Respective Contributions of Maternal Insulin Resistance and Diet to Metabolic and Hypothalamic Phenotypes of Progeny

Abstract

Maternal obesity can influence susceptibility to obesity and type 2 diabetes in progeny. We examined the relationship of maternal insulin resistance (IR), a metabolically important consequence of increased adiposity, to adverse consequences of obesity for fetal development. We used mice heterozygous for a null allele of the insulin receptor (Insr) to study the contributions of maternal IR to offspring phenotype without the potential confound of obesity per se, and how maternal consumption of high-fat diet (HFD) may, independently and interactively, affect progeny. In progeny fed a 60% HFD, body weight and adiposity were transiently (5–7 weeks) increased in wild-type (+/+) offspring of Insr+/− HFD-fed dams compared to offspring of wild-type HFD-fed dams. Offspring of HFD-fed wild-type dams had increased body weight, blood glucose, and plasma insulin concentrations compared to offspring of chow-fed wild-type dams. Quantification of proopiomelanocortin (POMC) and neuropeptide-Y (NPY) populations in the arcuate nucleus of the hypothalamus (ARH) of offspring of wild-type vs. Insr+/− dams was performed to determine whether maternal IR affects the formation of central feeding circuits. We found a 20% increase in the number of Pomc-expressing cells at postnatal day 9 in offspring of Insr+/− dams. In conclusion, maternal HFD consumption—distinct from overt obesity per se—was a major contributor to increased body weight, adiposity, IR, and liver triglyceride (TG) phenotypes in progeny. Maternal IR played a minor role in predisposing progeny to obesity and IR, though it acted synergistically with maternal HFD to exacerbate early obesity in progeny.

Long-lived crowded-litter mice exhibit lasting effects on insulin sensitivity and energy homeostasis

“…It is well established that prenatal and immediate postnatal variations in nutrient availability can modulate metabolic status and disease susceptibility in rodents and in humans, but most previous studies have focused on factors that impair adult health, often by increased obesity and impairments in glucose and insulin homeostasis (11,41). A largely separate research tradition has shown that restriction of caloric intake (21,22,28,39,43), or in some cases intake of the amino acid methionine (49), throughout adult life can prevent or delay a wide range of late-life illnesses and thereby increase mean and maximal longevity.…”

Feed Your Head: Neurodevelopmental Control of Feeding and Metabolism

“…In contrast, it is well established that maternal HFD is a major trigger for long-term deleterious effects on progeny body weight and metabolism (152). HFD increases protein, cholesterol, and triglyceride content in breast milk, elevating total caloric and fat intake in nursing pups (153).…”

Roles of the placenta in fetal brain development

“…Maternal high-fat diet affects neuropeptide expression in offspring brain regions that control energy homeostasis and affective states (12). In addition, maternal hyperinsulinemia, even in the absence of obesity, influences the differentiation of critical neuronal lineages regulating food intake and energy expenditure (13). To date, among the missing pieces of the puzzle has been the question of how changes in placental gene expression are conveyed to the developing fetus to influence formation and function of neuronal circuits.…”