Shared Effects of Genetic and Intrauterine and Perinatal Environment on the Development of Metabolic Syndrome

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.

A High Fat Diet During Pregnancy and Lactation Induces Cardiac and Renal Abnormalities in GLUT4 +/- Male Mice

“…The CD1 mouse model is an outbred strain and was chosen because of a strong heterogeneity in its genome [27]. WT female mice were bred to non-littermate GLUT4 heterozygote (G4+/-) males [28, 29]. Genotyping was performed as previously described [30].…”

“…Male offspring were the focus of this study to circumvent the confounding effects of estrogen in metabolism. In addition, we previously demonstrated that only male offspring exposed to HFD during IU/L develop hypertension in adult life [28]. Body weight was recorded weekly until 12 weeks of life and then bi-weekly until the end of the study.…”

“…This study utilized the GLUT4 heterozygous (G4+/-) mouse that exhibits insulin resistance [27] and develops hypertension when exposed to a HFD during IU/L [28]. Since, to the best of our knowledge, the role of GLUT4, the major glucose transporter in the heart that is also present in the kidney [27, 28], has not been investigated in the genesis of fetal programming of CRS or CRMS, we provide a mouse model that is novel for investigating these diseases.…”

Effects of genetics and in utero diet on murine pancreatic development

“…Increased globalization, associated with a nutritional transition towards Western diets, is thought to be a contributing factor to the increasing prevalence of obesity and T2D globally (Popkin 2006)). In addition to poor diet and genetics, evidence suggests that an altered intrauterine environment (IU) plays a key role in the development of MetS (Vuguin, et al 2013) and that interactions between the IU environment and lifestyle can increase risk of MetS and T2D in people who are genetically susceptible (Hu 2011). …”

“…Poor nutrition during pregnancy impacts fetal growth and development particularly that of the endocrine pancreas (Snoeck, et al 1990; Vuguin, et al 2013). Specifically, alterations in the IU environment caused by a low calorie, low protein or a high fat diet (HFD) affects the function of the endocrine pancreas by altering islet size, islet vascularization, number of insulin-cells (INS), insulin content, function, and parasympathetic innervation (Cerf, et al 2005; Dahri, et al 1991; Ford, et al 2009; Garofano, et al 1997; Ng, et al 2010; Rodriguez-Trejo, et al 2012; Vogt, et al 2014).…”