Abstract
The steady increase in the prevalence of obesity and associated type II diabetes mellitus is a major health concern, particularly among children. Maternal obesity represents a risk factor that contributes to metabolic perturbations in the offspring. Endoplasmic reticulum (ER) stress has emerged as a critical mechanism involved in leptin resistance and type 2 diabetes in adult individuals. Here, we used a mouse model of maternal obesity to investigate the importance of early life ER stress in the nutritional programming of this metabolic disease. Offspring of obese dams developed glucose intolerance and displayed increased body weight, adiposity, and food intake. Moreover, maternal obesity disrupted the development of melanocortin circuits associated with neonatal hyperleptinemia and leptin resistance. ER stress-related genes were up-regulated in the hypothalamus of neonates born to obese mothers. Neonatal treatment with the ER stress-relieving drug tauroursodeoxycholic acid improved metabolic and neurodevelopmental deficits and reversed leptin resistance in the offspring of obese dams.
Highlights
A major shift in our nutritional environment has greatly contributed to the recent obesity epidemic
Because our results indicated that maternal obesity alters offspring’s leptin levels and arcuate nucleus of the hypothalamus (ARH) leptin signaling, we investigated whether maternal obesity disrupts the development of ARH circuits by examining POMC/α-melanocyte-stimulating hormone and agouti-related peptide (AgRP) neuronal projections, two arcuate neuropeptidergic systems that play a critical role in energy balance
We report that maternal obesity induces Endoplasmic reticulum (ER) stress in key tissues involved in energy metabolism during critical periods of growth and development, in the arcuate nucleus and pancreas
Summary
A major shift in our nutritional environment has greatly contributed to the recent obesity epidemic. There is growing evidence that adverse fetal and early postnatal environments increase the risk of developing obesity. Accumulative evidence from both human and animal studies demonstrated that exposure to maternal obesity predisposes offspring to obesity and other metabolic dysfunctions later in life [1,2,3]. The hypothalamus is involved in the control of food intake and energy expenditure. Its development is greatly influenced by the maternal and postnatal nutritional environment [1,2,4,5,6,7]. Primary importance has been given to the arcuate nucleus of the hypothalamus (ARH) because it contains 3 main neuronal populations that play a major role in energy homeostasis: anorexigenic pro-opiomelanocortin
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