Explore This Research Unit
The Metabolism Unit, of the Massachusetts General Hospital Endocrine Division and recently formed in 2019, was previously known as the Massachusetts General Hospital Program in Nutritional Metabolism. The chief of the unit is Steven Grinspoon, MD, a recognized expert in substrate metabolism, with a focus on the regulation of ectopic adipose tissue and related inflammatory conditions. Dr. Grinspoon also directs the Nutrition Obesity Research Center at Harvard, a P30 Center with over 100 faculty, 3 cores and a robust Pilot and Feasibility Award program.
Unit Research Themes and Accomplishments
Led by Dr. Grinspoon, Metabolism Unit faculty have advanced our understanding of the nutritional regulation of hypothalamic function, nutrient trafficking and substrate metabolism and the mechanisms/consequences of ectopic adipose tissue accumulation in obesity and acquired lipodystrophies. Additionally, Metabolism Unit faculty have advanced knowledge on the interplay between innate immune activation, adipose tissue dysfunction and cardiometabolic disease in special populations, including people with obesity, metabolic syndrome and HIV. Based on this work, the unit is exploring novel hormonal and immune strategies to prevent or treat metabolic and cardiovascular disease in diverse patient populations.
Major accomplishments of the faculty include:
- Demonstration of the effects of leptin administration to restore endocrine homeostasis in caloric deprivation
- Demonstration of the effects of TNF-alpha antagonism on inflammatory markers and glucose homeostasis among patients with obesity and metabolic dysregulation
- Determination of the novel effects of lipolytic blockade on metabolic endpoints in obesity
- Assessment of the relationship between mitochondrial dysfunction and insulin resistance in obesity
- Demonstration of the potential utility of hypothalamic GH secretagogues to restore GH physiology and improve excess visceral adiposity and liver fat in central obesity
- Determination of the role of DICER in dysfunctional adipose tissue in lipodystrophy
- Demonstrating of the novel regulation and anti-inflammatory effects of RAAS blockade in lipodystrophy
- Exploration of novel imaging agents to quantify macrophage infiltration in atherosclerotic lesions
- Application of magnetic resonance spectroscopy to quantify ectopic fat accumulation in cardiac myocytes among women at increased risk for heart failure
Researchers in the Metabolism Unit have published over 300 articles in peer-reviewed journals, including publications in Nature, NEJM, JAMA, JAMA Cardiology, the Annals of Internal Medicine and Lancet HIV.
Meet Our Team
The Metabolism Unit, with 9 faculty members, fellowship trainees and a staff of over 20, is located in 2800 square feet of newly renovated office space in Charles River Park, adjacent to Massachusetts General Hospital. Faculty members and collaborators have a broad array of expertise ranging from neuroendocrinology, pediatric endocrinology, nutrition, infectious diseases, immunology and advanced non-invasive radiographic imaging. This team utilizes state-of-the-art techniques including insulin clamp, positron emission tomography (PET), magnetic resonance spectroscopy and novel imaging techniques to determine metabolic function and substrate flux.
Steven K. Grinspoon, MD
Dr. Steven Grinspoon, unit chief, is a professor of medicine at Harvard Medical School, director of the Nutrition Obesity Research Center at Harvard and the Massachusetts General Hospital endowed chair in neuroendocrinology and metabolism. He is a member of the American Society of Clinical Investigation and the Association of American Physicians. He received the 2014 Edward H. Ahrens Jr. Award for Patient Oriented Research from the Association for Clinical and Translational Science and was recently named to receive the 2016 Gerald Aurbach Laureate Award from the Endocrine Society for Translational Research.
Dr. Grinspoon is a recognized expert in the nutritional regulation of pituitary function. His work encompasses a broad focus including the mechanism by which neuroendocrine function regulates adipose tissue distribution, the mechanisms of insulin resistance in fat redistribution and acquired lipodystrophy and the role of altered nutrient trafficking to ectopic adipose depots in association with visceral obesity. His efforts investigating GHRH1-44, to selectively reduce visceral fat. His efforts led to the FDA approval in November 2010 of GHRH as the first therapy to reduce visceral fat in HIV lipodystrophy. He has co-chaired the Research Affairs Committee for the Endocrine Society and directed the Endocrine Society’s Clinical Investigators Workshop. In addition, he has served as the Pfizer Visiting Professor at University of California at Davis.
In addition, Dr. Grinspoon has chaired the AHA State of the Science Conference on Cardiovascular Disease in HIV. In this regard, he directs a large multicenter NIH-funded trial, REPRIEVE, to investigate strategies to prevent cardiovascular disease in HIV, stemming in part from his work demonstrating a unique atherosclerotic phenotype related to immune activation in HIV. REPRIEVE includes a large sub-study investigating the inflammatory mechanisms of cardiovascular disease in HIV using CT angiography and flow cytometric analyses. He is also investigating the effects of mineralocorticoid receptor blockade to improve insulin resistance and inflammation in HIV-infected patients.
Metabolism Unit Faculty
Sarah Chu, MSN, ANP-BC
Ms. Chu is an adult nurse practitioner engaged in clinical research at Massachusetts General Hospital. Her research interests include the mechanisms by which systemic immune activation and inflammation influence cardiovascular health amongst special populations, particularly women with HIV. Ms. Chu is helping to lead an NIH-R01 funded study on this theme and is also helping to conduct other research studies on related themes – including a study on whether statin therapy helps preserve diastolic function among people with HIV. In addition to conducting clinical research, she serves as a member of the MGH Steering Clinical Research Nurse Committee and as the COVID Safety Officer of the MGH Metabolism Unit.
Harvard Catalyst Profile
Meghan Feldpausch, MSN, ANP-BC
Ms. Feldpausch, ANP-BC is clinical research co-investigator focused on clinical-translational research. Her research interests include ectopic fat deposition leading to liver pathology, as well as ways in which activation of the renin-angiotensin-aldosterone system predisposes to systemic inflammation and cardiometabolic disease. Ms. Feldpausch has helped successfully steer NIH R01-funded studies on these themes and is also expert on regulatory aspects of human subjects’ research. Her work has been published in JAMA, JAMA Cardiology, the Journal of Clinical Endocrinology and Metabolism and the Journal of Infectious Diseases. Ms. Feldpausch has been recognized with the Emerging Researcher award by the Yvonne L. Munn Center for Nursing Research at Massachusetts General Hospital. In addition to her research activities, Ms. Feldpausch participates in volunteer work and community education at AIDS service organizations in the Greater Boston area.
Kathleen Fitch, MSN, FNP
Ms. Fitch is a family nurse practitioner in the HIV/AIDS Infection Care and Treatment Program at Massachusetts General Hospital and a principal associate in medicine at Harvard Medical School. Ms. Fitch’s research examines the manner in which diet and nutrition can influence cardiometabolic health and disease in special populations, including people aging with HIV. Ms. Fitch serves as project manager for the REPRIEVE trial—the largest international randomized placebo-controlled trial testing a heart disease prevention strategy among individuals aging with HIV. She has published important work demonstrating effects of exercise and metformin to improve cardiometabolic health in special populations. Her work has been published in the Journal of Infectious Diseases, AIDS, JAIDS and the Journal of Nutrition. She has received the Outstanding Researcher Award from the Association of Nurses in AIDS Care. In addition to her research activities, Ms. Fitch served as a National Health Service Corps Scholar and is a volunteer community educator at several AIDS service organizations throughout Massachusetts.
Lindsay Fourman, MD
Dr. Fourman is an endocrinologist at Massachusetts General Hospital and an instructor of medicine at Harvard Medical School. Dr. Fourman’s research explores mechanisms of ectopic fat deposition and downstream pathology in the liver and in the heart. She has published on the manner in which redressing ectopic fat deposition through administration of a hypothalamic hormone analogue improves end-organ function and on the role of anti-inflammatory proteins in potentially mitigating end-organ pathology in special populations. Her latest research interests include mechanisms by which epigenetic imprinting may predispose HIV exposed but uninfected infants to metabolic complications later in life. Her work has been published in the Journal of Infectious Diseases, AIDS and JAIDS. She has received a KL2 MeRIT grant from the Harvard Catalyst and the John Potts Pilot Award from Mass General's Endocrinology Division.
Dr. Lo is an endocrinologist at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School. Dr. Lo’s research aims to elucidate mechanisms contributing to increased atherosclerotic cardiovascular disease risk among people with HIV including systemic immune activation driven by such factors as enhanced microbial translocation and epigenetic reprogramming of macrophages. She is principal investigator of two NIH R01-funded projects on these themes. Dr. Lo has published important work demonstrating increased subclinical atherosclerotic plaque burden among men with HIV treated with antiretroviral therapy and revealing effects of statin therapy to reduce such plaque. Dr. Lo’s work has been published in JAMA, Lancet HIV, AIDS, JAIDS, Journal of Infectious Diseases and the Journal of Clinical Endocrinology and Metabolism. She has been recognized with the Claflin Distinguished Scholar Award from the Massachusetts General Hospital Executive Committee on Research and with the Gil Daniels Teaching Award from the Massachusetts General Hospital Endocrine Division. Dr. Lo also serves as associate program director of the Endocrinology Fellowship Program and director of the Neuroendocrine Clinical Conference and Journal Club, both at Massachusetts General Hospital.
Sara Looby, PhD, ANP-BC, FAAN
Dr. Looby is a leader in the Yvonne L. Munn Center for Nursing Research at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School. Dr. Looby’s research focuses on metabolic complications among individuals living with HIV including bone loss, ectopic fat accumulation and disturbances associated with reproductive aging. She was the first to report reduced bone density associated with high bone-turnover among women living with HIV and increased cardiometabolic risk related to abdominal fat accumulation and associated inflammation in this population.
Dr. Looby recently completed a NIH-funded investigation of metabolic, psychological and vasomotor symptoms among perimenopausal women with HIV. Moreover, she is principal investigator of an NIH R01-funded project investigating the intersection of reproductive aging and cardiovascular disease risk among women living with HIV. Her work has been published in the Journal of Clinical Endocrinology and Metabolism, Menopause, the Journal of Infectious Diseases, AIDS, JAIDS, and the Journal of the Association of Nurses in AIDS Care. Dr. Looby has received the Claflin Distinguished Scholar award from the Massachusetts General Hospital Executive Committee on Research and of the Connell Nursing Research Scholar Award.
In addition to her research activities, Dr. Looby is a dedicated volunteer health educator at local AIDS service organizations and has received honors for her community work and compassionate care of individuals living with HIV.
Dr. Srinivasa is an endocrinologist at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School. Her research concentrates on exploring mechanisms and treatment strategies for inflammation and cardiometabolic disease in HIV. She has led work exploring how activation of the renin-aldosterone-angiotensin system (RAAS) may contribute to adipose tissue dysfunction, systemic/arterial inflammation and end-organ cardiovascular disease. Further, she serves as principal investigator of an NIH K23 award and an NIH R01 project-award exploring effects of RAAS blockade to ameliorate cardiometabolic risk in special populations. Another focus of Dr. Srinivasa’s research to is to explore whether reduced adipose-specific Dicer expression in HIV contributes to the development of metabolic and lipodystrophy-related complications in HIV. Her work has been published in the Journal of Clinical Endocrinology and Metabolism, the Journal of Infectious Diseases, AIDS and JAIDS. She has been recognized with the Endocrine Society Early Investigator Award also the recipient of a Gilead Research Scholar Award.
Dr. Stanley is a pediatric endocrinologist at Massachusetts General Hospital and an associate professor of pediatrics at Harvard Medical School. Dr. Stanley’s research centers on better understanding hormonal, metabolic and body composition abnormalities in obesity and HIV-infection, as well as the relationship between growth hormone dynamics and nonalcoholic fatty liver disease (NAFLD). She also has a strong interest in characterizing the endocrine and metabolic characteristics of individuals with Williams Syndrome. She published important work on effects of growth hormone releasing analogue to reduce ectopic fat deposition in the visceral adipose depot and in the liver. She is principal investigator of an NIH R01-funded project further exploring this theme. Her work has been published in JAMA, the Journal of Clinical Endocrinology and Metabolism, the International Journal of Pediatric Endocrinology, Obesity, Pediatric Obesity and Clinical Endocrinology. Dr. Stanley serves as program director of Mass General's Pediatric Endocrinology Fellowship. Additionally, through the Nutrition Obesity Research Center at Harvard, Dr. Stanley serves as director of the Pilot and Feasibility Program, co-director of the Diversity Scholars Program and a member of the Executive Committee.
Dr. Toribio is an endocrinologist at Massachusetts General Hospital and an instructor of medicine at Harvard Medical School. Dr. Toribio’s research focuses on atherosclerotic cardiovascular disease risk and heart failure in diverse patient population. She has published on novel techniques to quantify arterial macrophage infiltration as well as on effects of statins on markers of immune activation and on the proteome among people with HIV. She has also published on the effects of newly initiated antiretroviral therapy on arterial inflammation and cholesterol efflux in this population. Her latest research investigates cardiometabolic effects of gender-affirming hormonal therapy among transgender individuals. Her work has been published in JAMA Cardiology, the Journal of Clinical Endocrinology and Metabolism, and the Journal of Infectious Diseases. She has been awarded an individual Ruth L. Kirschstein National Research Service Award (NRSA) from the National Institutes of Health, a KL2 MeRIT grant from the Harvard Catalyst, a research development award from the Harvard University Center for AIDS Research, the Sanchez and Ferguson Research Faculty Award from the Massachusetts General Hospital Department of Medicine and the Harold Amos Medical Faculty Development Award from the Robert Wood Johnson Foundation.
Dr. Zanni is an endocrinologist at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School. Dr. Zanni’s research centers on elucidating hormonal and immune mechanisms of cardiometabolic risk in special populations. She is principal investigator of three NIH R01-funded projects focused on myocardial infarction and heart failure risk among individuals with HIV, particularly women. Dr. Zanni also serves as vice chair of the largest international randomized placebo-controlled trial testing a heart disease prevention strategy among individuals aging with HIV–the REPRIEVE Trial. Her work has been published in JAMA Cardiology, Journal of the American College of Cardiology, AIDS, JAIDS, Journal of Infectious Diseases, and the Journal of Clinical Endocrinology and Metabolism. She has been recognized with the Claflin Distinguished Scholar Award from the Massachusetts General Hospital Executive Committee on Research. Dr. Zanni sustains a strong commitment to teaching and mentoring. She serves as the director of the Harvard Medical School Clinical Elective in Endocrinology and the founding co-director of the Endocrine Division Faculty Mentoring Initiative, both at Massachusetts General Hospital.
Steven Grinspoon, MD:
Effects of Eplerenone on Cardiovascular Disease in HIV (MIRACLE HIV Study) (NIH R01 DK049302)
HIV-infected individuals treated with antiretroviral medications are living longer, but have an increased risk of heart disease when compared to non-HIV-infected individuals. Aldosterone, which regulates blood pressure and sodium balance, is elevated in the HIV population in association with increased visceral fat and altered glucose metabolism. Increased aldosterone may also be associated with abnormal blood flow, inflammation and coronary plaque in the heart. This study will evaluate whether therapies to reduce the actions of aldosterone may decrease the burden and progression of heart disease in the HIV population. This is a 12-month randomized, placebo controlled study enrolling HIV-infected individuals with no known history of cardiovascular disease. Eplerenone is a mineralocorticoid receptor antagonist, which can block aldosterone activation. This medication is approved by the FDA for high blood pressure and heart failure. This study aims to investigate the effect of eplerenone on other measures of cardiovascular disease in HIV. Using PET, MRI and CT imaging technology, this study will evaluate whether eplerenone can improve coronary flow reserve and myocardial inflammation/fibrosis, in addition to atherosclerotic plaque build-up among the HIV population.
Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) (NIH U01 HL123336)
(Kathleen Fitch, MSN, FNP: Project Manager)
The risk of cardiovascular disease is increased 50-100% among HIV-infected patients. HIV patients have recently been shown to demonstrate increased prevalence of subclinical atherosclerosis, with high risk morphology plaque in association with immune activation. No therapy has yet been established to prevent cardiovascular disease in HIV-infected patients. Statins are known to decrease not only LDL, but also monocyte chemo-attraction and immune activation, and are thus a logical therapy for primary CVD prevention in HIV. REPRIEVE is a large 7500 person randomized, placebo-controlled clinical trial to test the efficacy of pitavastatin to prevent MACE events in HIV. This NIH funded trial is being conducted across 100+ sites in the US and internationally. REPRIEVE includes a sub-study to be performed among 800 patients assessing CT angiography and immunological phenotyping to determine the mechanisms of statin effects in this population.
Tesamorelin Effects on Liver Fat and Histology in HIV: A Collaborative UO1 Grant (NIH U01 AI115711)
This study investigates the effects of tesamorelin, a growth hormone releasing hormone analog, on liver fat content and liver histology in people with HIV-infection and nonalcoholic fatty liver disease (NAFLD). Tesamorelin is known to reduce visceral (belly) fat in individuals with HIV-infection and increased visceral adiposity. Building on an earlier finding that tesamorelin decreases liver fat content in individuals with increased belly fat, this study is testing the hypothesis that tesamorelin will reduce liver fat content in individuals with HIV and NAFLD and have beneficial effects to ameliorate the histopathological findings of steatohepatitis.
Kathleen Fitch, MSN, FNP:
Assessment of Sweetener Knowledge and Consumption in People Living with HIV (NIH P30 DK040561)
Preliminary studies suggest increased sweetener intake in association with metabolic dysregulation and cardiovascular risk in HIV. This study will identify among people living with HIV, areas of knowledge deficit and detailed consumption patterns of added sweeteners and characterize these variables by key social determinates of health among people living with HIV. Findings will inform the future development of an evidenced-based education tool-kit on added sweeteners, tailored to educate a diverse population of individuals living with HIV about potential negative health consequences of added sweetener consumption.
Lindsay Fourman, MD:
Growth Hormone Dynamics and Cardiac Steatosis in HIV
Cardiac steatosis is increased among individuals with HIV, and may predispose to cardiac mechanical dysfunction and subsequent heart failure. The pathogenesis and treatment of cardiac steatosis is not well understood. Investigators in the Metabolism Unit have previously shown that perturbed growth hormone (GH) secretion in HIV contributes to ectopic fat accumulation in the viscera and the liver. Moreover, unit investigators have found that augmentation of endogenous GH secretion with the FDA-approved medication tesamorelin reduces visceral and hepatic fat. In this longitudinal study, Dr. Fourman will examine patients with HIV and abdominal fat accumulation who either plan or do not plan to initiate tesamorelin prescribed clinically. It is hypothesized that blunted GH secretion in HIV is associated with cardiac steatosis and that use of tesamorelin for 6 months will result in a reduction in intramyocardial fat and preserved cardiac function.
HIV Exposure In Utero and Metabolic Disease Risk in HIV-Negative Young Adults (The HIV HEREDITY Study)
Worldwide, over 1 million babies are born to mothers with HIV each year. With the advent of prenatal antiretroviral therapy, up to 98% of these individuals may be HIV-exposed but uninfected (HEU). While growing, evidence suggests metabolic and immune disturbances among HEU individuals in early life, there is scant evidence surrounding the long-term health implications of in utero HIV exposure among HIV-negative individuals at the critical transition to adulthood. The HIV HEREDITY Study investigates the metabolic and immune phenotype of HEU young adults as compared to well-matched HIV-unexposed uninfected (HUU) controls. We also evaluate potential mechanisms of disease with a focus on epigenetics. Understanding long-term health outcomes among HEU individuals is a necessary first step toward optimizing care for this expanding global population.
Janet Lo, MD, MS:
A Study of the Gut Barrier and Blood Vessel Inflammation in Individuals With and Without HIV (NIH R01 HL123351)
The purpose of this research study is to determine whether teduglutide can repair a "leaky" gut, decrease inflammation, and prevent or treat plaque, a build-up of fat and other materials in the blood vessels of the heart, in people with HIV. HIV disease is linked to inflammatory changes and leakiness of the gut. These changes or conditions may increase the risk of developing heart and blood vessel disease. The investigators believe teduglutide can help repair the gut barrier in people with HIV, leading to a decrease in inflammation and plaque in the blood vessels of the heart. As more people with HIV gain access to combination antiretroviral therapy (cART), cardiovascular disease has become increasingly prevalent and a significant cause of mortality. Activation of the innate immune system may stimulate inflammatory mechanisms of atherosclerosis development. Loss of gastrointestinal (GI) mucosal epithelial integrity and loss of CD4+ T-lymphocytes in the intestinal lamina propria occur in HIV-infected patients and are not fully restored by cART. Translocation of microbial products from the intestinal lumen into the systemic circulation has been demonstrated to be increased in HIV-infected patients and the investigators hypothesize that it is a key driver of monocyte and macrophage activation. In turn, these pro-inflammatory monocytes and macrophages can induce atherosclerotic disease development. The purpose of the research study is to determine the effects of a glucagon-like peptide-2 analog, teduglutide, on intestinal epithelial integrity, microbial translocation across the gut lumen, markers of innate immune system activation including the monocyte transcriptome, bone, arterial inflammation and atherosclerosis in a 6-month randomized, double-blind placebo-controlled proof of concept trial in HIV-infected individuals.
Sara Looby, PhD, ANP-BC, FAAN:
Cardiovascular Disease Risk in HIV-infected Women: Sex-specific Mechanisms of Risk and Risk Reduction among REPRIEVE Trial Participants (NIH R01 AI123001 PI: Sara Looby, PhD; Markella V. Zanni, MD)
This study will assess whether women with HIV have unique factors which put them at increased risk for heart disease and whether a common class of medicines, statins, affects these factors. The proposed study will be performed as part of the recently launched REPRIEVE trial—a 7500-person study of statin therapy among individuals with HIV. As part of this study, reproductive aging and systemic immune activation will be uniquely related to cardiovascular risk and risk reduction in HIV. This project is also designed to stimulate and assess optimal strategies to increase recruitment of women to the parent REPRIEVE trial.
Suman Srinivasa, MD, MS:
MIRABELLA HIV (MIneralocorticoid Receptor Antagonism By EpLerenone to Lower Arterial Inflammation in HIV) (NIH K23 HL136262)
RAAS activation is seen in association with insulin resistance and increased inflammation among persons with HIV (PWH). Eplerenone is a mineralocorticoid antagonist that blocks aldosterone and is FDA approved for high blood pressure or heart failure. In thiss tudy, the effects of RAAS blockade are being examined to improve cardiovascular disease in HIV in a 12-month randomized, placebo controlled study. Using CT, PET, and MRI imaging technology, effects of eplerenone to improve coronary flow reserve, myocardial inflammation/fibrosis, arterial inflammation and Datherosclerotic plaque build-up among the HIV population are being examined.
ENding subClinical Heart failure using an Aldosterone and Natriuretic peptide Targeted treatMENT in HIV (The ENCHANTMENT HIV study) (NIH K23 HL136262)
Heart disease is a leading cause of non-communicable disease-related morbidity and mortality in the well-treated HIV population, and heart failure with preserved ejection fraction (HFpEF) is rising in prevalence. Rigorous hormonal testing from our group among PWH show increased renin-angiotensin-aldosterone system (RAAS) activation is relation to reduced natriuretic peptide (NP) and increased inflammation and monocyte/macrophage activation. NPs have cardioprotective effects, and relatively reduced NPs could impair activities related to natriuresis, vasodilation, myocyte hypertrophy and fibroblast proliferation, altering stability of the myocardium. We further postulate relatively reduced NP, a phenotype shown in highly metabolic groups and now demonstrated for the first time in HIV, may allow permissive RAAS activation leading to downstream inflammation and myocardial damage. We aim to investigate the cardiac phenotype associated with reduced NP among PWH compared to uninfected individuals utilizing advanced CV imaging techniques (cardiac MRI, cardiac TTE) and circulating myocardial biomarkers to comprehensively assess myocardial inflammation, structure and function. We will also determine the effect of sacubitril/valsartan, a dual angiotensin II receptor antagonist and neprilysin inhibitor, vs. placebo on longitudinal changes in myocardial inflammation, structure and function among PWH in a 6-month randomized controlled trial. These studies apply a novel concept in studying PWH, among whom we postulate a therapy to simultaneously increase NP and decrease RAAS activation may be beneficial for heart disease based on unique RAAS-NP physiology in HIV.
Takara Stanley, MD:
Augmenting Growth Hormone to Ameliorate Nonalcoholic Fatty Liver Disease in Adolescents (Novo Nordisk)
Fatty liver disease is an increasing problem in overweight and obese young adults. The purpose of this study is to test the effect of growth hormone on liver fat in obese young adults ages 18-29 with increased liver fat. Non-alcoholic fatty liver disease (NAFLD) is a significant health problem in obese adolescents. Obese children and adolescents have significant reductions in growth hormone secretion, and it is hypothesized that augmenting growth hormone in this population will decrease liver fat. Growth hormone inhibits hepatic de novo lipogenesis, which is an important source of hepatic lipid. Patients with pituitary GH deficiency have a higher prevalence of NAFLD and non-alcoholic steatohepatitis (NASH) than the general population, and replacement of GH in these individuals reduces signs of liver damage. The purpose of this study is to test the hypothesis that growth hormone treatment will decrease liver fat quantity in young adults who begin the trial with more than 5% liver fat measured by magnetic resonance spectroscopy.
Growth Hormone Releasing Hormone Analog to Improve Nonalcoholic Fatty Liver Disease and Associated Cardiovascular Risk (NIH R01 DK114144)
Nonalcoholic fatty liver disease (NAFLD) is common in individuals with obesity and is a significant threat to public health, because it can lead to impaired liver function and liver failure. Growth hormone is an important regulator of metabolism and growth. Individuals with obesity, demonstrated altered GH secretory dynamics and secrete less growth hormone than individuals without obesity. There are data to suggest that growth hormone may help to reduce the amount of fat and inflammation in the liver, both of which would be helpful to individuals with NAFLD. The purpose of this study is to investigate whether treatment with tesamorelin, a growth hormone releasing hormone analogue, will decrease liver fat and improve liver inflammation and scarring in obese individuals with NAFLD.
Williams Syndrome Strength, Hormones, Activity & Adiposity, DNA Programming, Eating Study (SHAAPE)
Williams syndrome (WS) is a rare microdeletion genetic disorder that has a broad phenotype including many endocrine and metabolic abnormalities. Dr. Pober and colleagues at Mass General have reported the following findings in adults with WS: abnormal body composition (excess body fat accumulation with a lipedema phenotype), decreased bone mineral density, abnormal glucose tolerance, and reduced lean mass. Despite the high prevalence and potential effect of metabolic abnormalities on the health of persons with WS, their full phenotypic range, potential causal factors (either genetic and/or hormonal) along with their impact on other aspects of health (such as risk of falls and fractures or interaction with emotional behavioral concerns) remain incompletely characterized. The purpose of the current study in a large cohort of subjects with WS is to: collect further information to characterize the timing of onset and distribution of body fat; better characterize hormonal status of WS subjects and screen for genetic variation using single-nucleotide-polymorphism (SNP) analysis that could elucidate genetic contributors to the lipedema phenotype as well as the other observed metabolic and bone abnormalities.
Mabel Toribio, MD:
Use of 99mTc-tilmanocept for Imaging of Macrophage-specific Inflammation
The purpose of this study is to evaluate uptake of intravenously administered 99mTc-tilmanocept using single photon emission computed tomography (SPECT/CT) scanning in individuals with HIV and individuals without HIV. People living with HIV (PLWH) have an increased risk of cardiovascular disease (CVD) compared to individuals without HIV. Increased systemic immune activation and arterial inflammation are thought to contribute to this increased risk by affecting the highly inflammatory process of atherosclerotic plaque formation and progression. This study will evaluate whether intravenous administration of a macrophage-specific imaging agent, 99mTc-tilmanocept, followed by SPECT/CT scanning can permit quantification of aortic 99mTc-tilmanocept uptake, reflective of aortic macrophage-specific inflammation among participants with HIV. Aortic 99mTc-tilmanocept uptake will be compared in participants with HIV to uptake in participants without HIV. Markers of immune activation and traditional CVD parameters will be investigated in relation to imaging assessments.
Effects of Gender-affirming Hormone Therapy Among Transgender Women (NIH K23 HL147799)
This study will investigate the cardiometabolic effects of gender-affirming hormone therapy among transgender women living with HIV. Transgender women living with HIV prior to initiation of hormone therapy face heightened cardiometabolic disease risk due to the HIV infection and anti-retroviral therapy. Studies investigating the effects of gender-affirming hormone therapy among transgender women living without HIV have shown that these women may also face heightened cardiometabolic disease and cardiovascular disease risk factors, such as insulin resistance. We hypothesize that gender-affirming hormone therapy among transgender women living with HIV will have complex beneficial and adverse effects (due to concomitant testosterone suppression and estrogen replacement) on the following key cardiometabolic endpoints: ectopic fat deposition (visceral adipose tissue and intramyocardial adipose tissue), body composition (lean mass, total and regional fat mass), glucose homeostasis (insulin sensitivity and insulin secretion), lipid homeostasis, cardiac structure and function and coagulation. Cardiometabolic study endpoints will be assessed before and after 12 months of gender-affirming hormone therapy among transgender women living with HIV.
Markella Zanni, MD:
Arterial Inflammation and Coronary Microvascular Dysfunction Among Women with HIV: Missing Pieces to the MI Risk Puzzle (NIH R01 HL146267 PI: Markella V. Zanni, MD)
Women with HIV (WHIV) face a three-fold increased risk of myocardial infarction as compared with women without HIV. As part of this clinical-translational research study, our interdisciplinary team is combining state-of-the art non-invasive cardiovascular imaging with detailed molecular immune cell and endothelial cell phenotyping to describe mechanisms predisposing women with HIV to MI. Studying a prospectively recruited cohort of WHIV vs. women without HIV, we will test the following hypothesis: Among women, HIV infection prompts systemic monocyte activation and endothelial cell pathology, predisposing to increased arterial inflammation. Arterial inflammation and endothelial cell pathology, in turn, promote not only non-calcified epicardial artery plaque but also coronary microvascular dysfunction. We plan to show that arterial inflammation and coronary microvascular dysfunction represent thus far neglected but potentially critical mechanisms of HIV-attributable MI risk among women—missing puzzle pieces. We also aim to delineate, on a molecular level, how circulating monocyte and vascular endothelial cell phenotypes differ among WHIV vs. women without HIV. Finally, we will investigate how pathologic monocyte/endothelial cell phenotypes may engender arterial inflammation, non-calcified epicardial artery plaque, and/or coronary microvascular dysfunction among WHIV. Characterization of pathways predisposing WHIV to MI will enable the development of rational MI prevention strategies and the targeted delivery of such strategies to women in need.
Mechanisms of Cardiac Dysfunction in HIV and the Effect of Statins: A Cardiac MRI Study (NIH R01 HL137562 PI: Markella V. Zanni, MD; Tomas G. Neilan, MD)
People with HIV (PHIV) face a two-fold increased risk of heart failure and worse heart failure outcomes as compared with individuals without HIV. Anteceding clinical heart failure, PHIV may experience diastolic dysfunction, driven by structural myocardial pathology including myocardial steatosis and/or myocardial fibrosis. Our clinical-translational research study tests the hypothesis that statin therapy (vs. placebo) will forestall the progression of myocardial steatosis and/or fibrosis and preserve diastolic dysfunction among asymptomatic PHIV. This hypothesis stems from evidence that statins not only act on lipid homeostasis but also dampen systemic immune activation—a problem which persists despite effective suppression of HIV viremia with combination antiretroviral therapy (ART). As part of this study, approximately 130 PHIV recruited from three US regions (Boston, Dallas, LA) and from Cape Town, South Africa will undergo advanced non-invasive cardiovascular imaging (cardiac MR spectroscopy and cardiac MR imaging) as well as detailed metabolic/immune phenotyping at baseline and after 2 years of statin (vs. placebo) therapy. Metabolic and immune mechanisms of cardiac dysfunction among PHIV will be assessed, as well as statin effects on these pathways. This work will have relevance to identifying strategies for preventing progression to cardiac dysfunction and heart failure among individuals aging with HIV.
Nutrition Obesity Research Center
The Nutrition Obesity Research Center at Harvard, or NORCH, is one of the Nutrition Obesity Research Centers funded by the National Institutes of Diabetes, Digestive, and Kidney Diseases. The NORCH was estaelished in 1994, and Dr. Grinspoon has served as the principal investigator since 2015. The NORCH supports a research base of over 100 investigators in nutrition, obesity and metabolism across the Harvard system. Three cores—the Genomics and Cell Biology Core, the Metabolic Phenotyping Core and the Metabolic Imaging Core—provide services to investigators in order to facilitate relevant research. Additionally, the NORCH hosts an annual symposium and provides pilot and feasibility funding for research related to nutrition, obesity and metabolism. More information is available on the NORCH website.
Recent Grants and Awards
Dr. Lindsay Fourman
- John T. Potts, Jr. Pilot Award Program of the Mass General Endocrine Division
- Nutrition Obesity Research Pilot and Feasibility Award - Metabolic Sequelae of in Utero HIV Exposure: A Pilot Study
Dr. Suman Srinivasa
- Gilead Sciences Research Scholars Program in HIV - Critical Effects of Dicer on Adipose Tissue in HIV Lipodystrophy
Dr. Mabel Toribio
- NIH/NHLBI - K23HL147799 - Cardiometabolic Effects of Gender-Affirming Hormonal Therapy among Transgender Women with HIV
Dr. Markella Zanni
- NIH/NHLBI - R01HL146267 - Arterial Inflammation and Coronary Microvascular Dysfunction among Women with HIV: Missing Pieces to the MI Risk Puzzle
Dr. Steven Grinspoon
- University of Virginia, School of Medicine - Michael O. Thorner Distinguished Lectureship in Endocrinology
Dr. Mabel Toribio
- Massachusetts General Hospital, Department of Medicine - The Sanchez and Ferguson Research Faculty Award
- Robert Wood Johnson Foundation - The Harold Amos Medical Faculty Development Award
Ewelinka (Nika) Grzejka, MS — Ms. Grzejka received her BS in health management and policy from the University of New Hampshire and recently received her master's of science degree in research administration from Emmanuel College. Ms. Grzejka manages all budgetary aspects of the Metabolism Unit and the Nutrition Obesity Research Center at Harvard, including grants and awards. She also supervises the Pilot and Feasibility Program and tracks recharge supplements to the various cores of the NORCH, including core usage.
Pamela Yurrita, BA — Ms. Yurrita received her BA in psychology, with a focus in neuropsychology and a minor in deaf studies from Boston University in May 2017. She serves as the administrative coordinator for the Nutrition Obesity Research Center at Harvard as well as staff assistant for the entire Metabolism Unit, where she continues to grow, manage and assist in all aspects pertaining to the NORCH and the Metabolism Unit.
To contact us for support or questions, please email HarvardNORC@mgh.Harvard.edu, or call the main research office at 617-724-9109. Thank you!