The incidence of Type 2 diabetes mellitus (T2DM) and the Metabolic Syndrome has reached epidemic proportions. Human and rodent studies provide strong support for a genetic predisposition to these pathologies. The GLUT4 mouse model (G4) represents an example of an `At Risk' individual as male G4 mice develop insulin resistance, hypertension and T2DM with age. Despite genetic predisposition, it is clear that other factors play an important role in disease transmission and incidence. Studies have shown that alterations in nutrients during early life `program' increased susceptibility to metabolic disease and hypertension in adult life. However, these studies provide limited insight into the epigenetic mechanisms underlying these processes. Consumption of a western style, high fat (HF) diet during pregnancy has also been linked to vascular dysfunction, dyslipidemia and hyperglycemia in adults. Modulation of hepatic substrate utilization and insulin sensitivity is crucial for maintenance of whole body glucose homeostasis as it integrates signals from the gut, peripheral tissue and central nervous system. This process is disrupted in diseases such as TD2M and the Metabolic Syndrome. Several models with alterations in the intrauterine (IU) milieu display pathologic alterations in genes of hepatic glucose and lipid utilization (including PPAR1 and G6Pase) often associated with T2DM. The central hypothesis of this proposal is that consumption of a high fat (HF) diabetogenic diet during pregnancy and lactation `programs' offspring for increased susceptibility to Metabolic Syndrome and T2DM. We propose that increased susceptibility to the development of Metabolic Syndrome is mediated by altered methylation of genes that regulate glucose and lipid utilization in liver. We predict dietary intervention by adding one carbon donors will prevent these epigenetic modifications. Strong preliminary data suggests PPAR1 may play a pivotal role in mediating these effects. The contribution of environmental factors (IU diet) and offspring genetics (hemizygous lesion in peripheral glucose uptake, G4) to alterations in hepatic gene expression and methylation related to the incidence of T2DM and Metabolic Syndrome will be measured. Molecular mechanisms underlying the early life programming of these metabolic derangements will be revealed. Additional studies are proposed to test the response of high fat IU offspring to diets that alter body weight and metabolism including a high fat diabetogenic diet or a weight loss ketogenic diet during their adult life. Results of these studies may yield new information for setting dietary guidelines for pregnant and lactating women that may protect offspring from enhanced susceptibility to these metabolic diseases.

Public Health Relevance

Type 2 diabetes mellitus (T2DM) and the Metabolic Syndrome are modern day plagues of societies in industrialized and developing nations alike. Studies have shown that alterations in nutrients during early life `program' increased susceptibility to metabolic disease. However, these studies provide limited insight into the potential epigenetic mechanisms underlying these processes. This proposal seeks to define the molecular basis underlying the programming of Metabolic Syndrome and T2DM using normal mice and ones genetically `at risk' for developing metabolic diseases. Results of these studies may yield new information for setting guidelines for pregnant and lactating women that may protect offspring from enhanced susceptibility to these metabolic diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK081194-01
Application #
7463147
Study Section
Special Emphasis Panel (ZRG1-EMNR-A (02))
Program Officer
Castle, Arthur
Project Start
2008-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
1
Fiscal Year
2008
Total Cost
$249,000
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Seki, Yoshinori; Suzuki, Masako; Guo, Xingyi et al. (2017) In Utero Exposure to a High-Fat Diet Programs Hepatic Hypermethylation and Gene Dysregulation and Development of Metabolic Syndrome in Male Mice. Endocrinology 158:2860-2872
Williams, Lyda; Seki, Yoshinori; Vuguin, Patricia M et al. (2014) Animal models of in utero exposure to a high fat diet: a review. Biochim Biophys Acta 1842:507-519
Plata, Maria del Mar; Williams, Lyda; Seki, Yoshinori et al. (2014) Critical periods of increased fetal vulnerability to a maternal high fat diet. Reprod Biol Endocrinol 12:80
Lin, Chia-Lei; Williams, Lyda; Seki, Yoshinori et al. (2014) Effects of genetics and in utero diet on murine pancreatic development. J Endocrinol 222:217-27
Suter, Melissa A; Ma, Jun; Vuguin, Patricia M et al. (2014) In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model. Am J Obstet Gynecol 210:463.e1-463.e11
Kruse, Michael; Seki, Yoshinori; Vuguin, Patricia M et al. (2013) High-fat intake during pregnancy and lactation exacerbates high-fat diet-induced complications in male offspring in mice. Endocrinology 154:3565-76
Seki, Yoshinori; Williams, Lyda; Vuguin, Patricia M et al. (2012) Minireview: Epigenetic programming of diabetes and obesity: animal models. Endocrinology 153:1031-8
Lee, Young; Wang, May-Yun; Du, Xiu Quan et al. (2011) Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60:391-7
Vuguin, Patricia Myriam (2010) Interventional studies for polycystic ovarian syndrome in children and adolescents. Ped Health 4:59-73
Hartil, Kirsten; Vuguin, Patricia M; Kruse, Michael et al. (2009) Maternal substrate utilization programs the development of the metabolic syndrome in male mice exposed to high fat in utero. Pediatr Res 66:368-73