Obesity Research Center
Summary of research interest:
The Obesity Research Center (ORC) was founded in 1997 as a collaborative environment to foster basic and clinical research in body fuel regulation by senior scientists committed to serve as mentors and leaders. ORC comprises faculty members from the Department of Medicine and several basic science departments at BUSM. Barbara E. Corkey, Ph.D., Professor of Medicine, is the Director of the ORC and Susan Fried is the PI and Director of the citywide NIH-funded Boston Nutrition Obesity Research Center (BNORC). ORC founders and leaders also includes Caroline Apovian, M.D., Professor of Medicine and Director of the Nutrition and Weight Management Center; Stephen Farmer, Ph.D., Professor of Biochemistry; James Hamilton, Ph.D., Professor of Biophysics and Physiology; and Paul Pilch, Ph.D., Professors of Biochemistry and Biophysics. The ORC members are located throughout the campus but the main site of operations is on the 8th floor of the Evans Biomedical Research Center at 650 Albany Street. ORC serves as a nidus for collaborative studies, mentoring and educational events.
General field of research:
Metabolic Tissue Regulation, Fuel Metabolism, Energetics and Signal Transduction, Metabolic Disease
Barbara E. Corkey
650 Albany Street, rm808
Phone: (617) 638-7091
Fax: (617) 638-7124
Obesity; Diabetes; Metabolism; Fat cells; ß-cell; Signal Transduction, Hepatocytes, Mitochondria, Lipids
Technologies available for sharing upon request:
Analytical Instrumentation Core: http://www.bumc.bu.edu/analytical-core/
Cellular Imaging Core: http://www.bu.edu/cores/home/cellular-imaging-core/
IVIS Imaging Core: http://www.bu.edu/cores/home/ivis-imaging-core/
High Field MRI/NMR Imaging Core: http://www.bu.edu/cores/home/mri-core/
Metabolic Phenotyping Core: http://www.bu.edu/cores/home/metabolic-phenotyping-core/
High Throughput Screening Core: http://www.bu.edu/cores/home/high-throughput-screening-core-2/
Intracellular ion measurement in real time in living cells
Metabolic pathway analysis in response to glucose, amino acids and fatty acids
Endocrinology, Diabetes, Nutrition, and Weight Management
Dr. Apovian’s focus is on clinical research in obesity and diabetes. Her group investigates weight loss and its effects on endothelial cell function, adipose cell metabolism and inflammation, research in the bariatric surgery population and novel pharmacotherapeutic antiobesity agents. She has become an expert in the technique for subcutaneous adipose tissue aspirations, and has been performing these aspirations on research subjects at Boston University for over 5 years. Other research projects include dietary and physical activity interventions in underserved post-partum women and the investigation into the effects of increased dietary protein on lean body mass, maximal voluntary muscle strength and power in older men with mobility limitations.
The Vascular Biology Unit led by Dr. Richard Cohen seeks to understand why oxidants impair function of diseased arteries. His group has found that in diabetes, hypertension, and atherosclerosis, the vasodilator, nitric oxide is inactivated by superoxide, an oxidant produced in diseased blood vessels. As a result of this reaction an even more potent oxidant, peroxynitrite, is formed. At low levels, peroxynitrite S-glutathiolates proteins including the sarcoplasmic reticulum calcium ATPase and p21ras, modulating cell signaling. High levels of peroxynitrite can be blamed for inactivating these and other important proteins, such as manganese superoxide dismutase. As part of the BU Cardiovascular Proteomics Center, Dr. Cohen and his group are identifying chemical modifications of proteins formed by oxidants with mass spectrometric and protein tagging strategies. These modifications may serve as biomarkers for abnormal cell signaling and/or disease. Such markers have been found in diseased human arteries and platelets.
Within the ORC basic science environment, Dr. Corkey’s laboratory focuses on the metabolic regulation of signal transduction and energy metabolism and fuel partitioning in fat cells, fuel-stimulated insulin secretion by the pancreatic ß-cell, and cytokine signaling in human fibroblasts from patients with inborn errors of fatty acid oxidation and Type 1 diabetes. The main questions in the Corkey laboratory concern how fuels regulate insulin secretion and how the fat cell determines whether to store or burn fat. We seek to answer these questions by studying the fuel-induced signals that modulate secretion, electrical activity, metabolism and gene expression. Recent discoveries include a putative role for reactive oxygen species in insulin secretion, digital calcium signaling in pancreatic ß-cells and a role for inhibition of the respiratory chain in regulating fat storage in adipocytes. The main tools used in the laboratory include measurement of intracellular ions such as Ca2+ and H+, plasma and mitochondrial membrane potential, oxygen consumption, the signaling consequences of cellular energy state, the influence of ROS and fatty acids on protein kinases and the role of fatty acids and long chain fatty acyl CoA on signal transduction. Work is done in collaboration with scientists at Boston University, the Karolinska Institute, the Universities of Montreal, Pennsylvania and Chicago.
Research being conducted by Jude Deeney, Ph.D., Assistant Professor of Medicine, is designed to discern the nutrient-derived metabolic signals leading to glucose- and fatty acid (FA)-induced insulin exocytosis from the pancreatic ß-cell. FA acutely stimulates glucose-induced insulin secretion (GSIS) while chronic exposure to elevated FA and glucose can result in glucolipotoxicity (GLT) with basal hypersecretion and inhibition of GSIS. Despite the adverse effects of chronic exposure, FA is known to be required for normal exocytosis from the ß-cell. Deciphering the dual effects of FA on GSIS will lead to the possible development of therapies that would reduce the inhibitory effects while sparing the stimulatory effects of FA on the ß-cell. Studies in his laboratory are aimed at identifying the lipids or lipid classes involved in enhancing and suppressing GSIS and assessing their effects on lipid-modulated or modulating proteins.
Pharmacology and Medicine
The central focus of Dr. Denis’ research in obesity is the molecular mechanism of the obesity-associated cancers, including stratification of risk for cancers among obese ‘metabolically healthy’ patients and obese ‘metabolically unhealthy’ patients. These risks are likely mediated in part by the different inflammatory profiles of these two groups of obese humans; supporting a hypothesis that transcriptional networks and crosstalk among adipocytes, infiltrating immune cells and cytokines affects cancer cell properties. The BET family of bromodomain proteins function squarely at the nexus of these networks, thus effort has focused specifically on the role of Brd2 and Brd4 in obesity, inflammation and cancer.
The broad goal of my research is to understand the role of T cells in the pathogenesis of autoimmune diseases and to apply this knowledge for the development of new therapeutic interventions. My laboratory uses in vivo models of autoimmune diseases to follow T cell responses against tissues (e.g. pancreatic islets) and to identify molecules (e.g. cytokines) that orchestrate the autoimmune attack. In addition, we are developing novel gene-deficient and transgenic models to obtain mechanistic insights into the cytokine signaling pathways and transcription factors that drive autoreactive T cells.
Dr. Farmer has had a long-standing interest in understanding the mechanisms controlling the development and function of adipose tissue. His focus is directed towards identifying the transcriptional events regulating the genes that control these processes.
His present research is designed to determine the mechanisms controlling development of brown-like adipocytes (beige/brite) within white adipose tissue. These cells can arise from conversion of mature white adipocytes through the induction of brown adipose genes bestowing brown adipose functions to the white cells (brite cells). Beige cells express many brown functions but arise from a unique progenitor by unknown mechanisms. In the case of brite cells, Farmer’s research is focused on the role of PPARg (the master regulator of adipose formation) in selectively activating brown gene expression. With respect to beige cells, Farmer and colleagues have recently discovered a novel-signaling pathway controlling development of beige progenitors that relies on suppression of a transcriptional complex referred to as MRTFA/SRF. In both cases, studies are designed to identify co-regulators of PPARg and MRTFA/SRF with the goal of discovering novel targets for therapeutics that enhance energy expenditure in white adipose tissue.
Endocrinology, Diabetes, and Nutrition
Director of the Boston Nutrition Obesity Research Center (BNORC)
Obesity, particularly abdominal obesity, confers increased risk for cardiovascular disease, type 2 diabetes, osteoarthritis, stroke and cancer. The long-term goal of research in Dr. Fried’s laboratory is to understand how fat deposition in different anatomical depots is regulated, and why abdominal obesity is associated with metabolic abnormalities.
Physiology and Biophysics
A major focus of Dr. Hamilton’s research in obesity and diabetes is on molecular aspects of fatty acid binding interactions and transport in plasma, cell membranes, and the cytosol, using state-of-the art methods in structural and cell biology. The interactions of fatty acids, bilirubin, and drugs with serum albumin are assessed by 13C NMR spectroscopy, and correlating NMR results with crystallographic data to achieve site-specific information. To study the mechanisms by which fatty acids cross the membrane barrier between the plasma and the cytosol, a combination of fluorescence probes are used to distinguish and quantify individual steps of fatty acid transport in membranes. The mechanism by which FA move across membranes has immediate and important implications for the treatment of diseases and targeting of pharmacological interventions to reduce accumulation of fat in cells.
Endocrinology, Diabetes, and Nutrition
Progression of prostate cancer to androgen independence represents a major step in the evolution of this disease to its aggressive and deadly form. Prevention or amelioration of this androgen independent state could significantly improve the treatment of this disease.
Evidence in our laboratory indicates fish oil and omega 3 polyunsaturated fatty acids may slow down the progression of prostate cancer cells to androgen independence. Our research focuses on understanding of cellular and molecular mechanisms that account for the effects of omega 3 fatty acids on prostate cancer. Ultimately, this research will help improve the safety and efficacy of prostate cancer treatment in men.
Pharmacology and Experimental Therapeutics
Dr. Jiang is mainly focused on studying obesity-related early stage inflammation. In particular, he is investigating the role of neutrophils and their enzymes in diet-induced obesity. They are also examining the role of CDP138, a newly identified phosphoprotein, in insulin signaling and glucose and fatty acid metabolisms. The Jiang lab webpage can be found in the website with the Department of Pharmacology & Experimental Therapeutics:
Dr. Kandror’s lab studies molecular mechanisms of insulin action in adipose cells. The areas of their primary interest are the effects of insulin on glucose uptake, lipolysis, lipogenesis, and protein synthesis.
Mi Jeong Lee
Marc Liesa Roig
Lynn L. Moore
Preventative Medicine and Epidemiology
Dr. Moore is an epidemiologist with a long-standing interest in the causes and consequences of obesity throughout the lifespan. Particular areas of interest include the role of nutrition and other behavioral risk factors in the development of obesity and its associated conditions, such as inflammation and high blood pressure, and ultimately chronic diseases such as cardiovascular and metabolic disorders. She has carried out studies of obesity and nutritional health effects in a number of diverse populations during critical life periods including early childhood, adolescence, pregnancy and during the older adult years.
Another of her specific areas of interest includes the role of dietary protein on body composition and strength. We are carrying out studies of the type and amount of protein needed to prevent muscle breakdown and promote muscle protein synthesis at different ages. The development and treatment of aging-related sarcopenia is a particular focus of my current research.
Dr. Nikolajczyk’s current research focuses on immunometabolism, or the role the immune system plays in obesity and type 2 diabetes. She published the first comprehensive analyses identifying functions of B cells and T cells in type 2 diabetes patients. This work includes a molecular understanding of mechanisms responsible for pro-inflammatory lymphocyte functions in these patients. Complementary mouse work in Dr. Nikolajczk’s lab rigorously tests concepts identified for humans in a whole animal model. Her work in both human subjects’ material and mouse models demonstrates facility in multiple major experimental approaches and is a strong example of success from concurrent bench-to-bedside and bedside-to-bench work with cross-disciplinary impact.
The major goals of the Perissi lab is to understand ubiquitin signaling in the regulation of inflammatory responses and nuclear receptors transcriptional activity.
Dr. Pilch’s lab studies the cell biology of fuel utilization in adipocytes and skeletal muscle.
The modern Western diet coupled with a sedentary lifestyle has led to an epidemic of obesity, a consequence of which is a dramatic rise in the incidence of type II diabetes mellitus, a malfunction in insulin-regulated metabolism. At the cellular level, type II diabetes is characterized by failure of insulin to act in liver, muscle and fat. We study aspects of adipocyte and muscle cell biology to understand the interplay between glucose and fat metabolism as well as the interplay between adipocytes and muscle required for overall metabolic homeostasis. Indeed, we wish to uncover the mechanism(s) by exercise also regulates some of these same parameters independent of insulin. Understanding these pathways will help us to figure out how they are compromised in pathophysiological states such as diabetes.
Endocrinology, Diabetes, and Nutrition
Impairment of fat metabolism is one of the primary causes of type II diabetes, obesity and other metabolic diseases. Our future research will address a key question in human metabolic diseases: what are the molecular mechanism(s) regulating free fatty acid metabolism that further influence insulin sensitivity in humans.
Lucia Rameh Plant
Studies in the Rameh Lab (http://sites.bu.edu/rameh-lab/) are aimed at understanding how phosphoinositide lipids affect different aspects of the diabetes/obesity cycle. As regulator of many cellular processes, such as vesicle trafficking and hormone signaling, phosphoinositide kinases are promising targets in the treatment of these diseases. The Rameh Lab is particularly interested in determining the role of the phosphoinositide PtdIns-5-P in pancreatic beta cell function. Recent data from the Lab show that PtdIns-5-P 4-kinases can regulate nutrient-independent TORC1 signaling that activates basal protein translation. They are currently investigating how these can impact basal insulin production and secretion in the pre-diabetic state. The Rameh Lab uses state-of-the art high performance liquid chromatography (HPLC) coupled to flow scintillation analysis to measure cellular phosphoinositides in cultured cells. They have recently developed a unique method for PtdIns-5-P detection that will aid future research on the cellular function of this lipid.
Our unit for many years has examined the concept that dysregulation of fuel (glucose and fatty acid) metabolism contributes to the pathogenesis of type 2 diabetes and its complications. In addition we have examined at a mechanistic level how exercise may be therapeutically useful in treating and preventing these disorders. Over the past 10-15 years we have demonstrated that exercise acts at least in part by activating in many tissues AMP-activated protein kinase (AMPK), a fuel sensing enzyme that in response to a decrease in cellular energy state increases metabolic processes (e.g. fatty acid oxidation) that generate ATP and inhibits others (e.g. lipid synthesis) that consume ATP, but are not acutely necessary for survival. In the process we have identified many endogenous (e.g. adiponectin, IL-6) and exogenous (e.g. thiazolidinediones) AMPK activators and have demonstrated that AMPK protects endothelial cells, adipocytes and retinal pericytes against the insulin resistance, inflammation, mitochondrial dysfunction, and apoptosis caused by excess glucose and fatty acid and inflammatory cytokines. Most recently we have described a link between AMPK and Sirt1, a histone/protein deacetylase that has been linked to the increase in longevity caused by calorie restriction.
Mitochondrial oxidative damage plays a key role in cellular degeneration, aging and metabolic diseases. The goal of the Shirihai lab is to determine how damage is prevented or contained, how dysfunctional mitochondria are recognized and removed, and how mitochondrial networks participate in these processes.
Dr. Shirihai studies two disease models in which oxidative damage to mitochondria play a key role in the development of pathology. In diabetes, nutrient-induced oxidative damage has been shown to be a major mediator of endocrine dysfunction and beta cell loss. In bone marrow, oxidative damage induced by iron and heme-intermediates, leads to the development of sideroblastic anemia and myelodysplastic syndrome.
Cellular imaging is central to our research and much effort is dedicated to developing of novel techniques for monitoring living cells under the microscope.
Endrocrinology, Diabetes, and Nutrition
Dr. Tornheim previously studied spontaneous oscillatory behavior of glycolysis in muscle extracts. These oscillations involve the regulatory properties of the key control enzyme, phosphofructokinase, which was therefore the object of related kinetic studies. He is now testing the hypothesis that such oscillatory behavior of glycolysis and the ATP/ADP ratio underlies glucose-stimulated oscillations in intracellular free Ca2+ and insulin secretion in pancreatic islets. Such oscillations can increase the potency of insulin, and loss or derangement of these oscillations may contribute to the development of type 2 diabetes.
Xiaolai Julia Xu
The main goal of Dr. Zang’s laboratory is to investigate the physiological and pathological regulation of novel nutrient signaling in energy homeostasis and in diabetes and its cardiovascular complications. A major focus is to determine how protein kinases or their signaling networks modulate hepatic glucose and lipid metabolism through regulation of kinase phosphorylation, protein-protein interactions and gene expression, and their implication in the pathogenesis of diabetes.
Raphael A. Zoeller
Physiology and Biophysics
Lipids are not only structural units of membranes. They also participate in important cellular functions, serving as second messengers, hormones, pheromones and membrane anchors for proteins. Although several “active” lipid species have been identified, there are many others that remain undiscovered. To identify functional roles for lipids, Dr. Zoeller and his lab develop mutant animal cell lines that are deficient in the biosynthesis of specific lipid species. Using these mutants, they can determine what cellular processes are affected by the loss of the lipid, establishing a role for the lipid in that process. The mutants can also serve as tools for the isolation of the genes involved in the biosynthesis of the lipid. Most importantly, the study of these mutants leads to new biochemistry, not achievable through conventional approaches.
Students, Postdocs, and Staff:
David Chess, PhD
Emily Lacy Coleman
Jason DeFuria, PhD
Weimin Guo, PhD
Albert Richard Jones, MS
Kalypso Karastergiou, MD, PhD
R. Taylor Pickering
Vera Schultz, PhD
Amber Simmons, PhD
Rudy Valentine, PhD
Siu Wong, MBA
Yuanyuan Emily Wu, PhD
Wikstrom, J., Mahdaviani, K., Sereda, S, Si, Y., Liesa, M., Las, G., Twig, G., Corkey, B., Cannon, B., Nedergaard, J. and Shirihai, O. (2014) Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. EMBO J doi:10.1002/embj.201385014.
Simmons, AL., Schlezinger, JJ and Corkey, B. E. (2014) What are we putting in our food that is making us fat? Food additives, contaminants, and other putative contributors to obesity. Current Obesity Reports, In press
Husni, N.R., Jones, IV, A.R., Simmons, A.L. and Corkey, B. E. (2014) Fibroblasts From Type 1 Diabetics Exhibit Enhanced Ca2+ Mobilization after TNF or Fat Exposure. PLoS One, 9(1): e87068
DeFuria J., Belkina A. C., Jagannathan-Bogdan M., Snyder-Cappione J., Carr J. D., Nersesova Y. R., Markham D., Strissel K. J., Watkins A. A., Zhu M., Allen J., Bouchard J., Toraldo G., Jasuja R., Obin M. S., McDonnell M. E., Apovian C., Denis G. V., Nikolajczyk B. S. (2013) B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile, PNAS 110(13):5133-5138.
Denis G.V. & Obin M.S. (2013) ‘Metabolically healthy obesity’: Origins and implications, Mol. Aspects Med. 34(1):59-70.
Wang F., Deeney J.T., & Denis, G.V. (2013) Chapter 3: Brd2 gene disruption causes “metabolically healthy” obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes, Vitam. Horm. 91:49-75.
Chakrabarti, P., Kim, J-Y, Singh, M., Shin, Y-K., Kim, J., Kumbrink, J., Wu, Y., Lee, M-J., Kirsch, K.H., Fried, S.K., and Kandror, K.V. (2013) Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway, Mol. Cell. Biol., 33(18): 3659-3666.
Huang, G., Buckler-Pena, D., Nauta, T., Singh, M., Asmar, A., Shi, J., Kim, J. Y., and Kandror, K.V. (2013) Insulin responsiveness of glucose transporter 4 in 3T3-L1 cells depends on the presence of sortilin. Mol. Biol. Cell, 24(19):3115-3122.
Mansuy-Aubert V, Zhou QL, Xie X, Gong Z, Huang JY, Khan AR, Aubert G, Candelaria K, Thomas S, Shin DJ, Booth S, Baig SM, Bilal A, Hwang D, Zhang K, Lovell-Badge R, Smith SR, Awan FR, Jiang ZY. (2013) Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure. Cell Metab. 2013 Apr 2; 17(4):534-48. PMID:23562077
Kim, J-Y. & Kandror, K.V. The first luminal loop confers insulin responsiveness to the glucose transporter 4. (2012) Mol. Biol. Cell, 23(5):910-917.
Corkey, B. E. (2012) Banting lecture 2011 Hyperinsulinemia: Cause or Consequence? Diabetes. 61:4-13.
Corkey, B. E. and Shirihai, O. (2012) Metabolic Master Regulators: Sharing Information among Multiple Systems, Trends Endocrinol Metab. 23(12):594-601.
Corkey, B. E. (2012) Diabetes: Have we got it all Wrong? Insulin Hypersecretion and Food Additives: Cause of Obesity and Type 2 Diabetes? Diabetes Care. 35(12):2432-2437.
Saadeh M., Ferrante T.C., Kane A., Shirihai O., Corkey B.E. and Deeney J.T. (2012) Reactive oxygen species stimulate insulin secretion in rat pancreatic islets: studies using mono-oleoyl-glycerol. PLOS One e30200.
Krawczyk, S. A., Haller, J. F., Ferrante, T., Zoeller, R. A. and Corkey, B. E. (2012) Reactive Oxygen Species Facilitate Translocation of Hormone Sensitive Lipase to the Lipid Droplet During Lipolysis in Human Differentiated Adipocytes. PLoS One; 7(4):e34904.
Johnston-Cox H., Koupenova M., Yang D., Corkey B., Gokce N., Farb M.G., Lebrasseur N., Ravid K. (2012) The a2b adenosine receptor modulates glucose homeostasis and obesity. PLoS One. 7(7):e40584.
Guo, W., Li, Y., Liang, W., Wong, S., and Corkey, B. E. (2012) Beta-mecaptoethanol Suppresses Inflammation and Induces Adipogenic Differentiation in 3T3-F442A Murine Preadipocytes, PLoS One. 7(7):e40958.
Kandror K. V., Pilch P. F.(2011) The sugar is sIRVed; sorting Glut4 and its fellow travelers. Traffic, 12(6):665-671.
Bogan JS, Kandror KV. Biogenesis and regulation of insulin-responsive vesicles containing GLUT4. Curr. Opin. Cell Biol. 2010, 22, 506-512.
Perissi V., Jepsen K., Glass C.K. & Rosenfeld, M.G. (2010) Deconstructing repression: evolving models. Nat. Rev. Genetics 11:109-123.
Rameh LE. Type 2 PIP4-kinases. Chapter 131, In Handbook of Cellular Signaling 2010, Three-Volume Set 2 edn (Bradshaw, R.A. and Dennis, E.A., eds), pp1043-1048, Elsevier.
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Vernochet C, Peres SB, Davis KE, McDonald ME, Qiang L, Wang H, Scherer PE, Farmer SR. (2009) C/EBPalpha and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor gamma agonists. Mol. Cell. Biol. 29:4714-4728.
Farmer SR. (2008) Molecular determinants of brown adipocyte formation and function. Genes & Dev. 22:1269-1275.
Last updated Feb. 25, 2014 by Amber Simmons