Basic Biomedical Research:
The main goal of work in the Corkey laboratory is to determine how fuels generate the signals to communicate among different organs in the body to modulate hormone and adipokine exocytosis, electrical activity, metabolism and gene expression. It involves assessment of the influence of metabolites and mitochondrial energy state on intracellular signal transduction in adipocytes, pancreatic ß-cells, liver and human fibroblasts. Recent emphasis has been on ion handling, respiration, the signaling consequences of cellular energy state, the influence of fatty acids on protein kinases and the role of fatty acids and long acyl CoA on signal transduction. Unique resources of the laboratory include imaging, fluorescence and amperometric techniques to measure responsiveness of living cells to various treatments and stimuli. Work is done in collaboration with scientists at Boston University School of Medicine, the BioCurrents Laboratory of the Marine Biological Institute, the Karolinska Institute, the Universities of Chicago, Montreal and Pennsylvania, and the Hamner Institutes for Health Sciences.
The overall focus of my laboratory is to understand the molecular mechanisms controlling the formation and function of adipocytes with a focus on identifying the signaling pathways and transcription factors that regulate adipogenesis. Projects presently under investigation include the role of PPARgamma (peroxisome proliferator-activated receptor gamma) and the C/EBPs (CCAAT/enhancer binding proteins) in regulating the sequential expression of the adipogenic factors that control the differentiation of preadipocytes into adipocytes and expression of genes that control various adipocyte functions including insulin-dependent glucose uptake and production of adiponectin. We are also investigating the mechanisms by which the adipocyte responds to changes in energy balance by focusing on role of the NAD-dependent deacetylase, SIRT1, and the hypoxia-induced factor-1 alpha (HIF-1alpha) in regulating adipocyte gene expression.
Adipocytes are highly specialized cells that store and release energy according to the needs of the organism. They are also now recognized as endocrine cells that synthesis and release hormones in proportion to energy storage and changes in nutritional status (e.g. obesity/overfeeding, fasting and refeeding). My research focuses on the mechanism regulating adipocyte metabolism and endocrine function. Because adipocytes from different regions of the body display distinct metabolic properties, a major goal of my laboratory is to understand the molecular mechanisms underlying regional differences in adipocyte metabolic and endocrine function. The long-term goal is to understand why obesity and an upper body fat distribution are is associated with metabolic abnormalities such as type 2 diabetes and atherosclerosis, and why a lower body adipose tissue (femoral-gluteal) typical of women is actually protective. My lab’s recent work addresses the regulation of leptin, an adipocyte hormone that regulates metabolism and appetite and is centrally involved in the regulation of body weight. Our current studies focus on the regulation of leptin translation. We have demonstrated that elements within the 5-UTR of leptin stimulates, while the 3-UTR inhibits translation. The insulin stimulation of leptin mRNA translation requires both UTRs. Current studies are investigating the cis elements and trans acting factors that mediate the nutritional regulation of leptin mRNA translation. Another line of investigation is directed at understanding the molecular basis of sex and depot differences in adipocyte and adipose tissue function. Specifically, we are using microarrays to identify the primary targets of glucocorticoid in human adipose tissues in vivo and in vitro, and assessing the functional roles of these genes. We are also initiating studies of estrogen action in human adipose tissue.
Dr. Hamilton’s laboratory is developing and applying novel physical approaches to study of obesity, metabolic syndrome, and cardiovascular disease. 13C NMR methods pioneered in his laboratory have been used to describe the interactions of fatty acids and drugs with binding sites on albumin, and new studies are currently correlating important details predicted by NMR with recent x-ray crystal structure. New fluorescence approaches have been developed to characterize the diffusion of fatty acids into adipocytes and evaluate the effects of drugs and inhibitors on fatty acid uptake. A newer focus of research is the application of magnetic resonance imaging (MRI) to examine fat tissue and atherosclerosis. These studies extend from animal model systems (mouse and rabbit) to humans. The work emphasizes interactions of different disciplines on translation of basic biophysics to human disease aspects. Our study of subjects with metabolic syndrome and obesity explores the hypothesis that a unifying feature of metabolic syndrome is enhanced deposition of lipids throughout the body outside of the normal adipose stores. These inappropriate stores include hepatocellular triglyceride, perivascular and pericardial triglyceride. MR imaging will identify and quantify site-specific abnormalities in obese patients such as cardiac functions. In our animal studies of atherosclerosis, imaging of live mice allows us to follow diseases and therapies in a single animal over a long period of time. A rabbit model of the acute event of atherosclerosis, plaque rupture and thrombosis is being studied to develop MRI for prediction of unstable and high risk plaques. In humans with advanced carotid atherosclerosis who are undergoing endarterectomy, we will use MRI to determine evidence of inflammation and plaque vulnerability and perform in vivo and ex vivo to enhance the application of MRI to carotid plaque characterization.
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 insulin signaling and action in the latter two tissues. Insulin resistance in muscle (and fat) derives from the failure of insulin to activate the tissue-specific glucose transporter GLUT4. The activation mechanism for this process involves vesicle trafficking and protein targeting with regard to GLUT4 and the insulin receptor. We are characterizing the formation and protein content of GLUT4-containing vesicles; we are trying to identify the organelles through which they pass on their way to and from the cell surface and we are determining the communication mechanism(s) (signaling) from the insulin receptor to the GLUT4-containing vesicles. These studies involve both fat and muscle cells, and we are also studying the physiological role of cell surface (plasma membrane) micro-domains called caveolae that are particularly abundant in these tissues. We have evidence for the hypothesis that caveolae (for little caves that are small invaginations of the plasma membrane into the cytosol) are involved in lipid trafficking. We continue to study other 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.
Diabetes mellitus represents one of the major health threats to modern civilization, and its worldwide prevalence is increasing at an alarming rate. In diabetes, insulin cannot stimulate glucose entry into the cell, as it does in normal individuals. As a result, extra glucose stays in the blood and causes multiple health problems. As insulin-regulated glucose transport is the major molecular defect in diabetes, it represents the main focus of our lab. Insulin activates glucose uptake by translocating glucose transporter isoform 4 (Glut4) from its intracellular vesicular storage pool to the plasma membrane. This process, along with exocytosis of synaptic vesicles in neurons, insulin-containing granules in the pancreas, water channel-containing vesicles in the kidney, etc., represents an example of a widely spread type of the biological regulation via regulated exocytosis. Impaired translocation of Glut4-containing vesicles in diabetes may have two explanations. First, the molecular defect may lie in the signal transduction pathway that connects the insulin receptor in the plasma membrane and intracellular Glut4-vesicles. Second, the cell biology (i.e. the protein composition, biogenesis, intracellular trafficking) of Glut4-vesicles may be impaired. Our lab pursues both these directions using the wide arsenal of modern techniques that include molecular biological methods, protein biochemistry, subcellular fractionation, microscopy and in vivo studies.
Dr. Ray’s research interests include the structural biology of the vitamin D and estrogen endocrine systems (structure of hormone receptors, structure-activity relationship studies); proteomic/combinatorial approaches to develop drugs for cancers of prostate and breast, and novel approaches to site-specific delivery of cancer drugs.
Dr. Ruderman’s research deals with the effects of insulin, exercise, and fuels on cellular metabolism, signal transduction, and most recently, gene expression. Its focus in the past 10 years has been on a malonyl CoA fuel sensing and signaling mechanism described by his laboratory and its regulation by AMPK. His group has proposed that dysregulation of this mechanism, leading to increases in fatty acid esterification and/or the generation of reactive O2 species, plays a causal role in the pathogenesis of many forms of insulin resistance in skeletal muscle and the early endothelial cell damage that antedates atherosclerosis in diabetes. Their research also examines the notion that activation of AMPK prevents this dysregulation and, perhaps independently, B-mediated gene expression). Some of theklater events that it causes (e.g., NF investigators in his unit and their fellows work primarily with skeletal muscle (Saha), some with cultured vascular cells (Ido), and still others with adipocytes (Luo). Thus, from a conceptual perspective, mechanisms worked out in one system are often tested in others. The techniques employed by the Ruderman laboratory include reporter gene assays, adenoviral gene transfer (cultured vascular cells), immunofluorescence microscopy, protein separation, enzyme analysis, and metabolite determination by spectrophotometric and chromatographic methods. The models used include incubated tissues, cultured cells, intact rodents and, in some collaborative efforts, humans. Many program faculty are co-investigators and/or advisors in this work, as are individuals from other institutions. The latter include Drs. Marc Prentki, University of Montreal (malonyl CoA regulation); E.W. Kraegen, Garvan Institute, Australia (insulin resistance in rodents in vivo); Guenther Boden, Temple University (insulin resistance in humans); and David Carling, Hammersmith Hospital, U.K. (molecular biological approaches to study AMPK action in vascular cells).
Mitochondrial oxidative damage plays a key role in degeneration, aging and metabolic diseases. Our goal is to determine how damage is prevented or contained, how dysfunctional mitochondria are recognized and removed, and how mitochondrial networks participate in these processes. We study 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 β-cell loss. In bone marrow, oxidative damage induced by iron and hemeintermediates, leads to the development of sideroblastic anemia and myelodysplastic syndrome. By tagging and tracking individual mitochondria in intact β-cells we discovered the existence of a quality control mechanism that relies on both fusion and fission. Following mitochondrial fission some daughter units depolarize. These units display a lower likelihood for subsequent fusion and are apparent targets of autophagy. Moreover, this model predicts that the inhibition of mitochondrial dynamics (MtDy) by Gluco-lipo-toxicity (GLT) may have a cumulative effect and result in an increased portion of dysfunctional units over time. Such enrichment of dysfunctional mitochondria could explain the long lasting effect of GLT, a phenomenon that has been shown to impact animals’ prognosis many months after a high fat diet has been discontinued. More information can be obtained by going to his lab’s website:
I 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. We are 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. Fuel metabolism and AMP-activated protein kinase in vascular tissue, muscle and other tissues. This research project, in collaboration with other members of the Diabetes and Metabolism Unit, in part concerns the metabolic changes that may be responsible for the frequently occurring vascular complications of diabetes.
Clinical and Translational Research:
Dr. Apovian’s ongoing research includes several areas of weight loss, weight maintenance, and the molecular effects of weight change. In conjunction with the Department of Cardiology, she is looking at weight loss and its effects on endothelial cell function, adipose cell metabolism and inflammation. Dr. Apovian is also researching the bariatric surgery population in the Nutrition and Weight Management Center. In collaboration with Beth Israel Deaconess Medical Center, she is studying quality of life before and after weight loss surgery. She is also looking at the effects of bariatric surgery on adipose tissue and the effects of a novel meal replacement program on body composition. Dr. Apovian’s research also includes novel pharmacotherapeutic antiobesity agents, such as leptin. She is currently completing a study designed to quantify the relative inflammatory burden and cytokine expression of adipose cells in human fat stores in obese participants after weight loss treatment with low-fat vs. low-carbohydrate diets.
Dr. Cook conducts research on food insecurity and energy insecurity, and their impacts on the health of young low-income children and their mothers. Current research also includes assessment of affordability and accessibility of healthy foods in low-income neighborhoods of Boston and Philadelphia, and viable approaches to food systems reform. Dr. Cook is a Senior Research Scientist with Children’s HealthWatch, and is project evaluator for several programs within the Department of Pediatrics’ Nutrition and Fitness for Life (NFL) program, including its FANtastic Kids intervention to reduce obesity among elementary-school-age children. He also consults with America’s Second Harvest, the Nation’s Foodbank Network and chairs the Technical Advisory Group for its national research studies.
Davidson Hamer is a Professor of International Health and Medicine at the Boston University School of Public Health and School of Medicine. He has twenty years of field experience in neonatal and child survival research including studies of micronutrient interventions, maternal and neonatal health, malaria, pneumonia, and diarrheal diseases. Major current projects include a large neonatal survival study, community-based interventions to reduce neonatal and under-5 child morbidity from common diseases, the role of specific micronutrients in reducing the burden of disease due to malaria in pregnancy, and an evaluation of the association of vitamin D deficiency with pneumonia in Ecuadorian children.
Dr. Holick and his team of researchers continue to be leaders in the field of vitamin D, osteoporosis, metabolic bone disease, psoriasis and hair research. Dr. Holick’s work explores the nature of vitamin D deficiency and concludes it to be one of the most commonly unrecognized medical conditions, a condition that leaves millions at risk of developing not only osteoporosis and fractures but also numerous serious and often fatal diseases, including several common cancers, autoimmune diseases, infectious diseases and heart disease. Because the skin is an important source of vitamin D, a human skin equivalent and a liposomal model have been developed to mimic the photoproduction of vitamin D in human skin. Using these models systems, researchers demonstrated that during exposure to solar simulated-sunlight, a unique membrane-associated mechanism stabilizes the previtamin D3 in a cis,cis-conformation and results in its rapid conversion to vitamin D3. It has now been demonstrated that human skin also produces several photoproducts including tachysterol and lumisterol, which may have important biologic functions in the skin. Research is underway to further evaluate this. They have initiated a program to evaluate the effect of vitamin D deficiency in advancing colon tumor growth.
Nutrition and cancer; regulation of cell proliferation and the effects of polyunsaturated fatty acids on cancer; insulin resistance in obesity; mechanisms of cardiovascular disease in obesity.
Dr. Lenders has been the medical director of the NFL Program (Pediatrics – Nutrition & Fitness for Life) since 2003. She also heads the Pediatric Nutrition Support Services at Boston Medical Center, and she serves as attending physician for the Nutrition Support Team at the Children’s Hospital of Boston.
Dr. Lenders is a former family practitioner with a master’s degree in tropical medicine, who graduated with honors from the State University of Liege, Belgium. She spent several months in the Congo with Médecins sans Frontières and three years in Bangladesh at the International Center of Diarrheal Diseases and Research.
She was a fellow in pediatric nutrition at the Children’s Hospital of Philadelphia (University of Pennsylvania School of Medicine), a resident in pediatrics at the Massachusetts General Hospital, and a fellow in the Combined Program of Pediatric Gastroenterology (MGH and Children’s Hospital of Boston-CHB) at Harvard Medical School. She also served as the co-director of the Optimal Weight for Life (OWL) program at CHB from 1998 to 2003.
She is board certified by the American Board of Pediatrics and the American Board of Physician Nutrition Specialists. Dr. Lenders is also an assistant professor at Boston University School of Medicine (BUSM) and on faculty at Harvard Medical School. She has received several education grants and is involved in the vertical integration of nutrition at BUSM. She recently edited a clinical guide book on overweight and obesity with Caroline Apovian, MD, that earned an outstanding review in the Journal of the American Medical Association. Her current research interests include the relationship of selective dietary components and medications to weight gain and obesity-related conditions.
Lynn L. Moore, D.Sc., Associate Professor of Medicine, directs the Framingham Children’s Study, which has shown how lifestyle factors starting early in life relate to the development of obesity during childhood and later cardiovascular risk. Much of Dr. Moore’s recent research has dealt with key analytic questions related to obesity and diabetes: the effect of obesity and diabetes, including gestational diabetes, on pregnancy outcome; effects of sustained and non-sustained weight loss on the risk of adult-onset diabetes, hypertension, and cardiovascular disease; effects of weight and weight gain on cancer risk (colon, breast, prostate, lung); the causes and consequences of obesity in childhood; and the effects of anemia on the risk of heart failure and cardiovascular disease.
Associate Professor, Nutrition, Department of Health Sciences, College of Health and Rehabilitation Sciences:Sargent College, Boston University
Assistant Professor, Department of Epidemiology, and Department of Social & Behavioral Sciences, Boston University School of Public Health
Dr. Ramachandran is a senior investigator at The Framingham heart Study, which is a long-standing ongoing longitudinal epidemiological cohort study. Over the years, careful monitoring of the Framingham Study population has led to the identification of major CVD risk factors, as well as valuable information on the effects of these factors such as blood pressure, blood triglyceride and cholesterol levels, age, gender, and psychosocial issues. Risk factors for other physiological conditions such as dementia have been and continue to be investigated. In addition, the relationships between physical traits and genetic patterns are being studied.
Dr. Mengwei Zang is the Associate Professor of Medicine at Boston University School of Medicine in 2011. She earned her MD at Wannan Medical College, her MS at Henan Medical University, and her PhD from Peking Union Medical College in 1998 in China. From 1998 to 2003, she was a postdoctoral fellow at Mayo Clinic and at Boston University School of Medicine. She was appointed as the the Assistant Professor of Medicine at Boston University School of Medicine in 2004.