Our Basic Diabetes Research

“We are probably close to breakthroughs in Type 1 diabetes, and I think we will soon unravel the brain mechanisms that regulate body weight, appetite and energy metabolism, which in turn would enable us to better control obesity, a very important contributor to Type 2 diabetes.”

Rudolph Leibel, MD
Co-Director of research at the Berrie Center

Beyond our walls, in research laboratories at Columbia University, our parent institution, world-renowned physician-scientists are working with the Berrie Center on a wide range of diabetes studies moving the understanding of diabetes ahead and ever closer to a cure.

It’s time-consuming, painstaking research that can take decades. Initiatives currently under way include:

  • Understanding mechanisms of pancreatic insulin-producing cell formation and cell death
  • Development of cellular and stem cell therapies (including islet cell transplantation) for patients
  • Suppressing the immune processes that destroy beta cells in Type 1 diabetes
  • Searching for genes that cause diabetes and obesity
  • Neutralizing the metabolic pathways that lead to the disease’s deadly complications
  • Understanding the biology of body weight regulation

“You take cells from a patient who’s been totally insulin-dependent for 20 years and in the lab those cells are making insulin. It gives you goosebumps.”

Robin S. Goland, MD
Co-Founder and Co-Director

See the list of our own Berrie Center labs and the type of research they specialize in.

Domenico Accili, MD Laboratory

The Accili laboratory is interested in insulin action and pancreatic–cell function.

Recent discoveries include:

Role of bile acids in the pathogenesis of diabetic lipid abnormalities

The association of type 2 diabetes with elevated plasma triglyceride (TG) and very low density lipoproteins (VLDL), and intrahepatic lipid accumulation represents a pathophysiological enigma and an unmet therapeutic challenge. We have uncovered a link between insulin action through FoxO1, bile acid (BA) composition, and altered lipid homeostasis that brings new insight to this longstanding conundrum. FoxO1 ablation brings about two signature lipid abnormalities of diabetes and the metabolic syndrome, elevated liver and plasma TG. These changes are associated with deficiency of 12-hydroxylated BAs and their synthetic enzyme, Cyp8b1, that hinders the TG-lowering effects of the BA receptor, Fxr. Accordingly, pharmacological activation of Fxr with GW4064 overcomes the BA imbalance, restoring hepatic and plasma TG levels of FoxO1-deficient mice to normal levels. We propose that generation of 12-hydroxylated products of BA metabolism represents a signaling mechanism linking hepatic lipid abnormalities with type 2 diabetes, and a treatment target for this condition.

Reversal of atherosclerosis through inhibition of FoxO

The three FoxO transcription factors (isoform 1, 3a, and 4) are Akt substrates that regulate metabolic pathways in different tissues. We have reported that ablation of the three genes in vascular endothelial cells prevents atherosclerosis in Low-density lipoprotein receptor knockout mice. The preventive effect of FoxO ablation on atherosclerosis likely ensues from its ability to increase cell survival and nitric oxide availability, and dampen inflammation, chemotaxis, and superoxide generation. The data demonstrate that FoxO inhibition in endothelial cells has the potential to mediate wide-ranging therapeutic benefits for diabetes-associated cardiovascular disease.

Generation of functional insulin-producing cells in the gut by Foxo1 ablation

Restoration of regulated insulin secretion is the ultimate goal of type 1 diabetes therapy. We have shown that, surprisingly, somatic ablation of Foxo1 in Neurog3+ enteroendocrine progenitor cells gives rise to gut insulin-positive cells (Ins+) that express markers of mature-cells, and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments show that gut Ins+ cells arise cell-autonomously from Foxo1-deficient cells. Following ablation by the-cell toxin, streptozotocin, gut Ins+ cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3+ enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins+ cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.

Discovery of a new receptor that mediates food intake in AgRP neurons

Neurons expressing the peptide Agouti-related protein (AgRP) drive food intake. We have reported the unexpected finding that the orphan G protein-coupled receptor, Gpr17 mediates some effects of AgRP neurons on food intake. Drugs that activate Gpr17 promote eating, while antagonists of Gpr17 promote satiety. Given the ready availability of the latter compounds, currently used as anti-platelet aggregating agents, we suggest that this pathway be explored as a therapeutic target in the treatment of obesity. 

Brown remodeling of white adipose tissue by Sirt1 and Pparγ

Brown adipocytes possess desirable metabolic properties that have the potential to prevent obesity. We have shown that it’s possible to confer critical ‘brown-like’ features on white adipocytes by activating the deacetylase SirT1. We have demonstrated that SirT1 promotes this process by deacetylating nuclear receptor Pparγ, a stalwart of adipogenesis and a key target for the TZD class of insulin sensitizers. The data raise the possibility of using low-dose TZD and SirT1 agonists as combination therapy to induce browning and fight obesity.

Pancreatic -cell dedifferentiation as mechanism of diabetic -cell failure

Diabetes is thought to arise through a decrease in pancreatic -cell mass, brought about partly through apoptosis. We have challenged this paradigm by showing that -cells undergo dedifferentiation during the course of diabetes, effectively regressing to a progenitor-like, multipotent developmental stage secondary to loss of FoxO1. These cells far outnumber apoptotic cells in diabetic mice, raising the possibility that combined cytoprotective and pro-differentiation treatments could restore -cell health and prevent disease progression.

Recent Publications:

  • H.V. Lin, L. Plum, H. Ono, R. Gutiérrez-Juárez, M. Shanabrough, E. Borok, T.L. Horvath, L. Rossetti, D. Accili (2010). Divergent Regulation of Energy Expenditure and Hepatic Glucose Production by Insulin Receptor in AgRP and POMC Neurons. Diabetes. 59: 337-346.
  • H. Ren, D. Accili, C. Duan (2010). Hypoxia converts the myogenic action of insulin-like growth factors into mitogenic action by differentially regulating multiple signaling pathways. Proc. Natl. Acad. Sci. USA. 107: 5857-5862.
  • A. Nandi, X. Wang, D. Accili, D.J. Wolgemuth (2010). The effect of insulin signaling on female reproductive function independent of adiposity and hyperglycemia. Endocrinology 151: 1863-1871.
  • R.A. Haeusler, S. Han, D. Accili (2010). Hepatic Foxo1 ablation exacerbates lipid abnormalities during hyperglycemia. J. Biol. Chem. 285: 26861-26868.
  • L. Qiang and D. Accili (2010). Uncoupling of acetylation from phosphorylation regulates Foxo1 function independent of its sub-cellular localization J. Biol. Chem. 285: 27396-27401.
  • S. Xuan, M. Szabolcs, F. Cinti, S. Perincheri, D. Accili, A. Efstratiadis (2010). Genetic analysis of IGF1 receptor signaling through Irs1 and Irs2 in pancreatic b cells. J. Biol. Chem, in press.
  • M.G. Myers Jr, C.R. Kahn, D. Accili (2010). Leptin therapy for type 1 diabetes gains traction. Nat. Med. 2010 16: 380.
  • R.A. Haeusler, M. Pratt-Hyatt, C.L. Welch, C.D. Klaassen, D. Accili (2012) Impaired Generation Of 12-Hydroxylated Bile Acids Links Hepatic Insulin Signaling With Dyslipidemia. Cell Metab. 15: 65-74 PMC3253887
  • K. Tsuchiya, J. Tanaka, S. Yu, C.L. Welch, R.A. DePinho, I. Tabas, A.R. Tall, I.J. Goldberg, D. Accili (2012) FoxOs Integrate Pleiotropic Actions Of Insulin In Vascular Endothelium To Protect Mice From Atherosclerosis. Cell Metab. 15: 372-381 PMC3315846
  • C. Talchai, S. Xuan, T. Kitamura, R.A. DePinho, D. Accili (2012) Generation Of Functional Insulin-Producing Cells In The Gut By Foxo1 Ablation. Nat. Genet. 44: 406-412 PMC3315609
  • L. Qiang, D. Accili (2012) FGF21 and the second coming of PPAR. Cell 148: 397-398
  • H. Ren, I.J. Orozco, Y. Su, S. Suyama, R. Gutiérrez-Juárez, T.L. Horvath, S.L. Wardlaw, L. Plum, O. Arancio, D. Accili (2012) G protein-coupled purinergic receptor GPR17 mediates orexigenic effects of FoxO1 in AgRP neurons. Cell 149: 1314–1326
  • L. Qiang, L. Wang, N. Kon, W. Zhao, S. Lee, Y. Zhang, M. Rosenbaum, Y. Zhao, W. Gu, S.R. Farmer, D. Accili (2012) Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Pparγ. Cell 150: 620-632 PMC3413172
  • C. Talchai, S. Xuan, H.V. Lin, L.Sussel, D. Accili (2012) Pancreatic -Cell Dedifferentiation As A Mechanism Of Diabetic -Cell Failure. Cell 150: 1223-1234 PMC3445031 
  • Q.C. Zhang, D. Petrey, L. Deng, L. Qiang, Y. Shi, C.A. Thu, B. Bisikirska, C. Lefebvre,
  • D. Accili, T. Hunter, T. Maniatis, A. Califano, B. Honig (2012) Structure-based prediction of protein-protein interactions on a genome-wide scale. Nature 490: 556-560

Angela Christiano, PhD Laboratory

An international team of researchers led by Dr. Christiano recently found that the immune genes carried by patients with an autoimmune form of hair loss, alopecia areata, are nearly identical to those carried by patients with type 1 diabetes, celiac disease and rheumatoid arthritis. The study was published in the July 1 issue of Nature. This new finding suggests that the hair follicle and the scalp may be useful to study immune mechanisms in type 1 diabetes, a very important advance.

Dr. Christiano and colleagues discovered that a gene called ULBP3 acts as a homing beacon for killer immune cells. ULBP3 is turned off in normal hair follicles but turned on in alopecia areata follicles. In its activated state, ULBP3 attracts killer immune cells with a special receptor called NKG2D, which triggers an autoimmune attack.

Christiano and colleague Raphael Clynes, an assistant professor of medicine and microbiology,are now trying to find a way to moderate the response and to compare the disease progression of alopecia to type 1 diabetes. (Read more on Dr. Christiano)

Wendy Chung, MD PhD Laboratory

Research interests:

My research interests are in the genetic basis of diabetes and obesity and whether elucidating this underlying basis can be used to improve outcomes by tailoring treatment based upon the molecular mechanism of disease. To achieve this goal we screen patients for mutations in the genes associated with diabetes and obesity and perform studies to identify novel diabetes and obesity genes. For patients with monogenic forms of diabetes and obesity, we study the natural history of their disease and carefully characterize it and try to recapitulate the molecular phenotype using induced pluripotential stem cells. (Read more on Dr. Chung)

Projects:

  • Screening for monogenic forms of diabetes and obesity
    We continue to receive samples from around the world including for genetic evaluation of neonatal diabetes, isolated familial diabetes, Wolfram syndrome, and obesity. We have analyzed these patients to screen for 1) paternal duplication/uniparental disomy of chromosome 6 and mutations in the following genes: Insulin, IPF1, and KCNJ11 for neonatal diabetes; 2) Glucokinase, HNF1a, and HNF4 a in Maturity Onset Diabetes of Youth; 3) Wolframin in Wolfram syndrome; and 4) MC4R, POMC and contiguous gene deletions/duplications for obesity. We have described the first known association of mutations in HNF1 a with neonatal hypoglycemia and extend the previously described similar phenotype in some HNF4 a mutation carriersWe have screened 45 patients with gestational diabetes for polymorphisms associated with type 2 diabetes in TCF7L2. We have identified patients with different genotypes and are now performing punch skin biopsies on these patients and patients with monogenic forms of diabetes to make induced pluripotential stem cells that can be differentiated into beta cells and studied in vitro to better understand the beta cell defect that leads to diabetes.
  • Genetics of obesity due to 2nd generation antipsychotic drugs.The amount of weight gained on these medications is variable and there is some evidence based upon twin studies that this variability may be in part due to genetic differences. In collaboration with Dr. Jeffrey Lieberman, we studied 800 subjects who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness Research Program (CATIE) study to determine if genetic variants in 18 candidate genes are correlated with weight gain after antipsychotic treatment. These studies could enable drug selection in specific subjects Genetics of obesity in bariatric surgery patients. We have recently received DNA from LABS and been approved by Teen LABS for access to the DNA samples which we will be using for high throughput, NextGeneration sequencing of 27 candidate genes for obesity. We will also analyze obese subjects for copy number analysis to identify gene duplications/deletions.
  • Characterization of obesity associated 16p11.2 deletions
    Deletions in 16p11.2 have recently been associated with obesity and in some cases with the autistic spectrum disorder. Dr. Chung is the principle investigator of a study funded by the Simons Foundation to clinically characterize 200 patients with the 16p11.2 deletion or duplication. The study will include a comprehensive medical interview including longitudinal growth data, questions about ingestive behavior, photographs for dysmorphology, sophisticated neuropsychological testing, and advance neuroimaging including resting state conductivity and fMRI.
  • Genetics of Taste and Relationship to Obesity
    In collaboration with Kathleen Keller (NYNORC)we have begun to study genetic variation in CD36, a fatty acid translocase that may play a role in oral fat detection and preference.
  • Genetics of function neural networks and the relationship to appetite and obesity
    In collaboration with Susan Carnell of the ORC, are studying the neurobiological pathways underlying appetitive responsivity in obese adolescents and those at high familial or genetic risk of becoming obese.

Recent Publications:

  • Gallagher , D., Larson , E.L., Wang, Y-H, Richards, B., Weng, C., Hametz, P., Begg, M.D., Chung, W.K., Boden-Albala, B., and Akabas, S.R., .Identifying interdisciplinary research priorities to prevent and treat pediatric obesity in New York City. Clinical and Translational Science. In press, 2010.
  • Rotstein M., Engelstad K., Yang H., Wang, D., Levy B., Chung, W.K., De Vivo, D.C. Glut1 Deficiency: Inheritance Pattern Determined by Haploinsufficiency. Annals of Neurology. Accepted. 2010.
  • Keller, K.L., Liang, L., McClean, J., May, D., Breen, C., Driggin, E., Tepper, B.J., Lanzano, P., Deng, L, Chung, W.K. Fat discriminability and consummative behaviors are associated with polymorphisms in the fatty acid translocase, CD36, in African-Americans. American Journal of Clinical Nutrition. Submitted. 2010.
  • Keller, K.L., Liang, L.C.H., Sakimura, J., May, D., van Belle, C., Breen, C., Driggin, E., Tepper, B.J., Lanzano, P.C., Deng, L., Chung, W.K.  Common variants in the CD36 gene are associated with oral fat perception, fat preferences, and obesity in African-Americans. Obesity. 20, 1066-1073. 2012.  PMID:22240721
  • Spiro, J.E., Beaudet, A.L., Brewton, C.M., Chu, Z., Dempsey, A.G, Evans, Y.L., Garza, S., Hunter, J.V., Kanne, S.M., Laakman, A.L., Lasala, M.W., Llorens, A.V., Marzano, G., Moss, T.J., Nowell, K.P., Proud, M.B., Ramocki, M.B., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K.P., Kessler, S., Khan, S.Y., Qasmieh, S., Bibb, A.L., Paal, A.M., Page, P.Z., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, A.L., Cerban, B., Gallagher, A.S., Grant, E., Green Snyder, L.A., McNally-Keehn, R., Miller, D., Miller, F., Olson, J., Spence, S., Triantafyllou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, G., Greenup, M., Packer, A., Tjernagel, J., Aaronson, B., Bukshpun, P., Cheong, M., Dale, C., Gobuty, S., Hinkley, L., Jeremy, R., Lee, H., Luks, T., Marco, E., Martin, A., Mukheriee, P, Nagarajan, S., Owens, J., Paul, B., Pojman, N., Sinha, T., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenmann, K., Aylward, E., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Steinman, K., Stevens, A., Ward, T., Wenegrat, J, Roberts, T., Ledbetter, D., Lese Martin, C., Goin-Kochel, R.P., Bernier, R., Faucett, W.A., Sherr,  E., Hanson, E., Chung, W.K. Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders. Neuron. 73(6):1063-7.  2012.  PMID.  22445335. 2012.
  • Zufferey*, F. Sherr*, E.H., Beckmann* , N.D., Hanson* , E., Maillard, A.M., Hippolyte, L., Macé, A., Ferrari, C., Kutalik, Z., Andrieux, J., Aylward, E., Barker, M., Bernier, R.,  Bouquillon, S., Conus, P., Delobel, B., Faucett, W.A., Goin-Kochel, R.P., Grant, E., Harewood, L., Hunter, J.V.,   Lebon, S., Ledbetter, D.H., Martin, C.L., Mannik, K., Martinet, D., Mukherjee, P., Ramocki, M.B.,  Spence, S.J., Steinman, K., Tjernagel, J., on behalf of the Simons VIP Consortium&, on behalf of the 16p11.2 European Consortium&, Spiro, J.E., Reymond, W.,  Beckmann§, J.S., Chung§,W.K., Jacquemont§, S., A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders§ Contributed equally.  Journal of Medical Genetics.  49(10):660-668. PMID: 23054248

Remi Creusot, PhD Laboratory

Research Update

Dr Creusot has been studying type I diabetes for 10 years at Stanford University. He has contributed to many advances in the field including, most recently, the seminal discovery of the association between the DEAF1 gene and the progression of type I diabetes in both mice and humans, and the development of cellular gene therapies employing reprogrammed immune cells to target sites of disease initiation and to re-educate the immune system such that pathogenic immune cells are eliminated or no longer cause disease. Now at Columbia University, Dr Creusot is starting a program to translate his pre-clinical scientific findings to treat the human disease and bring forward new approaches for prevention and therapy of type I diabetes in concert with clinicians at the Naomi Berrie Diabetes Center. The ultimate goal of his research is a stable induction of immune tolerance, meaning that immune cells would no longer attack insulin-producing cells, or any islet transplant if applicable.

Immune Tolerance and Autoimmunity: A Brief Introduction

Immune tolerance is a process by which the body eliminates or suppresses T cells that may react against self or innocuous environmental antigens. Defects in immune tolerance can lead to autoimmune or allergic disorders. In the case of Type 1 diabetes (T1D) for example, T cells reactive to pancreatic islet antigens are not sufficiently eliminated and/or controlled. The role of eliminating or educating self-reactive T cells is normally fulfilled by specialized “tolerogenic” cells that coexist with immune cells within the thymus, the lymph nodes and the spleen. These cells are referred to as tolerogenic because of two important properties: (1) the ability to present self-antigens (either expressed endogenously or acquired from their surrounding environment) and, as a consequence, to form antigen-specific contacts with self-reactive T cells, and (2) the ability to deliver tolerogenic signals that will cause the deletion or inhibition of those self-reactive T cells, or the induction of suppressive – rather than destructive – functions within those self-reactive T cells. During their development in the thymus, self-reactive T cells have an opportunity to recognize their self-antigens on tolerogenic cells and be adequately dealt with before they can be released into the periphery. Thus, many potentially self-reactive T cells, while in the thymus, can be eliminated or converted into regulatory T cells, which block other self-reactive T cells and protect our tissues from autoimmunity. This process is not perfect, even in healthy individual: some self-reactive T cells escape this selection process and get a step closer to reacting against self-tissues. Fortunately, they get to meet additional tolerogenic cells along the way, as they circulate in our body through lymph nodes and spleen.

Tolerogenic cells comprise two types of cells:
1) Immature dendritic cells: they can exogenously acquire self-antigens in tissues and transport them to lymphoid tissues for presentation. They are considered professional antigen-presenting cells as they can become “immunogenic” upon maturation in the context of inflammation or infection. They therefore constitute double-edge swords that can both prevent and induce autoimmunity. Whether or not these cells can also endogenously express tissue-specific self-antigens remains controversial.
2) Stromal cells: these are non-professional antigen-presenting cells with limited antigen-presentation capabilities. They are unable to process exogenous antigens and mount immune responses. However, some of them have the capacity to ectopically express tissue-specific antigens at low levels, and possess many tolerogenic tools to induce tolerance.

Particular stromal cells in the thymus have the ability to express tissue-specific antigens, which is conferred by the function of AIRE. The importance of this process is demonstrated by the observation that AIRE-deficiency in both humans and mice leads to a severe autoimmune syndrome targeting multiple tissues (T1D is observed in ~20% of cases). We have recently discovered that ectopic expression of tissue-specific antigens can also be regulated by DEAF1, a regulator of gene expression that has some homologies with AIRE. In both T1D patients and NOD mouse model of T1D, the progression of disease is associated with a defective function of DEAF1 due the alternative mRNA splicing in the pancreatic lymph nodes. In the case of T1D, this particular tissue is central, both a major site of disease initiation and a site of competition between tolerogenic and immunogenic signals for islet antigens. Thus inability of tolerogenic T cells to ectopically express tissue-specific antigens in this tissue can tip the balance in favor of immunogenic / diabetogenic responses.

Research Interests

  •  Although DEAF1 is widely expressed as opposed to AIRE, it has unique functions that are dependent on the cell types in which it is expressed. We are particularly interested in studying the role and function of DEAF1 in tolerogenic cells, and the relevance of its association with T1D. Both the NOD mouse model of T1D and human lymphoid tissues are used in our studies.
  •  Distinct populations of tolerogenic cells, stromal or dendritic, are unique in the tolerogenic molecules and pathways that they utilize to mediate immune tolerance, resulting in different outcomes. We designed a platform to recreate different “tolerogenic interfaces”, either naturally occurring or employing novel combinations, to study how these different signals are perceived and integrated by self-reactive T cells and to determine the outcome of this interaction.
  • T1D is a complex disease, wherein the causes leading to loss of tolerance are both numerous and variable between individuals (in humans). The ever-increasing incidence of disease in Western countries calls for a better understanding of the environmental factors that contribute to this alarming trend. We have identified new potential factors that could impact the prevalence of disease and are exploring the mechanisms of action.

Lab Members

Shamael Dastagir, MA 

*The lab is currently considering applications from students and postdocs 

Selected Publications:

Creusot RJ, Yaghoubi SS, Kodama K, Dang DN, Dang VH, Breckpot K, Thielemans K, Gambhir SS, Fathman CG. Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice. Clin. Immunol. (2008) 127(2):176-187.

Kodama K, Butte AJ, Creusot RJ, Su L, Sheng D, Dang D, Hartnett M, Iwai H, Holness C, Soares LR, Fathman CG. Time-dependent and tissue-specific changes in gene expression during disease induction and progression in NOD mice. Clin. Immunol. (2008) 129(2):195-201.

Creusot RJ, Yaghoubi SS, Chang P, Chia J, Contag CH, Gambhir SS, Fathman CG. Lymphoid tissue specific homing of bone marrow-derived dendritic cells. Blood (2009) 113(26):6638-6647.

Yip L, Su L, Sheng D, Chang P, Atkinson M, Czesak M, Albert PR, Collier A, Turley SJ, Fathman CG, Creusot RJ. Deaf1 isoforms control peripheral tissue antigen expression in the pancreatic lymph nodes during type 1 diabetes. Nature Immunol. (2009) 10(9): 1026-1033.

Creusot RJ, Chang P, Healey DG, Tcherepanova IY, Nicolette CA, Fathman CG. A short pulse of IL-4 delivered by DCs electroporated with modified mRNA can both prevent and treat autoimmune diabetes in NOD mice. Mol. Ther. (2010) 18(12): 2112-2120.

Yip L, Creusot RJ, Pager CT, Sarnow P, Fathman CG. Reduced DEAF1 function during Type 1 diabetes inhibits translation in lymph node stromal cells by suppressing Eif4g3. J. Mol. Cell. Biol. (2012) [Epub Aug 24].

Junttila IS*, Creusot RJ*, Moraga I*, Bates DL*, Wong MT, Alonso MN, Suhoski MM, Lupardus P, Meier-Schellersheim M, Engleman EG, Utz PJ, Fathman CG, Paul WE, Garcia KC. Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nature Chem. Biol. (2012) 8(12): 990-998. (*Contributed equally)

Dieter Egli, PhD, Laboratory

Dieter Egli, PhD, is  a member of the Naomi Berrie Diabetes Center and the Robertson Stem Cell Investigator at The New York Stem Cell Foundation. Dr. Egli is also an Adjunct Associate Research Scientist in the Division of Molecular Genetics at  Columbia University. He received his PhD from the University of Zurich, Switzerland. Dr. Egli was a postdoctoral fellow in the laboratory of Kevin Eggan, PhD at the Department of Stem Cell and Regenerative Biology, Harvard University, studying reprogramming after nuclear transfer. His interest includes the generation of therapeutically relevant cells for diabetes.

Lab Description

 My laboratory uses stem cells to investigate the cellular and molecular biology of diabetes, with the aim to develop cell replacement therapies for diabetics. Diabetes is a disorder characterized by a loss of beta cell mass, and/or a loss of beta cell-autonomous function, leading to a deficiency of insulin and deranged regulation of blood glucose. Because of a limited ability of adult beta cells to spontaneously regenerate, an exogenous source of beta cells could be therapeutically useful. Though we can now routinely generate insulin-producing cells from stem cells, the use of such cells in cell replacement is a long-term goal. Much of my current research therefore focuses on using stem cells to investigate monogenetic forms of diabetes. Such disease models enable the direct analyses of the molecular physiology in these otherwise inaccessible cells, and allows testing strategies to improve beta cell function. The insight gained from beta-cells with these mutations will also be relevant to understand beta cell failure in the more common forms of diabetes, including in T1 and T2 diabetes.

T2D is caused by an increased demand for insulin that the beta cells are unable to meet. The most effective intervention in T2D is control of body weight, thereby reducing the demand for insulin. Human genetics and rodent biology point to the central nervous system as the primary mediator of control of body weight and susceptibility to obesity. My laboratory is using stem cells and reprogramming technologies to model monogenetic forms of human obesity in vitro by generating the cells relevant for energy homeostasis including components of the central nervous system. The insight from these monogenetic forms of obesity may also be relevant for the more common forms of obesity. 

Recent Publications:

1.)   Chan, M.M.*, Smith, Z.D.*, Egli, D.*, Regev, A., and Meissner, A., Mouse ooplasm confers context-specific reprogramming capacity. Nat Genet. 2012 Sep;44(9):978-80. *equal contribution

2.)   Noggle, S., Fung, H., Gore, A., Martinez, H., Crumm, C., Prosser, R., Oum, K., Paull, D., Druckenmiller, S., Freeby, M., Greenberg, E., Zhang, K., Goland, R., Sauer, M., Leibel, R., and Egli, D. Human oocytes reprogram somatic cells to a pluripotent state. Nature. 2011 Oct5;478(7367):70-5.

3.)   Egli, D., Chen, A.E., Saphier, G., Powers, D., Alper, M., Katz, K., Berger, B. Goland, R., Leibel, R.L., Melton, D.A., Eggan, K., Impracticality of egg donor recruitment in the absence of compensation. Cell Stem Cell. 2011 Oct4;9(4):293-4

4.)   Egli, D., Chen, A.E. et al. Reprogramming within hours following nuclear transfer into mouse but not human zygotes. Nat Commun. 2011 Oct 4;2:488

 

Anthony Ferrante, MD, PhD Laboratory

Immunobiology of Obesity

Ferrante Laboratory studies how the immune system is altered during the development of obesity and contributes to the development of diabetes and its complications. Our past efforts revealed that macrophages and related immune cells accumulate in adipose tissue and liver during the development of obesity and are central to the inflammatory state associated with obesity and insulin resistance. The Ferrante laboratory is building on these past efforts and now have several project to study the function of macrophages and other immune cells in adipose tissue physiology and whether immune cell phenotypes can predict the development of metabolic disease.

Macrophages in Obesity

Continuing studies of adipose tissue macropahges Aliki Kosteli and colleagues in the laboratory found that during the initial period weight loss macrophage accumulate in adipose tissue in a manner reminiscent of the recruitment of macrophages seen in fat tissue of obese individuals. These observations lead to finding that the breakdown and release of lipids from fat cells drives the accumulation of immune cells in adipose tissue and thereby leads to obesity-induced inflammation. It was further found by the Ferrante laboratory that adipose tissue macrophages release factors that suppress the breakdown of lipids by fat cells, so that when mice are treated with a compound that eliminates macrophages from adipose tissue mice, the fat pads of mice release lipid and are reduced. (Read more on Dr. Ferrante)

Publications:

  • He J, Le DS, Xu X, Scalise M, Ferrante AW, Krakoff J. Circulating white blood cell count and measures of adipose tissue inflammation predict higher 24-h energy expenditure. Eur J Endocrinol. (2010) 162:275-80
  • Obstfeld AE, Sugaru E, Thearle MS, Francisco AM, Gayet C, Ginsberg HN, Ables EV, Ferrante Jr AW CCR2 regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis.Diabetes (2010) 59:916-25.
  • Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R,Ferrante Jr AW. An Immune response to weight loss and lipolysis JCI in press

Paul Harris, PhD Laboratory

Imaging Beta Cells

We are seeking to identify and validate beta cell neuroendrocrine targets ( e.g. VMAT2, D2R, mGluR5) suitable for in vivo quantitation by positron emission tomography (PET) using probes developed for CNS imaging. We are conducting a crossectional human study of imaging ( and quantitation ) VMAT2 as biomarker of beta cell mass. Our hypothesis is that since VMAT2 is a beta cell restricted marker within the pancreas, measurements of VMAT2 in the pancreas by PET will enable us to make real time estimates of beta cell mass (BCM) that may have utility in management of diabetes. Not surprisingly expression of dopamine type 2 receptors is also beta cell and we are currently studying whether beta cell mass measurements can be made by quantitation of D2R in the pancreas as well. Because of important differences in PET probe binding and metabolism between man and rodents, these initial studies have been performed in a non human primate model. (Read more on Dr. Harris)

Publications:

  • Ichise M, Harris PE. Imaging of beta-cell mass and function. J Nucl Med. 2010 Jul;51(7):1001-4.
  • Witkowski P, Sondermeijer H, Hardy MA, Woodland DC, Lee K, Bhagat G, Witkowski K, See F, Rana A, Maffei A, Itescu S, Harris PE. Islet grafting and imaging in a bioengineered intramuscular space. Transplantation. 2009 Nov 15;88(9):1065-74.
  • Inabnet WB, Milone L, Harris P, Durak E, Freeby MJ, Ahmed L, Sebastian M, Lifante JC, Bessler M, Korner J. The utility of [(11)C] dihydrotetrabenazine positron emission tomography scanning in assessing beta-cell performance after sleeve gastrectomy and duodenal-jejunal bypass. Surgery. 2010 Feb;147(2):303-9. 2009 Oct 13.

Gerard Karsenty, MD, PhD Labororatory

Current Research Areas:

The current research areas remain centered on the coordinated regulation of bone remodeling and energy metabolism. they include the genetic dissection of how brain serotonin signals in the hypothalamus to regulate appetite; the regulation of bone mass by gut-derived serotonin; the regulation of insulin secretion and sensitivity b y the bone derived hormone osteocalcin; the study of the recently cloned osteocalcin receptor and of additional function of osteocalcin all related to the aging process. (Read more on Dr. Karsenty)

Publications:

  • Signaling through the M(3) muscarinic receptor favors bone mass accrual by decreasing sympathetic activity.
  • Shi Y, Oury F, Yadav VK, Wess J, Liu XS, Guo XE, Murshed M, Karsenty G.Cell Metab. 2010 Mar 3;11(3):231-8.
  • Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis.
    Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P. Nat Med. 2010 Mar;16(3):308-12. Epub 2010 Feb 7.
  • FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice.
    Rached MT, Kode A, Silva BC, Jung DY, Gray S, Ong H, Paik JH, DePinho RA, Kim JK, Karsenty G, Kousteni S.
    J Clin Invest. 2010 Jan 4;120(1):357-68. doi: 10.1172/JCI39901.
  • Ferron M, Wei J, Yoshizawa T, Del Fattore A, De Pinho RA, Teti A, Ducy P and Karsenty G. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell, 142: 296-308, 2010.
  • Oury F, Sumara G, Sumara O, Ferron M, Smith CE, Hermo L, Suarez S, Roth BL, Ducy P and Karsenty G. Endocrine regulation of male fertility by the skeleton. Cell, 144: 796-810, 2011.
  • Sumara G, Sumara O, Kim J, and Karsenty G. Gut-derived serotonin is a multi-functional determinant of the adaptation to fasting. Cell Metab. 16(5): 588-600, 2012.

Rudolph Leibel, MD Laboratory

Our work is focused on the molecular genetics and physiology of weight regulation and diabetes.

Projects:

  • The role of the genes FTO & FTM (RPGRP1L) in the regulation of body weight. These genes are in a region of the human genome that has largest impact yet detected on body weight in humans. ILDR2, a gene identified by us as a modifier of susceptibility to type 2 diabetes in obese mice, is novel in structure and unknown with regard to mechanisms of action. Cell biological, whole animal physiology and transgenic techniques are being used to understand this molecule. The gene may provide a connection between disordered lipid metabolism and type 2 diabetes. MGRN1, another gene identified here, has powerful effects on the obesity in mice mutations of the gene affect the intracellular trafficking of specific signaling proteins. This work may lead to identification of new controls of insulin signaling in cells.
  • Maternal obesity influences risk of obesity in offspring. The mechanism(s) for this effect are unknown. Using a mouse model of insulin resistance created by Dr. Accili and his associates, we have completed a study effects on body weight, fatness, beta cell function and brain anatomy of maternal insulin resistance as a surrogate for adiposity. The mechanisms underlying the growth (and cessation of expansion) of the beta cell mass of the islet. This process is poorly understood, but critical to elucidating the pathogenesis of diabetes, and perhaps ‘revising’ beta cell mass in patients.
  • Bio-behavioral responses to weight perturbation in mice and humans. These studies designed to elucidate the mechanisms underlying so-called ‘set point’ for body weight.
  • Creation of disease-specific stem cells (“dIPS”) from patients with type 1, type 2, monogenic diabetes, and specific genetic variations leading to obesity. We will use these cells to study disease pathogenesis. This work in collaboration with investigators in the New York Stem Cell Foundation, and the Helmsley Coalition for type 1 diabetes.
  • The genetic basis for extreme obesity and type 2 diabetes in patients taking 2nd generation antipsychotic drugs.
  • Genetic bases of extreme obesity in subjects undergoing bariatric surgery.
  • Role of the gut microbiome in response to diet and weight perturbation

(Read more on Dr. Leibel)

Publications:

  • Maehr, R, Chen, S, Snitow, M, Ludwig T, Yagasaki, L, Goland, R, Leibel, RL, Melton, DA. Generation of pluripotent stem cells from patients with type 1 diabetes. PNAS 2009 Sep 15;106(37):15768-73. PMID: 19720998 PMCID: PMC2735559
  • Bromberg, Y., Overton, J, Vaisse, C, Leibel, RL, Rost, B. In silico mutagenesis: a case study of the Melanocortin 4 Receptor. FASEB Journal. 2009 Sep;23(9):3059-69. PMID: 19417090 PMCID: PMC2735358
  • Goldsmith RL, Joanisse DR, Gallagher D, Pavlovich KH, Shamoon EL, Leibel RL, Rosenbaum M. Effects of experimental weight perturbation on skeletal muscle work efficiency, fuel utilization, and biochemistry in human subjects.et al. Effects of experimental weight perturbation on skeletal muscle work efficiency, fuel utilization, and biochemistry in human subjects. Am J Physiol Regul Integr Comp Physiol. 2010; 298: R79-88. PMID: 19889869
  • Zaghloul NA, Liu Y, Gerdes JM, Gascue C, Oh EC, Leitch CC, Bromberg Y, Binkley J, Leibel RL, Sidow A, Badano JL, Katsanis N. Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome. Proc Natl Acad Sci.107(23):10602-7, 2010. PMID: 20498079 PMCID: PMC2890780
  • Kinnally EL, Capitanio JP, Leibel R, Deng L, LeDuc C, Haghighi F, Mann JJ. Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes Brain Behav. (6):575-82. 2010. PMID: 20398062 PMCID: PMC2921011
  • Rosenbaum M, Kissileff HR, Mayer LE, Hirsch J, Leibel RL. Energy intake in weight-reduced humans. Brain Res. 2010 Sep 2;1350:95-102. PMID: 2059505 PMCID: PMC2926239
  • Myers MG, Leibel RL, Seeley RJ, Schwartz MW. Obesity and Leptin Resistance: Distinguishing Cause from Effect. Trends in Endocrinology and Metabolism. 2010. In Press.
  • Rosenbaum M and Leibel RL. Adaptive thermogenesis in humans. Int. J.Obesity. 2010. In Press.
  • Leibel RL and Rosenbaum M. Metabolic responses to weight perturbation. In K Clement et al. (eds.), Novel Insights into Adipose Cell Functions, Research and Perspectives in Endocrine Interaction, Springer-Verlag. Berlin Heidelberg, 2010. In Press.
  • Carmody, J.S., Wan, P., Accili, D., Zeltser, L.M., Leibel, R.L. Respective contributions of maternal insulin resistance and diet to metabolic and hypothalamic phenotypes of progeny. Obesity. 2010. In Press.

Virginia E. Papioannou PhD Laboratory

We are exploring the roles of two closely related genes, Tbx3 and Tbx2 in the pancreas with the long term goal of elucidating factors that could be manipulated for the derivation of stem or precursor cell populations for therapeutic use. Expression studies of the two genes during embryonic development and adult life have been extended by section in situ hybridization at later stages to confirm the whole mount expression studies. In addition, an antibody to Tbx3 was optimized and used to detect protein expression.

Currently, we are analyzing the functional roles of these two genes in the morphogenesis and differentiation of the pancreas using mice with null mutations in Tbx3 and Tbx2 genes. Pancreatic anlagen culture conditions have been optimized to allow studies of pancreas from mutant embryos, which die during midgestation. Expression of several genetic markers has been tested in mutant pancreas, although no differences have yet been detected.

Lori Sussel, PhD Laboratory

Research in the Sussel lab continues to focus on the development of the pancreas and maturation of the beta cell. We have primarily focused on understanding how the different islet cell types differentiate from a common progenitor. In addition, we have been exploring the mechanisms by which the insulin-producing cells become fully functional glucose sensing beta cells at birth. The information we gain from these studies can be directly applied to the generation of functional beta cells from endogenous and exogenous cell sources to be used in cell replacement therapies to treat Type 1 diabetes. (Read more on Dr. Sussel)

Papers:

  • Raum, JC, Artner, I, Hunter, C.S., Henderson, E., Guo, M., Elghazi, L., Sosa-Pineda, B., Mirmira, R.G., Sussel, L. and Stein, R. (2010). Islet {beta}-cell-specific MafA transcription requires the 5′-flanking conserved Region 3 control domain. Mol Cell Biol. Jun 28. [Epub ahead of print].
  • Hill, J.T., Anderson, K.R., Mastracci, T.L. and Sussel, L. (2010). Novel computational analysis of protein binding array data identifies direct targets of Nkx2.2 in the pancreas. Submitted.
  • Anderson,K.R. Balderes, D.A., Singer, R.A., Johnson, C.W., Artinger, K.B and Sussel, L. (2010) The L6 domain tetraspanin, Tm4sf4, regulates endocrine pancreas differentiation and directed cell migration. Submitted.

Megan Sykes, MD Laboratory

Dr. Sykes’s research focuses on utilizing bone marrow transplantation as immunotherapy to achieve graft-versus-tumor effects while avoiding graft-versus-host disease, the common complication of such transplants. Her laboratory studies in this area have led to novel approaches that have been evaluated in clinical trials. Another major area of her current research focuses on utilization of bone marrow transplantation for the induction of transplantation tolerance, both to organs from the same species (allografts) and from other species (xenografts). This work has resulted in the first successful trials of intentional allograft tolerance induction in humans. At Harvard, Dr. Sykes’ laboratory worked toward the development of clinically feasible, non-toxic methods of re-educating the T cell, B cell and NK cell components of the immune system to accept allografts and xenografts without requiring long-term immunosuppressive therapy. Her work has also extended into the area of xenogeneic thymic transplantation as an approach to tolerance induction, and into the mechanisms by which non-myeloablative induction of mixed chimerism reverses the autoimmunity of Type 1 diabetes. Her group has recently developed a model that allows them to study the pathogenesis of Type 1 diabetes and responses to therapies in mice with a human immune system. (Read more on Dr. Sykes)

Recent Publications:

  • Sykes M, Sheard MA, Sachs DH. Effects of T cell-depletion in radiation bone marrow chimeras. II. Requirement for allogeneic T cells in the reconstituting bone marrow inoculum for subsequent resistance to breaking of tolerance. J. Exp. Med. 1988;168: 661- 673.
  • Sharabi Y, Aksentijevich I, Sundt TM Jr, Sachs DH, Sykes M.  Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen. J. Exp. Med. 1990;172:195 - 202.
  •  Zhao Y, Swenson K, Sergio JJ, Arn JS, Sachs DH and Sykes M.  Skin graft tolerance across a discordant xenogeneic barrier.  Nature Med.  2(11):1211-1216, 1996.
  • Sykes M, Harty MW, Karlhofer FM, Pearson DA, Szot G, Yokoyama W.  Hematopoietic cells and radioresistant host elements influence natural killer cell differentiation.  J. Exp. Med. 1993;178:223-229.
  • Sykes M, Szot GL, Swenson KA, Pearson DA.  Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning.  Nat. Med. 1997;3:783-787
  • Yang Y-G, deGoma E, Ohdan H, Bracey JL, Xu Y, Iacomini J, Thall AD, Sykes M.  Tolerization of anti-gal1-3gal natural antibody-forming B cells by induction of mixed chimerism.  J. Exp. Med. 1998;187:1335-1342.
  • Wekerle T, Sayegh MH, Hill J, Zhao Y, Chandraker A, Swenson KG, Zhao G, Sykes M. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance.  J. Exp. Med. 1998;187:2037-2044.
  • Ohdan H, Yang Y-G, Shimizu A, Swenson KG and Sykes M.  Mixed bone marrow chimerism induced without lethal conditioning prevents T cell and anti-Gal1,3Gal antibody-mediated heart graft rejection. J. Clin. Invest. 104:281-290, 1999.
  • Nikolic B, Lee S, Bronson RT, Grusby MJ, Sykes M.  Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets.  J. Clin. Invest. 2000;105:1289-1298.
  • Wekerle T, Kurtz J, Ito H, Ronquillo JV, Dong V, Zhao G, Shaffer JM, Sayegh MH, Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.  Nat. Med. 2000;6:464-469.
  • Nikolic B, Takeuchi Y, Leykin I, Smith RN, Sykes M. Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. Diabetes 2004;53(2)376-383.  
  • Chakraverty R, Cote D, Buchli J, Cotter P, Hsu R, Zhao G, Sachs T, Pitsilldes C, Bronson R, Means T, Lin C, Sykes M.  An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues.  J. Exp. Med.  2006;203(8):2021-2031. PMCID: 2118376
  • Fudaba Y, Spitzer TR, Shaffer JM, Kawai T, Fehr T, Delmonico FL, Preffer FI, Tolkoff-Rubin, Dey BR, Saidman SL, Kraus A, Bonnefoix T, McAfee S, Power K, Kattelman K, Colvin RB, Sachs DH, Cosimi AB, Sykes M. Myeloma responses and tolerance following combined kidney and non-myeloablative marrow transplantation in vivo and in vitro analyses. Am. J. Transplant. 2006;6:2121-2133.
  • Shaffer J, Villard J, Means TK, Dombkowski D, Dey BR, McAfee S, Ballen KK, Saidman S, Preffer FI, Sachs DH, Spitzer TR, and Sykes M. Regulatory T cell recovery in recipients of haploidentical non-myeloablative hematopoietic cell transplantation with a humanized anti-CD2 mAb, MEDI-507, with or without fludarabine. Exp. Hemat. 2007; 35(7): 1140-1152. 
  • Gibbons C and Sykes M. Manipulating the immune system for anti-tumor responses and transplant tolerance via mixed chimerism. Immunol. Rev. 2008; 223:334-360. PMCID: 2680695
  • Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman S, Shaffer J, Preffer F, Ding R, Sharma V, Fishman J, Dey BR, Ko D, Hertl M, Goes N, Wong W, Williams W, Colvin RB, Sykes M, and Sachs DH. HLA-mismatched renal transplantation without maintenance immunosupression. New Engl. J. Med. 2008; 358(4):353-361. PMCID: 18216355
  • Andreola G, Chittenden M, Shaffer J, Cosimi A.B, Kawai T, Cotter P, LoCascio SA, Morokata T,  Dey BR, Tolkoff-Rubin NT, Preffer F, Bonnefoix T, Kattleman K, Spitzer TR, Sachs DH, Sykes M. Mechanisms of Donor-Specific Tolerance in Recipients of Haploidentical Combined Bone Marrow/Kidney Transplantation. Am J Transplant. 2011 Jun;11(6):1236-1247. doi: 10.1111/j.1600-6143.2011.03566 PMCID: 3140222
  • Kalscheuer H, Danzl N, Onoe T, Faust T, Winchester R, Goland R, Greenberg E, Spitzer TR, Savage DG, Tahara H, Choi G, Yang YG, Sykes M. A model for personalized in vivo analysis of human immune responsiveness. SciTranslMed. 2012 Mar 14;4(125):125ra30. PMID: 22422991 NIHMS in process.
  • Li H, Sykes M. Emerging concepts in haematopoietic cell transplantation. Nat Rev Immunol. 2012 May 25;12(6):403-16. doi: 10.1038/nri3226. PMID: 22627859  NIHMS in process.
  • Nikolic B, Onoe T, Takeuchi Y, Khalpey Z, Primo V, Leykin I, Smith RN and Sykes M. Distinct requirements for achievement of allotolerance versus reversal of autoimmunity via non-myeloablative mixed chimerism induction in NOD mice.  Transplantation, 2010; 89:23-32. PMCID: 3043373
  • Sykes M, Nikolic B.  Treatment of severe autoimmune disease by stem-cell transplantation.  Nature 2005;435:620-627.

Sharon Wardlaw, MD Laboratory

Research Activities:

The Central Melanocortin System and the Regulation of Energy Balance

The long-term objective of this project is to understand how the brain senses levels of peripheral energy stores and integrates these signals to maintain energy balance.  This project focuses on the melanocortin neuropeptide system  which plays a key role in regulating appetite and body weight and is an important target for leptin and insulin in the hypothalamus.  Studies center on the regulation of proopiomelanocortin (POMC) and the POMC-derived peptides, a-MSH,  g-MSH and ß-EP, together with agouti related protein (AgRP) which is synthesized in the hypothalamus and is a potent antagonist of the MSH peptides.     Transgenic and knockout mouse models are being used to study role of the melanocortin system in modulating metabolic responses to energy excess on a high fat diet and to food restriction and to characterize underlying mechanisms with respect to changes in body weight/composition and glucose and fat metabolism with a focus on energy expenditure and fuel oxidation.  An important focus is on the regulation pf POMC peptide processing with respect to energy balance.  These studies are highly relevant to human energy balance as mutations in POMC, POMC processing enzymes and in melanocortin receptors have all been associated with human obesity and there are many parallels with rodent models of melanocortin deficiency.

Lee M, Kim A, Chua SC,  Obici, S, Wardlaw SL: Transgenic MSH overexpression  attenuates the metabolic effects of a high fat diet.  Am J Physiol Endocrinol Metab 293: E121-E131, 2007.

Plum L, Lin HV, Dutia R, Tanaka J, Aizawa KS, Matsumoto M, Kim AJ, Cawley NX, Paik J, Loh YP, DePinho RA, Wardlaw SL, Accili D. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nature Medicine 15: 1195-201, 2009.

Wardlaw, SL: Hypothalamic proopiomelanocortin processing and the regulation of energy   balance. European J of Pharmacology 660: 213-219, 2011.

Ren H, Orozco IJ, Su Y, Suyama S, Gutierrez-Juarez R, Horvath TL, Wardlaw SL, Plum L, Arancio O, Accili D: FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149: 1314-1326, 2012.

Dutia R, Meece K, Dighe S, Kim AJ, Wardlaw SL: ß-Endorphin antagonizes the effects of a-MSH on food intake and body weight.  Endocrinology 153: 4246-4255, 2012.

Dutia R, Kim AJ, Mosharov E, Savontaus E, Chua SC, Wardlaw SL: Regulation of prolactin in mice with altered hypothalamic melanocortin activity. Peptides 37: 6-12, 2012.

Cerebrospinal Fluid Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy Balance

This proposal will focus on cerebrospinal fluid (CSF) POMC and AgRP measurements as a surrogate for hypothalamic melanocortin activity, as related to CSF leptin, insulin and nutrient levels.   Recent studies in the rodent show that levels of the intact POMC prohormone in CSF reflect hypothalamic POMC activity.   We have confirmed that the POMC prohormone is the predominant POMC peptide in human CSF and are examining the relationship of CSF POMC to BMI and adiposity. An important goal is to identify biomarkers in CSF that could predict responses to dieting and to pharmacotherapy for obesity that target the melanocortin system.

Xiao E, Kim AJ, Dutia R, Conwell I, Ferin M, Wardlaw SL: Effects of estradiol on cerebrospinal fluid levels of agouti-related protein in ovariectomized rhesus monkeys. Endocrinology 151: 1002-1009, 2010.

Page-Wilson G, Reitman-Ivashkov E, Meece K, White A, Rosenbaum M, Smiley RM, Wardlaw SL: Cerebrospinal fluid levels of leptin, proopiomelanocortin and agouti-related protein  in human pregnancy: Evidence for leptin resistance. J Clin Endocrinol Metab (in press). 

Lori Zeltser, PhD Laboratory

Our research is focused on characterizing two distinct developmental processes that could, in principle, impart persistent influences on obesity-related outcomes: (1) maternal influences on the specification of functionally antagonistic neuronal populations in the embryonic hypothalamus, and (2) the establishment of defended set-points for phenotypes related to adiposity and energy expenditure during the post-weaning period in rodents.  We developed a mouse model of early-onset obesity to study whether interventions that improve adiposity-related parameters in young animals can exert lasting effects on body composition.  By analyzing metabolic outcomes in conjunction with neuronal phenotypes, we hope to identify circuits regulating modifiable determinants of increased adiposity in young children.  In parallel, we are investigating the relationship between the establishment of defended baselines in metabolic circuits during adolescence and susceptibility to Anorexia Nervosa. 

 

Selected Publications

Padilla, S.L., Carmody, J.S. and Zeltser, L.M. (2010) Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits.  Nature Medicine 16(4):403-5.

Ring, L.E. and Zeltser, L.M.  (2010) Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels.  JCI, 120(8):2931-41.

Carmody, J.S., Wan, P., Accili, D., Zeltser, L.M., and Leibel, R.L. (2011)  Respective contributions of maternal insulin resistance and diet to metabolic and hypothalamic phenotypes of progeny. Obesity  19(3):492-9. 

Padilla, S.L., Reef, D. and Zeltser, L.M. (2012) Defining POMC neurons utilizing transgenic reagents: Impact of transient Pomc expression in diverse immature neuronal populations. Endocrinology 153(3):1219-31. 

Zeltser, L.M., Seeley, R.J, and Tschöp, M.H.  Synaptic Plasticity in Neuronal Circuits Regulating Energy  Balance. Nature Neuroscience. 15(10):1336-42.

 

Yiying Zhang, PhD Laboratory

Leptin Signalling

Leptin is a hormone secreted by adipose tissue, and plays a pivotal role in regulating energy homeostasis and metabolism. Regulation of protein turnover and intracellular trafficking of the leptin receptor and the impact of these processes on leptin signaling is the main focus of the research in Dr. Zhang’s laboratory. The lab uses cell and animal models and many cell and molecular biology techniques in these studies. The specific areas of interest including effects of cytokines and hormones on leptin receptor protein level, metalloproteinases involved in ectodomain shedding of the receptor, and receptor endocytotic pathways. They have recently shown that TNF-alpha, which is elevated in the obese state and causally related to insulin resistance, regulates leptin receptor trafficking and turnover via a PKC-dependent mechanism, leading to increases in both surface expression of the receptor and production of soluble leptin receptor via ectodomain shedding. 

Adipose Tissue Studies

Adipose tissue is a key player in the regulating energy balance and metabolism. Abdominal obesity in particular is a major risk factor for diabetes, cardiovascular disease, and metabolic syndrome.  Dr. Zhang’s group studies adipogenesis and adipose tissue gene expression with a focus on depot-related differences in these functions. The lab has developed preadipocyte transplantation and other techniques to study adipogenesis and cell-autonomous function of adipocytes in vivo. Dr. Zhang also serves as a co-director of the Adipose Tissue Core of the New York Obesity Nutrition Research Center and collaborates with many other investigators on adipose tissue studies. 

Dietary Leucine Effects on Diabetes and Body Weight

Dr. Zhang’s group has demonstrated that moderate increases in dietary leucine intake, a natural component of dietary proteins, attenuate high fat diet-induced weight gain and impairment in glucose and lipid metabolism in normal mice. Chronic dietary supplementation of leucine also significantly improves glycemic control (with ~1% unit reduction in HbA1c level) in multiple mouse models of obesity/type 2 diabetes. These findings strongly support the concept that macronutrient composition of diet can have significant effects on metabolism and that increasing protein intake would be beneficial in clinical management of obesity and diabetes. (Read more on Dr. Zhang)

Recent Publications:

  • Guo K, Mogen J, Struzzi S, Zhang Y (2009) Preadipocyte transplantation: an in vivo study of direct leptin signaling on adipocyte morphogenesis and cell size. Am J Physiol Regul Integr Comp Physiol 296:R1339-1347. PMID: 19193947; PMC2689822
  • Liu L, Shi X, Choi CS, Shulman GI, Klaus K, Nair KS, Schwartz GJ, Zhang Y, Goldberg IJ, Yu, YH (2009) Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1. Diabetes 58:2516-2524. PMID: 19675136; PMC2768165
  • Zhang Y (2010) Utility of transplantation in studying adipocyte biogenesis and function. Mol Cell Endocrinol 318:15-23. PMID: 19733623; PMC2826534
  • Guo K, Yu YH, Hou J, Zhang Y (2010). Leucine supplementation improves glucose metabolism in etiologically distinct mouse models of obesity and diabetes mellitus. Nutr Metabo (Lond) 7:57-66.  PMID: 20624298; PMCID: PMC2914079
  • Guo X, Roberts MR, Becker SM, Podd B, Zhang Y, Chua SC, Myers, MG, Duggal P, Houpt ER, William A. Petri, WA. Leptin Signaling in Intestinal Epithelium Mediates Resistance to Enteric Infection by Entamoeba histolytica. Mucosal Immunity. May 2011;4(3):294-303. PMID: 21124310
  • Gan L, Guo K, Cremona ML, McGraw TE, Leibel RL, Zhang Y. TNF-alpha Up-Regulates Protein Level and Cell Surface Expression of the Leptin Receptor by Stimulating Its Export via a PKC-Dependent Mechanism. Endocrinology. 2012 Oct 15. [Epub ahead of print], PMID: 23070544.

Xiaojuan Chen, MD, PhD Laboratory

The Chen laboratory utilizes islet transplantation models to explore areas of islet cellular and molecular biology that are pertinent to the development of diabetes as well as to the improvement of islet transplantation for the treatment of type 1 diabetes.  In addition, the laboratory aims to, by working closely with immunologists at the CCTI, develop clinically applicable strategies for the induction of donor specific transplantation tolerance in patients.  Current lines of investigation include:

  • Studies on the induction of specific tolerance to allogeneic islet transplants by an approach which utilizes mixed bone marrow chimerism and Treg.
  • Studies on developing approaches that optimize islet cell survival and function during islet processing, culture and engraftment.
  • Studies on the physiology of human islet alpha cells including their reprogramming potential under hyperglycemia in vivo as part of an effort in developing strategies that mimic the response to physiological or pathophysiological conditions that drive islet beta cell neogenesis.
  • Studies on islet beta cell replication including the mechanisms and the limiting factors involved.  These studies will allow us to gain greater insights into the fundamental physiological mechanisms that govern the normal growth and functioning of pancreatic islets.  In addition, it will provide a physiological basis to identify targets in signaling pathways that would be useful to design potential therapeutic strategies to generate new beta cells to prevent and/or cure type 1 and type 2 diabetes.

The future goals of the laboratory are to pursue each of the areas in more depth both physiologically and mechanistically and to continually pinpoint areas of therapeutic potential, particularly in preventing islet dysfunction post-transplantation and during the development of diabetes as well as in preventing auto- and allo-immunity against islets.

Selected Publication

  • Chen X, Zhang X, Larson CS, Baker MS, Kaufman DB. Visualization of Islets after Transplantation and Early Detection of Graft Rejection by In Vivo Bioluminescence Imaging. Transplantation 2006, 81:1421-7.
  • Chen X, Zhang X, Larson CS, Kissler H, Kaufman DB.  The epididymal fat pad as a transplant site for minimal islet mass.  Transplantation 2007, 84(9):122-5.
  • Chen X, Zhang X, Larson CS, Xia G, Kaufman DB. Prolonging islet allograft survival using in vivo bioluminescence imaging to guide timing of anti-lymphocyte serum treatment of rejection.  Transplantation 2008, 85(9):1246-52.
  • Chen X, Zhang X, Chen F, Larson CS, Wang L, Kaufman DB. Comparative study of regenerative potential of β-cells from young and aged donor mice using a novel islet transplantation model.  Transplantation 2009, 88(4):496-503. 
  • Chen X, Larson CS, West J, Zhang X, Kaufman DB. In vivo detection of extra-pancreatic insulin gene expression in diabetic mice by bioluminescence imaging. PLoS ONE 2010; Feb 24, 5(2): e9397. 
  • Rink SJ, McMahon KM, Chen X, Mirkin CA, Thaxton CS, Kaufman DB. 2010, Transfection of pancreatic islets using polyvalent DNA-functionalized gold nanoparticles.  Surgery 2010;148:335-45.
  • Rink SJ, Chen X, Zhang X, Kaufman DB.  Conditional and specific inhibition of NF-κB in mouse pancreatic β-cells prevents cytokine-induced deleterious effects and improves islet survival post-transplant. Surgery 2012; Feb;151(2):330-9. Epub 2011 Oct 6.

Working together to dissolve boundaries

At the Berrie Center, we feel the more brainpower we can apply to a research problem, the better. There's no place here for silos or turf wars. Our researchers are open to whatever it takes to get the job done. Which, in our experience, often means unlimited creative collaboration across the United States and across international borders. Along with the funding to support the work, wherever it's being done. Our research model is attracting a lot of attention and it's increasingly being copied as the best way to make progress. Some impressive organizations have lined up behind this apporoach, among them:

AstraZeneca Diabetes Research Program, initiated in 2008

The Berrie Center coordinates a collaborative research program with AstraZeneca that involves 4 labs at Columbia and includes studies of brain imaging (in humans and mice) related to obesity, the regulation of lipid metabolism, inflammation in obesity and diabetes, and the neurobiology and energetics of weight perturbation in mice.

The Leona M. and Harry B. Helmsley Charitable Trust Type 1 Diabetes Research Program, initiated 2009

Berrie Center is one of four lead institutions (with Harvard, UCSF, and U. Florida) that are participating in the Leona M. and Harry B. Helmsley Charitable Trust research program in type 1 diabetes. The program includes an emphasis on stem cell biology and the New York Stem Cell Foundation Lab is a collaborating site for some of this work.

Brehm Coalition, initiated 2008

Berrie Center is among a group of leading institutions that participate in the Brehm Coalition, a philanthropic initiative that supports efforts to accelerate research on a cure for type 1 diabetes. Seven academic medical centers, in addition to the Berrie Center, are active in the Brehm coalition: they include the universities of Michigan, Chicago, Colorado, and Florida (Gainesville), UCSF, UCSD, and Yale. The initiative has already spawned additional collaborations in clinical translational studies, genetics of pancreas development, and immunomodulation in the treatment of type 1 diabetes.

Beta Cell Biology Consortium

On the basis of our joint efforts with the NYSCF in creating insulin-producing cells frominduced pluripotential stem cells (iPS cells) derived from skin and other tissues, a second lab (Dr. Sussel’s is already a member) at Columbia (Leibel/Egli) has been made a member of the NIH-Sponsored BCBC Consortium. The mission of the Beta Cell Biology Consortium (BCBC) is to facilitate interdisciplinary approaches that will advance our understanding of pancreatic islet development and function with the long-term goal of developing a cell-based therapy for insulin delivery. This 2nd membership occurs through a grant entitled: “Formation of endocrine pancreas progenitors” of which Dr. Doris Stoffers at the University of Pennsylvania is PI. The aim of this project is to understand the epigenetic regulation of the pro-endocrine transcription factor, Ngn3, and the roles of Pdx1 and Hnf6 in the cross-regulatory transcription factor network of developing ß cells will inform efforts to improve the efficiency, fidelity and stability of the ß cell phenotype achieved through the guided differentiation of non-ß cell populations.

Inter-institutional Diabetes Research Seminars in New York City

Berrie Center investigators help coordinate several annual NYC scientific meetings aimed at fostering collaboration among research groups including:

Interinstitutional Diabetes Research Symposium
In collaboration with scientists and students at Cornell, Mt. Sinai, Einstein and Yale we hold an annual one day Interinstitutional research symposium, held most recently at Einstein on May 21, 2010. This meeting was attended by over 100 faculty and students of the participating institutions, as well as scientists from several local pharmaceutical companies. The oral and poster presentations were of extremely high caliber. The next will be held at Cornell.

D-Cure Meeting
Berrie Center faculty participated in the Annual D-Cure meeting, organized again by Dr. Jesse Roth and held in 2010 at the NY Academy of Medicine. D-Cure is an Israeli non-profit organization that promotes and funds scientific research in diabetes. Students and faculty from Einstein, Cornell, Columbia and Mt. Sinai attended.

Berrie Frontiers in Diabetes Research Symposium
The Berrie Center’s 12th annual research symposium is held annually in November. The 2010 conference is “Cardiovascular Consequences of Diabetes: The Role(s) of Inflammation.” The topic is particularly relevant to recent efforts of the Berrie Foundation to support clinical care and research in this area. A group of 8 outstanding scientists will present talks on their most recent – often unpublished – work.