Abstract
The dramatic increase in the prevalence of childhood obesity worldwide makes the investigation of its early developmental stages and effective prevention strategies an urgent issue. CCK1 deficient OLETF rats are a model of obesity previously used to study the early phases of this disorder. Here, we exposed wild type (LETO) females to an early obesogenic environment and genetically obese OLETF females to a lean postnatal environment, to assess long term alterations in leptin sensitivity, predisposition to diet induced obesity and adult female health. We found that genetically lean females reared by obese mothers presented early postnatal hyperleptemia, selectively reduced response to leptin and sensitivity to diet induced obesity when exposed to a high palatable diet as adults. The estrous cycle structure and intake profile were permanently disrupted, despite presenting normal adiposity/body weight/food intake. Genetically obese females reared by lean dams showed normalized early levels of leptin and reduced body weight, food intake and body fat at adulthood; normalized estrous cycle structure and food intake across the cycle, improved hormonal profile and peripheral leptin sensitivity and a remarkable progress in self-control when exposed to a high fat/palatable diet. Altogether, it appears that the early postnatal environment plays a critical role in determining later life coping with metabolic challenges and has an additive effect on the genetic predisposition that makes OLETF females morbidly obese as adults. This work also links, for the first time, alterations in the leptin system during early development to later life abnormalities related to female reproduction and health.
Highlights
Maternal obesity during pregnancy and lactation may predispose the offspring to increased adiposity, accompanied by higher leptin and glucose levels later in life, especially in the presence of a genetic tendency [1,2]
The sensitivity to leptin in the Arcuate nucleus (ARC) was determined by the early postnatal environment To determine the hypothalamic and the brainstem sensitivity to leptin between the groups, we examined c-fos activation in the ARC, in the dorsomedial hypothalamus (DMH) and the nucleus of the solitary tract (NTS) after exogenous leptin administration
Otsuka Long Evans Tokushima fatty (OLETF) rats failed to discriminate between the high fat and the low fat liquids regardless of the early postnatal environment, but LETO dams rearing OLETF pups (LdOp) females managed to limit overall food intake during the progressive food challenge trials, implying a relative moderation in their hyperphagia even in the presence of the strong genetic tendency to obesity
Summary
Maternal obesity during pregnancy and lactation may predispose the offspring to increased adiposity, accompanied by higher leptin and glucose levels later in life, especially in the presence of a genetic tendency [1,2]. The maternal nutritional and hormonal environment during the perinatal period programs life-long appetite and metabolism in the offspring. The hormonal, neuronal and autocrine mechanisms mediating the maintenance of energy balance develop during this period, making it of high relevance in determining the programming of later sensitivity or resistance to obesity [3]. In conditions with excess energy stores or metabolic disturbances, elevated serum or follicular fluid leptin levels have been reported, raising the possibility that leptin deficiency or resistance may be at least partly responsible for the reproductive abnormalities usually found in these conditions [13]
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