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

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

SOCS3 deficiency in leptin receptor-expressing cells mitigates the development of pregnancy-induced metabolic changes

Objective: During pregnancy, women normally increase their food intake and body fat mass, and exhibit insulin resistance. However, an increasing number of women are developing metabolic imbalances during pregnancy, including excessive gestational weight gain and gestational diabetes mellitus. Despite the negative health impacts of pregnancy-induced metabolic imbalances, their molecular causes remain unclear. Therefore, the present study investigated the molecular mechanisms responsible for orchestrating the metabolic changes observed during pregnancy. Methods: Initially, we investigated the hypothalamic expression of key genes that could influence the energy balance and glucose homeostasis during pregnancy. Based on these results, we generated a conditional knockout mouse that lacks the suppressor of cytokine signaling-3 (SOCS3) only in leptin receptor-expressing cells and studied these animals during pregnancy. Results: Among several genes involved in leptin resistance, only SOCS3 was increased in the hypothalamus of pregnant mice. Remarkably, SOCS3 deletion from leptin receptor-expressing cells prevented pregnancy-induced hyperphagia, body fat accumulation as well as leptin and insulin resistance without affecting the ability of the females to carry their gestation to term. Additionally, we found that SOCS3 conditional deletion protected females against long-term postpartum fat retention and streptozotocin-induced gestational diabetes. Conclusions: Our study identified the increased hypothalamic expression of SOCS3 as a key mechanism responsible for triggering pregnancy-induced leptin resistance and metabolic adaptations. These findings not only help to explain a common phenomenon of the mammalian physiology, but it may also aid in the development of approaches to prevent and treat gestational metabolic imbalances

Chronic leucine supplementation did not change the food intake and water ingestion of ob/ob mice.

<p>The food intake and water ingestion of ob/ob mice (<i>n</i> = 7) were assessed for 20 consecutive days. During the first 10 days, the mice received water to drink (H₂O, white bar), followed by 10 days of leucine supplementation in the drinking water (Leucine, black bar).</p

Hypothalamic mRNA expression of genes involved in the BCAA metabolism and energy balance regulation.

<p>Gene expression was assessed in mice receiving a low-fat diet (A, <i>n</i> = 10 per group) or a high-fat diet (B, <i>n</i> = 9-10 per group). *, significantly different (<i>P</i> < 0.05) from control group. †, <i>P</i> = 0.0532 versus control group.</p

Acute oral leucine administration induced phosphorylation of p70S6K in the hypothalamus.

<p>Bar graphs showing the quantification of the phosphorylation of p70S6K in the hypothalamus of mice that received oral gavage of water (CON group, <i>n</i> = 9) or leucine solution (LEU group, <i>n</i> = 9). The data were normalized to the expression of α-actinin. *, significantly different (<i>P</i> < 0.05) from the CON group.</p

Oral Leucine supplementation acutely increased food intake.

<p>A. Oral gavage of a leucine solution increased the 24 h food intake (Day 3 and Day 4) compared to the days when the animals received gavage of water (Day 1 and Day 2). B. No changes in body weight were observed among the experimental days. *, significantly different (<i>P</i> < 0.05) from D1 and D2 (gavage of water).</p