Interrupting the Vicious Cycle of Obesity and Metabolic Syndrome

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 DESCRIPTION (provided by applicant): The prevalence of maternal overweight and obesity continues to increase in the U.S. and spans the spectrum of age, race and ethnicity, and socioeconomic status. Alarmingly, although the rate of preadolescent obesity has stabilized over the last decade, 1 in 10 infants and toddlers are obese, and 1 in 5 youth are both obese and at-risk for metabolic syndrome prior to the onset of puberty. Our hypothesis is that maternal obesity and Western Style Diets (WSD) are causing damage to the development of key metabolic systems (liver, muscle and pancreas) thereby altering tissue function at the cellular and molecular level in young offspring of obese mothers. Furthermore, the persistence of abnormalities in postnatal animals switched to a healthy diet suggests that the developmental changes may have permanent effects that alter metabolic outcomes, linking early maternal obesity/WSD to long term risk for obesity and type 2 diabetes in the next generation. Life-course studies in human infants born to obese mothers, particularly at the molecular and cellular level in tissues relevant to diabetes and obesity, are completely lacking. Our group has spent the past decade developing and thereafter utilizing a sophisticated Non-Human Primate (NHP) model of maternal high fat/caloric dense WSD consumption that has critically important developmental and physiological similarities to humans. The major focus of this grant will be on detailed longitudinal based investigations in the offspring of obese mothers focusing on juvenile physiology (including food intake and energy expenditure), functional and morphological changes in 3 key tissues: liver, pancreas, and skeletal muscle, along with genomic events across tissues and time. In Aim 1 offspring of obese or lean mothers will be weaned to healthy chow-based control diet or continued WSD, and animals followed up to 3 years of age (just prior to puberty). To interrupt this viscous cycle, obese mothers consuming a WSD diet will be supplemented with Resveratrol (Aim 2), an antioxidant with anti-inflammatory properties, or a healthy chow based diet (Aim 3) just prior to conception. The offspring of both resveratrol and diet-switched mothers will be studied up to 14 mo. of age. Such studies will provide important mechanistic insights into how maternal diet and metabolic health impact development, adaptability and postnatal function of the liver, pancreas, and skeletal muscle--tissues that are inaccessible in humans, but with direct clinical and translational implications for the development of obesity and type 2 diabetes. Our studies continue to address the need for controlled, mechanistic studies to identify the respective contributions of maternal obesity and pre- and post-weaning diet exposures on key metabolic systems in offspring of a model directly relevant to humans.