Molecular Basis of Metabolic Disease (Obesity & Diabetes)

The global epidemics of Type 2 Diabetes Mellitus (T2DM), obesity and the Metabolic Syndrome cannot be explained simply by genetics and/or current lifestyles. Data suggests these adult diseases have their origin in the intrauterine and early postnatal environment. Epidemiological and animal studies have demonstrated that incidence of T2DM and obesity is increased in offspring whose mothers were themselves diabetic or obese pre-pregnancy, perpetuating disease prevalence. Using mouse models we have shown that exposure to a maternal high fat diet predisposes offspring to future development of these metabolic diseases. Combined these data strongly suggest epigenetic alterations of the fetal genome are the cause of increased incidence of disease in adults. At present we have identified significant changes in DNA methylation, as well as changes in histone modifications, associated with altered gene expression in offspring exposed to a maternal high fat diet. Additionally, we are interested in identifying the components of the maternal diet that are linked to the poor metabolic phenotype of offspring. By varying dietary fat content and adding antioxidants to the maternal diet, we hope to alter the disease susceptibility of offspring. The results of these studies may alter the guidelines recommended for a healthy pregnancy/postpartum diet.

We have expanded our mouse work in the field of the “Developmental Origin of Health and Disease” to study the epigenetic basis of early childhood obesity in children. We are conducting a major prospective study at Einstein/Montefiore using CD3+ T-cells purified from the umbilical cords of healthy term infants (intrauterine growth restricted and appropriate for gestational age) born to mothers at the Weiler Hospital to understand the molecular mechanism underlying early childhood obesity during the first 24 months of life. Recent studies have identified a key role for CD3+ T-cells in the initiation and regulation of adipose tissue inflammation and insulin resistance. We are characterizing the DNA methylation profiles of CD3+ T-cells from infants at birth and 24 months old and we are measuring T-cell function, metabolism and gene expression. We will use this information to determine whether T-cell DNA methylation and functional profiles are associated with infant growth velocity and adiposity in the first 24 months of life. Our ultimate goal is to characterize the epigenetic mechanisms underlying programmed T-cell dysfunction in healthy-term newborns as a critical early step in understanding obesity-associated inflammation preceding the onset of childhood obesity.

Additional studies are focused on two members of the glucose transporter gene family (GLUT4 and GLUT8). GLUT4 is insulin and exercise responsive and is the major glucose transporter expressed in cardiac and skeletal muscle and adipose tissue. GLUT8 is a member of the glucose transporter gene family that is expressed in many tissues (including brain, liver, placenta and various tumor cells). By using transgenic and gene knockout mouse models we study the role of GLUT4 and GLUT8 in whole body and organ specific glucose utilization in normal and disease states. In contrast to our studies on insulin action and glucose uptake we also study the glucagon receptor. Glucagon elevates serum glucose levels. We cloned the glucagon receptor gene and studied its regulation by hormones and nutrients. We are studying the role of glucagon action in the pathophysiology of T2DM using gene knockout and transgenic mouse models.

Selected References

Williams, L., E. Burgos, P.M. Vuguin, C.R. Manuel, R. Pekson, S. Munnangi, S.E. Reznik and M.J. Charron. N-acetylcysteine resolves placental vasculopathic changes in mice consuming a high fat diet. Am. J. Path. 189: 2246-2257 (2019).

Townsend, L.K., K. Medak, C.M. Knuth, W.T. Peppler, M.J. Charron and D.C. Wright. Loss of glucagon signaling alters white adipose tissue browning. FASEB J. 33(4):4824-4835 (2019).

Peppler, W.T., L.N. Castellani, J. Root-McCraig, L.K. Townsend, C.D. Sutton, S. Frendo-Cumbo, K.D. Medak, R.E.K. MacPherson, M.J. Charron and D.C. Wright. Regulation of hepatic follistatin expression at rest and during exercise in mice. Med. Sci Sports Exercise 51(6):1116-1125 (2019).

Dean, E.D., P.M. Vuguin and M.J. Charron. Glucagon, the name says it all, or not! Endocrinol. 160(5):1359-1361 (2019).

Manuel, C, M.J. Charron, C.R. Ashby and S.E. Reznik. Saturated and unsaturated fatty acids differentially regulate in vitro and ex vivo placental anti-oxidant capacity. Am. J. Reprod. Immunol. May 7:e12868. doi: 10.1111/aji.12868 (2018).

Patel, A., B. Usta, D. Matthews, M.J. Charron, R.J. Seeley and D.J. Drucker. GLP-2 receptor signaling controls circulating bile acid levels but not glucose homeostasis in Gcgr-/- mice and is dispensable for the metabolic benefits ensuing after vertical sleeve gastrectomy. Mol. Metab. 16:45-54. doi.org/10.1016/j.molmet.2018.06.006 (2018).

Galsgaard, K.D., M. Winther-Sørensen, C. Ørskov, H. Kissow, S.S. Poulsen, H. Vilstrup, C. Prehn, J. Adamski, S.L. Jepsen, B. Hartmann, J. Hunt, M.J. Charron, J. Pedersen, N.J. Wewer Albrechtsen and J.J. Holst. Disruption of glucagon receptor signaling causes hyper-aminoacidemia exposing a possible liver – alpha – cell axis. Am. J. Physiol. Endocrinol. Metab. 314:E93-E103 (2018).

Manuel, C, M.J. Charron, C.R. Ashby and S.E. Reznik. Saturated and unsaturated fatty acids differentially regulate in vitro and ex vivo placental anti-oxidant capacity. Am. J. Reprod. Immunol. May 7:e12868. doi: 10.1111/aji.12868 (2018).

Seki, Y., M. Suzuki, X. Guo, A.S. Glenn, P.M. Vuguin, A. Fiallo, Q. Du, Y-.A. Ko, Y. Yu, K. Susztak, D. Zheng, J.M. Greally, E.B. Katz and M.J. Charron. In utero exposure to a high fat diet programs hepatic hypermethylation and gene dysregulation and development of metabolic syndrome in male mice. Endocrinol. 158(9):2860-2872 (2017). (Featured with associated News and Views Endocrinol. 158(9):2716-2718 (2017) and YouTube video https://youtu.be/vabeX5vP3UI).

Mani, B.K., A. Uchida, Y. Lee, S. Osborne-Lawrence, M.J.Charron, R.H. Unger, E.D. Berglund, and J.M. Zigman. Hypoglycemic effect of combined ghrelin and glucagon receptor blockade. Diabetes 66(7):1847-1857 (2017).

Kruse, M., K. Hartil, A. Fiallo, E.B. Katz and M.J. Charron. A high fat diet during pregnancy and lactation induces cardiac and renal abnormalities in GLUT4+/- male mice. Kidney Blood Press. Res. 42(3):468-482 (2017).

Buyuk, E., O.A. Asemota, Z. Merhi, M.J. Charron, D.S. Berger, A. Zapantis and S.K. Jindal. Serum and follicular fluid monocyte chemotactic protein-1 levels are elevated in obese women and are associated with poorer pregnancy rate after in vitro fertilization: a pilot study. Fertil. Steril. 107(3):632-640 (2017).

Castellani, L.N., W.T. Peppler, C.D. Sutton, J. Whitfield, M.J. Charron and D.C. Wright. Glucagon receptor knockout mice are protected against acute olanzapine-induced hyperglycemia. Psychoneuroendocrinol. 82:38-45 (2017).

Williams, L. Y. Seki, F. Delahaye, A. Cheng, M. Fuloria, F. Hughes Einstein and M.J. Charron. DNA hypermethylation of CD3+ T-cells from cord blood of intrauterine growth restricted humans. Diabetologia 59(8):1714-1723 (2016).

Heyman-Linden, L., Y. Seki, P. Storm, H.A. Jones, M.J. Charron, K. Berger and C. Holm. Berry intake changes hepatic gene expression and DNA methylation patterns associated with high-fat diet. J. Nutr. Biochem. 27: 79-95. (2016).

Merhi, Z., K. Thornton, E. Bonney, M. Cipolla, M.J. Charron and E. Buyuk. Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1 (MCP-1). J. Assist. Reprod. Genet. 33:535-543 (2016).

Damond, N., F. Thorel, J.S. Moyers, M.J. Charron, P.M. Vuguin, A.C. Powers and P.L. Herrera. Blockade of glucagon signaling prevents or reverses diabetes onset only if residual -cells persist. eLife 5:e13828 (2016).