Metabolism, Endocrinology and Obesity Training Grant
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Program Faculty by research focus
Focus Area 1: Metabolic biology of Adipocytes, Muscle and Islets in Obesity and Diabetes
Barbara E. Corkey, Ph.D.
The Corkey laboratory is in engaged in research on obesity and diabetes, with a particular focus on metabolic signal transduction in ß-cells, adipocytes and hepatocytes, intercellular communication via circulating redox and the role of hyperinsulinemia in obesity and diabetes. Projects in metabolic regulation have been ongoing since 1981 using such techniques as single cell imaging, metabolic profiling, ionic fluxes and membrane potential, respiration, redox state, reactive oxygen species generation and diet-induced obesity and diabetes models. Recently we have begun to explore a potential role of obesogens in disrupting metabolic signal transduction under the leadership of Dr. Jude Deeney. A current major focus is on developing clinical/basic collaborative multi-PI grants to explore novel approaches to understand and treat obesity and diabetes.
Stephen R. Farmer, Ph.D.
My research is directed towards identifying the mechanisms controlling adipose tissue development and function with the goal of developing therapeutic strategies to combat obesity-related disorders including type 2 diabetes and vascular diseases. The focus is on the transcriptional control of white, brown and beige adipocyte formation during the remodeling of different adipose depots in response to environmental stress including diet and cold exposure. I am particularly interested in factors that control fate decisions that direct perivascular progenitors along different lineages including adipogenic and profibrogenic. We have developed different mouse models to facilitate our investigations, including lineage tracing of different adipose cell types as well as conditional deletion of such transcription factors as PPAR gamma, myocardin-related transcription factor and TAZ/YAP.
Konstantin V. Kandror, Ph.D.
Adipocytes, skeletal myocytes and some neurons express a specific isoform of the glucose transporter protein, Glut4. Under basal conditions this transporter is localized in intracellular membrane vesicles which fuse with the plasma membrane upon insulin administration. Translocation of Glut4 plays a major role in post-prandial glucose clearance and, more generally, in glucose sensing and metabolic homeostasis in the body. For a number of years, my lab has been involved in the dissection of the “Glut4 pathway” in various insulin-sensitive cells. Another key physiological function of insulin is to inhibit lipolysis and to promote storage of triglycerides in fat tissue. Recently, we have discovered two novel pathways of regulation of lipolysis by insulin. One of these is mediated by the insulin- and nutrient-sensitive mammalian Target of Rapamycin Complex 1, while the other is mediated by the transcription factor FoxO1. Currently, we are engaged in the molecular dissection of both pathways.
Matthew D. Layne, Ph.D.
Our laboratory investigates the mechanisms of obesity and its complications in the cardiovascular system. Recent work focuses on the mechanisms of fibrotic remodeling in adipose tissue. These collaborative studies examin the role of transcriptional regulators including myocardin related transcription factor A in controlling both the differentiation of adipose tissue progenitor into beige adipocytes as well as matrix producing fibrotic cells. Specifically we examine the fate of white adipose tissue vascular progenitors in response to high fat diet and agonists that enhance thermogenesis in adipose tissue depots. Other projects investigate the mechanisms of the secreted collagen binding protein, aortic carboxypeptidase-like protein (ACLP) in murine and human adipogenesis and adipose tissue fibrosis. This work has uncovered mechanisms controlling the production of extracellular matrix and the source of extracellular matrix in fibrotic adipose tissue. Collectively this work is focused on the differentiation of vascular progenitors into adipose tissue and the metabolic complications of adipose tissue fibrosis.
Focus Area 2: Obesity, Vascular Biology, and Inflammation
Zhen Y. Jiang, Ph.D.
1. Exploring the role of neutrophils in the development of obesity-related adipose inflammation, insulin resistance and vascular dysfunction. We observed that high-fat diet feeding induces alteration of hematopoiesis with dramatic increase of pro-inflammatory neutrophil production in mice. Interestingly, mice lacking the neutrophil-specific protease, neutrophil elastase, are resistant not only to diet-induced neutrophil production but also high fat diet-induced adipose inflammation, vascular damage, liver steatosis and insulin resistance. We are studying how nutritional factors impact the regulation of neutrophil differentiation in the bone marrow and how this process is related to the development of systemic inflammation, adipose remodeling, and metabolic and vascular disorders. 2. CDP138 and its signal networks related to glucose and lipid metabolisms in adipose tissues. We recently identified a new phosphoprotein CDP138 that is involved in the regulation of vesicle trafficking. Currently, we are using knockout mouse models to study the signal network of CDP138 and its role in the regulation of catecholamine release, fat browning, thermogenesis, and lipid metabolism.
Reiko Matsui, MD.
We study vascular biology and oxidative stress, and in recent years my focus is the roles of glutaredoxin-1 (Glrx) in obesity, diabetes, and cardiovascular disease. Glutaredoxin regulates cellular signaling and transcription by reversing protein-glutathione adducts. We identified Glrx as an anti-angiogenic molecule. The role of Glrx on ischemia-induced vascularization in our NIH-funded proposal is a relevant to therapeutic approache to vascular complications in diabetes. Ischemic limb is one of the major complications of diabetes. We examine contribution of upregulated Glrx in poor vascularization of diabetic mice and patients. Also, we found that Glrx inhibition stabilizes and activates HIF-1a by protein-GSH adducts and the role of Glrx regulated HIF-1 on metabolism will be explored.
Valentina Perissi, Ph.D.
The Perissi Lab is dissecting the molecular mechanisms that control adaptive responses to metabolic stress and pro-inflammatory signals in adipocytes and immune cells. A major focus is on non-proteolytic K63 ubiquitination as a key regulatory event within multiple signaling pathways. This stems from the identification of G-Protein Suppressor 2 (GPS2) as a specific inhibitor of the ubiquitin-conjugating enzyme Ubc13. Investigating the role of the GPS2-Ubc13 module within different cellular compartments led us to discover an unexpected role for GPS2 as a suppressor of PI3K/AKT signaling downstream of the insulin receptor and as an inhibitor of TLR and TNFR pro-inflammatory signaling pathways. Recently, we also identified a novel nuclear-mitochondrial communication pathway based on GPS2 translocation from the mitochondria to the nucleus to regulate the expression of nuclear-encoded mitochondrial genes. Our data indicate that GPS2-mediated retrograde signaling is critical for responding to acute mitochondrial stress by depolarization, and for sustaining mitochondrial biogenesis during adipocyte differentiation. Ongoing studies investigate the relevance and synergism among these functions in the context of obesity-associated inflammation/insulin resistance.
Sayon Roy, Ph.D.
Research in Roy laboratory pertains to vascular complications of diabetic retinopathy, with a particular focus on structural changes in the retinal capillaries, cell-cell communication in retinal vascular homeostasis, strategies regulating abnormal gene expression in the retina, non-human primate model of diabetic retinopathy, and mitochondrial dysfunction. One project tests the hypothesis that increased lysyl oxidase (LOX) expression and activation triggered by high glucose (HG)/diabetes compromises basement membrane (BM) function and induces excess permeability and vascular cell death in diabetic retinopathy (DR). Previous findings show that diabetes increases expression of LOX, which is required for the formation and maturation of the BM, and that HG-induced LOX upregulation and over-activation compromises endothelial barrier function. Importantly, inhibition of HG-induced LOX overexpression results in reduced cell monolayer permeability. While LOX is known for its cross-linking activity, LOX propeptide (LOX-PP), released during LOX biogenesis, is known for regulating cell proliferation and survival through modulation of Akt and Erk pathways. Current data indicates that LOX overexpression promotes apoptosis in retinal endothelial cells, and LOX-PP is upregulated by HG. Furthermore, preliminary data indicates that LOX binds with high affinity to extracellular fibronectin under HG condition, and interferes with LOX internalization into the cell, a process unique to LOX. Specifically studies underway seek to test whether HG-induced LOX overexpression contributes to capillary leakage, and together with increased LOX-PP promotes apoptosis by modulating Akt and Erk pathways.
Francesca Seta, Ph.D.
A major research interest is to study the cardiovascular complications of metabolic syndrome (MS). MS significantly increases the risk of developing cardiovascular disease (CVD). Arterial stiffness (AS), or loss of compliance of large elastic arteries, is an independent CVD risk factor. AS is increased in obese and diabetic individuals with MS, even at a young age (10-24 years), increasing their risk of developing CVD later in life. The goal of our work is to find therapeutic targets to prevent AS and associated adverse cardiovascular outcomes in obese and overweight individuals. We were the first to demonstrate that in a mouse model of dietary obesity, AS develops within two months and precedes the development of hypertension. We further demonstrated that in diet-induced obese mice, increased aortic oxidants and inflammation lead to functional impairment of vascular smooth muscle (VSM) cells in the aortic wall contributing to AS in the setting of obesity. The genetic or molecular cues that trigger such VSM cell alterations in the aortic wall, causative of AS, remain to be fully elucidated. An ongoing project recently discovered that the transcription factor Bcl11b in VSM is a novel and crucial determinant of VSM cell lineage commitment and crucial for vascular function and structural integrity. Our future studies will examine whether Bcl11b is a possible novel therapeutic target to ameliorate AS in settings of obesity.
Focus Area 3: Translational Studies Related to Endocrine and Metabolic Disease
Caroline Apovian, MD, FACP, FACN, FTOS, ABOM.
Dr. Apovian is currently the Director of the Nutrition and Weight Management Center and Co-director of the Nutrition and Metabolic Support Service at Boston Medical Center. She also serves as Director of the Nutrition and Metabolism Research Center of Boston Medical Center and is Associate Director of Clinical Research and a member of the Executive Committee for the NIDDK-funded Boston Nutrition and Obesity Research Center (BNORC). As Director of the Nutrition and Weight Management Center at Boston Medical Center, Dr. Apovian’s 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 for over 8 years. Other recent NIH-funded research studies include a project to determine whether medium chain triglycerides affect insulin secretion dynamics and insulin sensitivity, investigation into the effects of increased dietary protein on lean body mass, maximal voluntary muscle strength and power in older men with mobility limitations, dietary and physical activity interventions in underserved post-partum women and studies to examine the role of inflammation as an accelerator of obesity-associated metabolic decline in humans marked by progression of pre-diabetes to type 2 diabetes.
Markus Bachschmid, Ph.D.
The cellular redox status and oxidants play an important role in regulating cell physiology and signaling through oxidative protein modifications. Reactive cysteines (thiolate) in proteins can react with oxidants and abundant intracellular glutathione to form glutathione adducts. The thioltransferases glutaredoxin remove glutathione adducts and restore the reactive state of cysteines. This sequence is part of a redox regulatory cycle, which modulates the activities of proteins in the cell. Oxidative stress, however, interrupts this cycle and causes irreversible oxidation of reactive cysteines. In metabolic disease, a perturbation in cellular redox homeostasis results in accumulation of protein glutathione adducts. Glutaredoxin-1 knockout mice also exhibit increased protein glutathione adducts and develop obesity, dyslipidemia, fatty liver, and metabolic cardiovascular disease. The Bachschmid lab has identified Sirtuin-1, a metabolic master regulator, as a target of glutaredoxin-1. Glutathione adducts inhibit Sirtuin-1 activity, which upregulates de novo lipogenesis and cause liver steatosis in glutaredoxin-1 knockout mice. We have created a non-oxidizable mutant Sirtuin-1 that normalized hepatic lipid metabolism and improved plasma dyslipidemia in glutaredoxin-1 knockout mice. Ongoing research focuses on the identification of new target proteins of glutaredoxin-1 using omics platforms and systems biology. Screening of small molecules to modify reactive cysteines and prevent protein inactivation by glutathione adducts is in progress.
Michael Holick, MD, Ph.D.
(1) Obesity is associated with vitamin D deficiency. We previously reported that this association is due to the fact that vitamin D, which is a fat-soluble vitamin, when ingested or produced in the skin from ultraviolet irradiation is diluted in the body fat reducing its bioavailability. We also reported that also human body fat has a high content of vitamin D and a patient who undergoes bariatric surgery loses as much as 50 kg of body fat does not result in any of the fat containing vitamin D to become bioavailable. We also observed that these patients have difficulty in absorbing the fat soluble vitamin. We developed an LED device that is specifically tuned to produce vitamin D and will determine if this device can be effective in raising blood levels of 25-hydroxyvitamin D in gastric bypass patients who have a fat malabsorption syndrome. (2) Obese patients and obese patients who have undergone gastric bypass surgery often have a difficult time in utilizing dietary vitamin D3 either because it gets diluted into their body fat or is unable to be efficiently absorbed. 25-hydroxyvitamin D3 is more hydrophilic and therefore may be more efficiently absorbed and utilized in patients with vitamin D deficiency associated with obesity and in gastric bypass patients. We plan to evaluate the bioavailability and the effectiveness of this vitamin D metabolite in patients who are morbidly obese and who have had gastric bypass surgery. (3) We previously published a study evaluating the metabolism of vitamin D3 and 25-hydroxyvitamin D3 in adipocytes and pre-adipocytes. We observed that the cells metabolize vitamin D and 25 hydroxyvitamin D and that some of the metabolites had biologic activities in the cells. We are interested in continuing to determine how adipocytes and pre-adipocytes metabolize and respond to vitamin D and its metabolites.
Bindu Kalesan, Ph.D., MPH.
We have developed “The MULTI sTUdy Diabetes rEsearch (MULTITUDE) Consortium”, a pooling project that harmonized data from 17 independent cohort studies and clinical trials to facilitate a better understanding of the determinants, risk factors, and outcomes associated with Type 2 Diabetes Mellitus (T2DM). MULTITUDE is an individual-level pooled database of demographics, co-morbidities, relevant medications, clinical lab values, cardiac health measures, and T2DM-associated events and outcomes across 45 US states and the District of Columbia. Among the 135,156 participants included in the consortium, 25% were diagnosed with T2DM at baseline. The average age of the participants was 54·3, while the average age of participants with diabetes was 64·2. Men (55·3%) and women (44·6%) were almost equally represented across the consortium. Non-whites accounted for 31·6% of the total participants and 40% of those diagnosed with T2DM. Over 85% of those with diabetes were reported as either overweight or obese at baseline, compared to 60·7% of those without T2DM. We observed differences in all-cause mortality, overall and by T2DM status, between cohorts. This important resource will be available to T32 candidates to test their hypotheses, design studies, perform analysis and provide assistance to produce manuscripts.
Michelle Long, MD.
I am an early career physician scientist interested in patient-oriented research studying fibrosis and inflammation in patients with non-alcoholic fatty liver disease (NAFLD). My clinical and research interests center on the relationship between NAFLD and cardiovascular disease. My research is primarily based at the Framingham Heart Study where I am the PI of a study evaluating the prevalence and risk factors for liver fat (steatosis) and fibrosis. I am investigating the clinical and genetic correlates of hepatic steatosis and fibrosis as measured by transient elastography. My expertise is in epidemiology, visceral fat, liver imaging including computed tomography, ultrasound, and transient elastography. I am also a clinical gastroenterologist and endoscopist. I am additionally interested in novel therapeutics for NAFLD and Non-alcoholic steatohepatitis (NASH) and run the clinical trials for the BMC Fatty Liver Clinic.
Lynn L. Moore, D.Sc.
I am a nutritional epidemiologist with a background in both epidemiology and biostatistics. My areas of research experience and interest include human studies of obesity, metabolic disorders and chronic disease outcomes. I have worked extensively with many large epidemiologic data sets including the adult Framingham Studies, the Framingham Children’s Study, the NHLBI Growth and Health Study, NHANES, the PREMIER Study, a cohort of 25,000 pregnant Massachusetts women, and others. I have published epidemiologic and clinical studies of body fat, body composition, bone mass, cancer, blood pressure and cardiometabolic outcomes. One of my long-term areas of interest is in separating out effects of individual foods and nutrients in epidemiologic studies from the larger dietary matrix. My current funded research includes studies of the following: (a) minerals (sodium, potassium, calcium, and magnesium) and BP and cardiovascular outcomes; (b) dietary fats and oils and cardiometabolic outcomes; (c) long-term effects of animal and plant proteins in the diet and functional decline in old age; (d) effects of dietary cholesterol on serum lipids in adults with impaired fasting glucose.
Elizabeth N. Pearce, MD, MSc.
Research interests include iodine nutrition, thyroid physiology, thyroid disease in pregnancy, environmental disruptors of thyroid function, and associations between thyroid status and cardiovascular risk. Iodine is an essential micronutrient and an integral component of the thyroid hormones, which are required for normal growth and development. Decreased thyroid hormone associated with even mild iodine deficiency may have adverse effects on the cognitive function of offspring. One area of focus is the identification of populations who are currently at risk for iodine deficiency or excess. Perchlorate is a competitive inhibitor of thyroidal iodine uptake, found ubiquitously in the environment. When present in sufficiently high concentrations, perchlorate decreases active transport of iodine into the thyroid and decreases thyroid hormone synthesis. We study the effects of exposure to perchlorate, and thiocyanate, another environmental disruptor, on thyroid function in pregnant women and other vulnerable populations. We also study influences on maternal thyroid function and effects of maternal thyroid function on child development and obstetric outcomes. Finally we study the effects of thyroid dysfunction on multiple cardiovascular risk factors, including hyperlipidemia, obesity, and left ventricular structure.
Devin Steenkamp, MD.
I am a clinical investigator focusing on facilitating, collaborating and supervising research efforts that have a translational impact on understanding the pathophysiological underpinnings of atypical diabetes phenotypes with a focus on atypical presentations of type 1 diabetes phenotypes. I am particularly interested in exploring the physiology of atypical patients with type 1 diabetes and the monogenic diabetes phenotypes that are often confused with type 1 diabetes. I also work as a clinical trialist investigating diabetes pharmacotherapy and novel diabetes technology and continue to be both a co-investigator and principal investigator on industry and NIH funded clinical trials.
Focus Area 4: Model Systems and Organisms in Regulation of Metabolism
Daniel Cifuentes, Ph.D.
Our focus is to uncover the role of glycogen synthesis using a zebrafish model of Lafora Disease (LD) and to identify drugs for future treatments. Most patients carry mutations in laforin (EPM2A) or malin (NHLRC1). The dogma in the field states that disruption of a laforin-malin complex leads to aberrant glycogen synthesis and neuronal apoptosis. However, abnormal glycogen bodies can be found in all other cell types without triggering apoptosis, prior to the onset of LD. Therefore, other factors may be involved. Interestingly, glycogen synthase (GYS1) in neurons localizes in the nucleus within Cajal Bodies, an RNA-processing center. Meanwhile, in all other cell types GYS1 is mainly cytosolic. Only when laforin-malin regulation is disrupted, GYS1 translocates to the cytosol of neurons and engage in glycogen synthesis. We hypothesize that GYS1 is a constitutive regulator of RNA processing in neurons and its demise leads to LD. These studies uncovered a novel layer of glycogen regulation, with profound impact in pediatric epilepsy. However, several fundamental questions remain unanswered. First, what is the role of GYS1 in the nucleus of neurons? Second, does GYS1 bind RNA and modulate gene expression? Third, is it possible to develop a small molecule-based treatment of LD? The potential of zebrafish as a platform to conduct drug screenings provides the ability to monitor complex behaviors like seizures in zebrafish screenings, a clear advantage over cell-based drug screenings and can be executed for a fraction of the time and cost of mouse-based screenings. By capitalizing on my expertise in glycogen metabolism regulation along with my postdoctoral experience in zebrafish genetic modeling of neurological disorders, we aim to uncover the role of nuclear glycogen synthase in neurons and screen small molecules.
Alla Grishok, Ph.D.
The interest of our lab is to connect metabolic changes to gene expression regulation in the nucleus. At the fundamental level, the mechanisms of gene regulation are almost identical in such diverse organisms as mammals and the fruit fly, Drosophila, or the nematode (worm), C. elegans. C. elegans is an established model for lifespan research and we are working on connecting metabolism and longevity. Specifically, we are pursuing two research directions: 1) regulation of the activity of the C. elegans homolog of Myc and Mondo proteins, MML-1, through O-GlcNAc modification, and 2) the role of a conserved lipase ATGL in promoting lifespan extension, in collaboration with Dr. Kandror’s laboratory. The O-GlcNAc modification of the carbohydrate response element binding protein (ChREBP, also called Mondo B) is important for its function in regulating metabolic genes in mammalian cells, and C. elegans ChREBP homolog, MML-1, is required for increased lifespan in dietary restriction and reduced insulin signaling models. We found that the O-GlcNAc modification of ChREBP/MML-1 is conserved and plan to investigate the significance of this modification in lifespan extension. Dr. Kandror’s group established that transcription of the ATGL gene is regulated by FOXO1 in adipose tissue. We have now confirmed that ATGL is regulated in a similar manner in C. elegans and will investigate the potential of ATGL in promoting longevity. Our studies should uncover basic conserved mechanisms linking metabolism, transcription and lifespan control.
Olga Gursky, Ph.D.
Dr. Gursky is a leading expert in lipoproteins biophysics and in structural thermodynamics of protein assemblies. One focus of her research is on the molecular mechanisms of function of plasma lipoproteins, such as Good and Bad Cholesterol, in health and in diseases of lipid metabolism such as diabetes, metabolic syndrome and atherosclerosis. Another focus is on protein misfolding and deposition in amyloid diseases and the role of lipids in these pathogenic processes. High-, low- and very low-density lipoproteins (HDL, LDL and VLDL) are nanoparticles that transport lipids and play critical roles in major metabolic disorders. Protein constituents of these nanoparticles, termed apolipoproteins, are over-represented in amyloid diseases wherein normally soluble proteins misfold in an insoluble cross-beta-sheet conformation and deposit in vital organs, causing damage and death. Our team uncovered molten globular properties of apolipoproteins that are critical for their normal functions as well as their misfolding in amyloid. Further, we have uncovered the kinetic origin of lipoprotein stability, elucidated its energetic and structural basis, and developed an experimental approach for quantitative studies of lipoprotein stability and remodeling. Projects currently underway in the Gursky lab: 1) the structural basis for HDL adaptation to the increasing lipid load during reverse cholesterol transport; 2) molecular mechanism of LDL aggregation and fusion; 3) normal and pathologic functions of Serum Amyloid A, an enigmatic ancient protein that becomes a major player in lipid metabolism during acute inflammation and injury. To this end, we use an integrated array of biophysical, biochemical, structural and computational methods, including circular dichroism, absorption and fluorescence spectroscopy; light scattering; electron microscopy, size exclusion chromatography, x-ray crystallography, as well as mass spectrometry techniques such as hydrogen-deuterium exchange, along with computational biology and bioinformatics.
James Hamilton, Ph.D.
The Hamilton laboratory developes and applies novel physical approaches to study of obesity, metabolic syndrome, and cardiovascular disease. Our studies encompass simplified model systems (model membranes, cells) to disease in patients, which is achieved by interactions of different disciplines to translate basic biophysics to human disease. We have developed fluorescence probes to distinguish and quantify individual steps of fatty acid (FA) transport in membranes, and separate transport from metabolism. I applied new methods and hypotheses to cells in collaborations with talented BUSM faculty including Barbara Corkey and Paul Pilch in early studies that examined effects of insulin on FA uptake in adipocytes and pancreatic islets. More recently, we performed innovative experiments showing that the putative FA membrane transport protein CD36 has a more definitive effect on intracellular metabolism than on membrane transport of FA, providing new therapeutic strategies. Since another major function of CD36 is the uptake of the inflammation-promoting oxidized LDL in plasma, we explored the relationship of fatty acids binding to LDL uptake and showed that dietary fatty acids, except for omega-3 fatty acids, greatly enhanced oxLDL uptake into HEK cells, which could provide new therapeutic approaches for mitigating pancreatic ß-cell dysfunction in diabetes. We also apply magnetic resonance imaging (MRI) to examine fat tissue, and progression of liver disease and atherosclerosis using mouse and rabbit imaging at to monitor atherosclerosis and fat accumulation, including serial imaging of the same animal to follow progression of disease. Recently we demonstrated inflammatory links between (i) oral disease and atherosclerosis and (ii) advanced atherosclerosis and liver fibrosis. We have established a link through systemic inflammation and are exploiting this link to treat oral, vascular and liver inflammation by oral application of natural molecules derived from omega-3 fatty acids (specialized pro-resolving mediators) that decrease both localized and systemic inflammation.