes in feeding behaviour in offspring.…”