The Charron Laboratory works on two classes of proteins that play critical roles in regulation of glucose homeostasis and energy balance.  Specifically, we study role of the glucose transporters GLUT4 and GLUT8 and also the glucagon receptor (Gcgr) in glucose homeostasis and insulin sensitivity.  Using transgenic and targeted gene strategies, we have generated mouse models to define the role of these proteins in cellular and whole body metabolism and energy balance.  The incidence of diabetes and obesity has reached epidemic proportions and treatment and diagnostic strategies are inadequate.  The complications of diseases of insulin resistance are vast and include heart attack and stroke.  In addition to genetic factors, the incidence of diabetes and obesity are influenced by environmental factors such as diet and exercise.  Strong evidence derived from experimental animal models and human epidemiology suggests that perturbation of the early developmental environment (e.g. nutrient, stress, toxins) has lasting effects that enhance the offspring’s susceptibility to metabolic and other diseases.  It is thought that these effects are mediated through alterations in the epigenome.  Alterations in DNA methylation are measured as they represent the most stable epigenomic modifications.  Mouse models are being used to evaluate the influence of maternal diet and metabolic status on the fetal/neonatal epigenome.  The stability of these epigenetic signatures and their association with disease incidence are under investigation.  A prospective clinical study has begun to evaluate the impact of a common environmental toxicant on DNA methylation profiles in umbilical cord and peripheral blood T cells and subsequent development of childhood obesity.  We hope to identify an epigenetic signature of increased risk for obesity that may be used for early diagnosis and intervention.  The ultimate goal of our studies is to define the molecular mechanism(s) underlying the pathogenesis of diabetes and obesity that may lead to novel therapeutics and potential cures for these and related metabolic diseases.

Ali, S., B.J. Lamont, M.J. Charron and D.J. Drucker.  Plasticity in the incretin axis revealed through dual elimination of the murine Gcgr and Glp1r.  J. Clin. Invest. 121:1917-1929 (2011).

Buyuk, E., N. Santoro, H.W. Cohen, M.J. Charron^* and S. Jindal^*.  Reduced neurotrophin receptor TrkA expression in human granulosa cells: A novel marker of diminishing ovarian reserve.  Fert. and Sterility 96:474-478 (2011).  (* indicates equal contribution).

Berglund, E.D. D.G. Lustig, R.X. Beheza, C.M. Hasenour, R.S. Lee-Young, B.M. Damon, E.P. Donahue, S.E. Lynes, L.L. Swift, M.J. Charron and D.H. Wasserman.  Hepatic glucagon is essential for exercise-induced reversal of mouse fatty liver.  Diabetes 60:2720-2729 (2011).

Ouhilal, S., P.M. Vuguin, L. Cui, R.W. Gelling, X.-Q. Du, S. Reznik, R. Russell, A.F. Parlow, C. Karpovsky, N. Santoro and M.J. Charron.  Hypoglycemia, hyperglucagonemia and feto-placental defects in glucagon receptor knockout mice: a role for glucagon action in pregnancy maintenance.  Am. J. Phys. Endo. Met. 302(5):E522-531 (2012).

Grigoryan, M., M.H. Kedees, M.J. Charron, Y. Guz and G. Teitelman.  Regulation of mouse intestinal L cell progenitors proliferation by the glucagon family of peptides.  Endo. 153:3076-3088 (2012).

Lee, Y., E.D. Berglund, M.Y. Wang, X. Fu, X. Yu, M.J. Charron, S.C. Burgess and R.H. Unger.  Metabolic manifestation of insulin deficiency do not occur without glucagon action.  Proc. Natl. Acad., Sci. USA 109:14792-14976 (2012).

Berger, J., M.J. Charron and D.L. Silver.  Major facilitator superfamily domain-containing protein 2a (MFSD2A) has roles in body growth, motor function, and lipid metabolism.  PLoS One 7(11):e50629 (2012).

Longuet, C., A.M. Robledo, D. Dean, C. Dai, S. Ali, I. McGuinness, V. de Chavez, P.M. Vuguin, M.J. Charron, A.C. Powers and D.J. Drucker.  Liver-specific disruption of the murine glucagon receptor produces alpha-cell hyperplasia: Evidence for a circulating a-cell growth factor.  Diabetes 62:1196-1205 (2013).

Mighiu, P.I., J.T.Y. Yue, B.M. Filippi, M. Chari, C.K.L. Lam, C.S. Yang, M.J. Charron and T.K.T. Lam.  Glucagon signaling in the mediobasal hypothalamus inhibits glucose production.  Nature Med. 19:766-772 (2013).

Vuguin, P.M., K. Hartil, M. Kruse, H. Kaur, C.-L. Lin, A.S. Glenn, A. Fiallo, A. Patel, L. Williams, Y. Seki, E.B. Katz and M.J. Charron.  Shared effects of genetic and intrauterine and perinatal environment on the development of metabolic syndrome.  PLoS One 8(5):e63021(2013).

Kruse, M., Y. Seki, P.M. Vuguin, X.Q. Du, A. Fiallo, A.S. Glenn, S. Singer, K. Breuhahn, E.B. Katz and M.J. Charron.  High-fat intake during pregnancy and lactation exacerbates high-fat diet-induced complications in male offspring in mice.  Endo. 154:3565-3576 (2013).

Mukharji, A., D.J. Drucker, M.J. Charron and S.J. Swoap.  Oxyntomodulin increases intrinsic heart rate through the glucagon receptor.  Physiol. Reports 1(5):e00112 (2013).

Scheufele, F. B. Wolf, M. Kruse, T. Hartmann, J. Lempart, S. Muehlich, A.F.H. Pfeiffer, L.J. Field, M.J. Charron, Z-Q Pan, S. Engelhardt and A. Sarikas.  Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signaling.  Cellular Sig. 26:233-239 (2014).

Lee, Y., E.D. Berglund, X. Yu, M.Y. Wang, M.R. Evans, P.E. Scherer, W.L. Holland, M.J. Charron, M.G. Roth and R.H. Unger.  Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells.  Proc. Natl. Acad. Sci USA 111:13217-13222 (2014).

Lin, C.L., L. Williams, Y. Seki, H. Kaur, K. Hartil, A. Fiallo, A.S. Glenn, E.B. Katz, M.J. Charron^* and P.M. Vuguin^*.  Effects of genetics and in utero diet on murine pancreatic development.  J Endo 222:217-227 (2014). (^*indicates corresponding authors).

Plata, M., L. Williams, Y. Seki, K. Hartil, H. Kaur, C.L. Lin, A. Fiallo, A.S. Glenn, E.B. Katz, M. Fuloria, M.J. Charron* and P.M. Vuguin*.  Critical periods of increased vulnerability to a maternal high fat diet.  Reprod. Biol. & Endocrinol. 12:80. doi: 10.1186/1477-7827-12-80 (2014). (^*indicates corresponding authors).

Maianti, J.P., A. McFedries, Z.H. Foda, R.E. Kleiner, X.Q Du, MA Leissring, W.J. Tang, M.J. Charron, M.A. Seeliger, A. Saghatelian and D.R. Liu.  Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.  Nature 511:94-98 (2014).

Suter, M.A., J. Ma, P.M. Vuguin, K. Hartil, A. Fiallo, RA Harris, M.J. Charron^* and K.M. Aagaard^*.  In utero exposure to a maternal high fat diet alters the epigenetic histone code in a murine model.  Am. J. Obstetrics & Gynecology 210:463.e1-463.e11 (2014). (^*indicates corresponding authors).

Ali, S., J.R. Ussher, L.L. Baggio, M.G. Kabir, M.J. Charron, O. Ilkayeva, C.B. Newgard and D.J. Drucker.  Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction.  Mol. Metab. 4:132-143 (2015).

Atkins, K.B., Y. Seki, J. Saha, F. Eichinger, M.J. Charron and F.C. Brosius.  Maintenance of GLUT4 expression in smooth muscle prevents hypertension-induced changes in vascular reactivity.  Physiol. Rep. 3(2):e12299 (2015).

Chi, Y., J.-F. Jasmin, Y. Seki, M. Duranski, M.P. Lisanti, M.J. Charron, D.J. Lefer and V.L. Schuster.  Inhibition of the prostaglandin transporter PGT lowers blood pressure in hypertensive rats and mice.  PLoS One 10(6):e013735 (2015).

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. Nutritional 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. Assisted Reprod. & Gen. 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 b-cells persist.  eLife 5:e13828 (2016).

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).

Neumann, U.H., J.S.S. Ho, M. Mojibian, S.D. Covey, M.J. Charron and T.J. Kieffer.  Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival.  Mol. Metab. 5(8):731-736 (2016).

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.  Fertility & Sterility 107(3):632-640 (2017).

Williams, L., M.J. Charron* and R.R. Sellers.  High post-natal mortality associated with defects in lung maturation and reduced adiposity in mice with gestational exposure to high fat and N-acetylcysteine.  Res. Vet. Sci. 114:262-265 (2017).  (* indicates corresponding author).

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).

**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.  Endocrinol. 58(9):2860-2872 (2017).

**Editor’s Choice for Featured Article (https://doi.org/10.1210/en.2017-00334) and Featured Author of the Month (Sept, 2017); Featured YouTube video (https://youtu.be/vabeX5vP3UI) and News and Views (High-Fat Diet and Pregnancy: Are You Ready To Take Risks for Your Offspring? Endocrinol. 158(9):2716–2718 (2017). (https://doi.org/10.1210/en.2017-00611). Also chosen by the Endocrine Society for their Thematic Issue on Diabetes (https://academic.oup.com/endocrinesociety/pages/thematic_issue_diabetes) (Nov, 2017); and highlighted in Endocrine Society Newsletter and Twitter following (Oct, 2017).

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 Pressure Res. 42(3):468-482 (2017).

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).