Reduced Milk Triglycerides in Mice Lacking Phosphoenolpyruvate Carboxykinase in Mammary Gland Adipocytes and White Adipose Tissue Contribute to the Development of Insulin Resistance in Pups

Abstract

Obesity and type 2 diabetes are growing problems worldwide in adults and children. This study focused on understanding the patterning of insulin resistance as a result of altered perinatal nutrition. We analyzed mice in which the binding site for peroxisome proliferator‐activated receptor γ (PPARγ) was deleted from the promoter of the cytosolic phosphoenolpyruvate carboxykinase gene (Pck1) (PPARE−/−). We analyzed pups from dams with the same genotype as well as fostered and cross‐fostered pups. Pck1 expression and triglyceride content in the milk were measured. The PPARE mutation reduced Pck1 expression in WAT to 2.2% of wild type (WT) and reduced Pck1 expression in whole mammary gland tissue to 1% of WT. The female PPARE−/− mice presented reduced lipid storage in mammary gland adipocytes and in WAT, resulting in a 40% reduction of milk triglycerides during lactation. Pups from PPARE−/− dams exhibited insulin resistance as early as 14 days after birth, a condition that persisted into adulthood. Wild type pups fostered by PPARE−/− dams have lower body weights and plasma insulin concentrations compared to WT pups reared by WT dams. PPARE−/− pups fostered by WT dams have improved glucose clearance compared to pups raised by PPARE−/− dams. PPARE+/− and PPARE−/− dams patterned the newborn pup for reduced growth and insulin resistance in utero as well. Thus, in utero environment and altered nutrition in the perinatal period cause epigenetic changes that last into adulthood and contribute to the development of insulin resistance. J Nutr. 139:1–9, 2009.