Selective Leptin Insensitivity and Alterations in Female-Reproductive Patterns Linked to Hyperleptinemia during Infancy

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.