Postnatal environment overrides genetic and prenatal factors influencing offspring obesity and insulin resistance

Abstract

There is growing evidence that the postnatal environment can have a major impact on the development of obesity and insulin resistance in offspring. We postulated that cross-fostering obesity-prone offspring to lean, obesity-resistant dams would ameliorate their development of obesity and insulin resistance, while fostering lean offspring to genetically obese dams would lead them to develop obesity and insulin resistance as adults. We found that obesity-prone pups cross-fostered to obesity-resistant dams remained obese but did improve their insulin sensitivity as adults. In contrast, obesity-resistant pups cross-fostered to genetically obese dams showed a diet-induced increase in adiposity, reduced insulin sensitivity, and associated changes in hypothalamic neuropeptide, insulin, and leptin receptors, which might have contributed to their metabolic defects. There was a selective increase in insulin levels and differences in fatty acid composition of obese dam milk which might have contributed to the increased adiposity, insulin resistance, and hypothalamic changes in obesity-resistant cross-fostered offspring. These results demonstrate that postnatal factors can overcome both genetic predisposition and prenatal factors in determining the development of adiposity, insulin sensitivity, and the brain pathways that mediate these functions. diet-induced obesity; hypothalamus; milk; development; plasticity; Agouti-related peptide; leptin MATERNAL INTAKE of a high-fat diet and the presence of obesity during pregnancy and lactation promote obesity in offspring, particularly in individuals with an obesity-prone genetic background (21,32,36,55). However, there is growing evidence that a variety of manipulations during the postnatal environment can override prenatal factors and increase the risk of developing metabolic disorders such as obesity and diabetes later in life. Raising pups in small litters leads to increased milk intake and the development of obesity, whereas raising pups in large litters has the opposite effect (16,23,26). Administration of insulin during early postnatal development results in obesity and altered development of hypothalamic neuropeptide systems involved in energy homeostasis (22, 50). Cross-fostering pups is another method of assessing the role of the postnatal environment in later development. A single study in mice has demonstrated that fostering inbred obesity-prone mouse pups with obesity-resistant dams attenuates their obesity, whereas fostering obesity-resistant pups with obesity-prone dams causes them to develop obesity and insulin resistance (51).Unlike many rodent models, the majority of human obesity is inherited as a polygenic disorder (6). For that reason, we have used a rat model of diet-induced obesity (DIO), in which obesity is also inherited as a polygenic trait (33, 38) in association with insulin resistance (33), hypertension (14), and hyperlipidemia (62). These rats also have several abnormalities of brain function, which antedate and may contribute to the later development o...

Adaptation to lactation in OLETF rats lacking CCK-1 receptors: body weight, fat tissues, leptin and oxytocin

“…51 In a similar study design, HE-fed DIO rats gained only half as much body weight than chow-fed DIO rats, when comparing premating and second lactation week data. 52 In Wistar rats fed control or HF diet for weeks prior to mating: 'during gestation, those fed the HF diet maintained their overweight compared with normally fed dams. After delivery, HF dams lost relatively more weight than did C dams, mainly during the second half of the lactation Adaptation to lactation in a model of obesity O Zagoory-Sharon et al period, and then the body weight became identical in the two groups at the end of the weaning period'.…”

Effect of a maternal cafeteria diet on the fatty acid composition of milk and offspring red blood cells

“…Cross-fostering studies in rodents have built on this evidence and shown that exposure to a maternal cafeteria diet during the suckling period alone is associated with adverse metabolic health outcomes in the offspring that are comparable to those resulting from exposure during the entire perinatal period [3,4]. Since maternal milk is the dominant source of nutrition for the offspring during suckling, these findings suggest that alterations to milk composition are likely to play an important role in the metabolic programming of the offspring.…”

Maternal preconceptional nutrition leads to variable fat deposition and gut dimensions of adult offspring mice (C57BL/6JBom)

“…Previous studies have investigated how a variety of nutritional compounds including fish oils, 19,20 vitamins, [21][22][23] minerals 24 and macronutrients 25,26 may affect offspring phenotype, but most studies have concerned protein composition in the mother's diet during pregnancy or lactation and obesity risk of offspring. 4,12,27,28 In this study, we investigate how variation in protein to carbohydrate balance of maternal food before mating affects fat deposition of adult offspring mice. As the size and function of the digestive system of many animals show pronounced phenotypic plasticity to variations in dietary quality and availability, [29][30][31] we also analyze whether preconceptional maternal diet affects the mass and lengths of different parts of the gut.…”