1869-P: Elevated Maternal BCAAs during Gestation and Lactation Reprograms Offspring’s Glucose Regulation

Abstract

Maternal nutrition impacts neonate development and can have long-lasting physiological effects. Newborns from obese and type 2 diabetes (T2D) mothers are at a higher risk of developing metabolic deficits later in life. Women with gestational diabetes (GD) or T2D often have elevated serum branched chain amino acids (BCAAs), one of the most accurate predictors of insulin resistance (IR) in adults. Since BCAAs are actively taken up by the placenta, fetuses are exposed to elevation of BCAAs in their mothers. Additionally, newborns can be exposed to high BCAA levels via breast milk or formula feeding. Interestingly, BCAAs levels are higher in breast milk from obese mothers and some infant formulas have higher BCAA content than average breast milk. However, the direct impact of BCAA overnutrition in utero and early postnatal life on newborn predisposition to obesity and T2D is poorly understood. To investigate the effects of exposure to high BCAA levels during gestation and postnatally, we fed female mice during pregnancy and lactation two different isocaloric diets with equal total protein content, but one of the diets enriched in BCAAs. Their offsprings was weaned onto normal or high fat (HFD) diets and evaluated for changes in body composition and systemic metabolic regulation over a six-month period. We found that maternal BCAA supplementation triggered hyperglycemia and impaired insulin secretion in newborns. Progeny from mothers fed the high BCAA diet exhibited elevated fasting glucose levels, reduced insulin secretion, and striking reductions in glucose tolerance and insulin sensitivity, which were exacerbated by HFD supplementation. These findings suggest that early exposure to BCAA overnutrition has a strong dysregulating effect on systemic glucose metabolism. We will provide insights into the molecular underpinnings at play. Disclosure J. Tzeng: None. A. Aguillard: None. D. Lorenzo: None. Funding American Diabetes Association (1-19-JDF-081 to D.L.); National Institute of Diabetes and Digestive and Kidney Diseases (DK072476-15225-UNC01)