Abstract
Genetic and environmental factors, including the in utero environment, contribute to Metabolic Syndrome. Exposure to high fat diet exposure in utero and lactation increases incidence of Metabolic Syndrome in offspring. Using GLUT4 heterozygous (G4+/−) mice, genetically predisposed to Type 2 Diabetes Mellitus, and wild-type littermates we demonstrate genotype specific differences to high fat in utero and lactation. High fat in utero and lactation increased adiposity and impaired insulin and glucose tolerance in both genotypes. High fat wild type offspring had increased serum glucose and PAI-1 levels and decreased adiponectin at 6 wks of age compared to control wild type. High fat G4+/− offspring had increased systolic blood pressure at 13 wks of age compared to all other groups. Potential fetal origins of adult Metabolic Syndrome were investigated. Regardless of genotype, high fat in utero decreased fetal weight and crown rump length at embryonic day 18.5 compared to control. Hepatic expression of genes involved in glycolysis, gluconeogenesis, oxidative stress and inflammation were increased with high fat in utero. Fetal serum glucose levels were decreased in high fat G4+/− compared to high fat wild type fetuses. High fat G4+/−, but not high fat wild type fetuses, had increased levels of serum cytokines (IFN-γ, MCP-1, RANTES and M-CSF) compared to control. This data demonstrates that high fat during pregnancy and lactation increases Metabolic Syndrome male offspring and that heterozygous deletion of GLUT4 augments susceptibility to increased systolic blood pressure. Fetal adaptations to high fat in utero that may predispose to Metabolic Syndrome in adulthood include changes in fetal hepatic gene expression and alterations in circulating cytokines. These results suggest that the interaction between in utero-perinatal environment and genotype plays a critical role in the developmental origin of health and disease.
Highlights
Obesity is a major risk factor for developing Type 2 Diabetes Mellitus (T2DM)
We previously reported that mice exposed to high fat diet (HF) in utero (IU) had decreased weight at birth compared to mice exposed to C IU/L [16]
HF IU was associated with decreased numbers of pups/litter at birth when compared to C diet [16]
Summary
Obesity is a major risk factor for developing Type 2 Diabetes Mellitus (T2DM). Genetic and environmental factors contribute to both. In addition to genetic predisposition and postnatal environment in determining susceptibility to T2DM and Metabolic Syndrome (MetS), exposures in utero (IU) play a role. Longitudinal studies in monozygotic and dizygotic twins support the idea that environmental factors are critical to the development of obesity [3] and altered glucose homeostasis [4]. Studies in Pima Indians support the concept of a non-genetic transgenerational transmission of T2DM [5]. Animal models [7,8] and epidemiological studies support the Thrifty Phenotype Hypothesis [9] and the Developmental Origins of Health and Disease (DOHaD) [10] which propose that malnutrition during fetal and early life predispose offspring to metabolic disease
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