Overview: The MGH Program in Nutritional Metabolism was formed in 2002 under the Direction of Dr. Steven Grinspoon, a recognized expert in neuroendocrinology and metabolism. The Program has advanced our understanding of the hormonal mechanisms contributing to and clinical consequences of visceral and ectopic adipose tissue accumulation in obesity and acquired lipodystrophies. The Program in Nutritional Metabolism, with 8 faculty members, three current fellowship trainees, and a staff of 10 is located in 2800 square feet of newly renovated office space in Charles River Park, adjacent to the Mass General Hospital. The goal of this multidisciplinary program is to study hormonal function, nutrient trafficking, and the metabolic consequences of fat redistribution in a broad number of disease conditions, including undernutrition, obesity and acquired lipodystrophy, for example among HIV-infected patients and children. Related interests include the interplay between adipose tissue and innate immune activation, and the inflammatory basis of cardiovascular diseases. Faculty members, representing a broad array of interests including neuroendocrinology, pediatric endocrinology, infectious diseases, nutrition and radiology, utilize state of the art techniques including insulin clamp, positron emission tomography (PET), magnetic resonance spectroscopy and K-40 isotope studies to determine metabolic function and body composition. Recent studies have investigated the use of a novel hypothalamic peptide to selectively reduce visceral fat in central obesity and a strategy to block inflammation in obesity with TNF-alpha antagonism. Among children with obesity, the relationship of mitochondrial function to insulin resistance is being studied. A major investigative focus on women has permitted the study of the effects of undernutrition on androgen metabolism and the novel use of testosterone in this population. NIH research grants to faculty have permitted a number of noteworthy accomplishments of Program staff, which include, among others:
Dr. Steven Grinspoon, Program Director, is a Professor of Medicine at Harvard Medical School, Co-Director of the Nutrition Obesity Research Center at Harvard and director of the Harvard Wide T32 Training Grant in Nutrition 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 (ACTS) 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. Dr. Grinspoon was one of the first to recognize the endocrine abnormalities associated with nutritional disturbances in HIV-infected patients and has served to Chair the Department of Health and Human Services Working Group on HIV and Wasting as well as on the World Health Organization, Technical Advisory Group on Nutrition and HIV/AIDS. He Co-Chaired the Research Affairs Committee for the Endocrine Society and Directed the Endocrine Society’s Clinical Investigators Workshop. He has served as the Pfizer Visiting Professor at University of California at Davis. Most recently he chaired the AHA State of the Science Conference on Cardiovascular Disease in HIV. Prior research focused on blocking TNF in obesity and use of hypothalamic peptides, including 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. Most recently he has investigated the effects of blocking lipolysis on skeletal muscle insulin resistance and mitochondrial function in obesity. In addition, 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 CVD in HIV using CT angiography and flow cytometric analyses (see www.REPRIEVEtrial.org). He is also investigating the effects of mineralocorticoid receptor blockade to improve insulin resistance and inflammation in HIV-infected patients.
Janet Lo, M.D., M.Sc. is an Assistant Professor of Medicine at Harvard Medical School. Her research involves the investigation of cardiovascular disease and fat redistribution in HIV disease. She used 64 slice CT to compare plaque volume and monocyte activation in HIV vs. non HIV-infected patients and demonstrated an increased prevalence of subclinical atherosclerosis in HIV infected patients uniquely linked to monocyte activation. She published an important paper in JAMA demonstrating the long-term effects of physiological Growth Hormone to reduce visceral fat in HIV-infected patients and most recently demonstrated for the first time the potent effects of statin therapy on plaque progression in HIV-infected patients, published in Lancet HIV. Her independent research interests focus on the linkage between disturbances in the gut epithelial barrier and arterial inflammation in HIV, and she is testing this hypothesis in an NIH R01 grant using a novel strategy to tighten the gap junctions and decrease microbial translocation and its cardiovascular effects in HIV.
Takara Stanley, M.D. is a Pediatric Endocrinologist and Assistant Professor in Pediatrics at MGH. She has recently shown that relative overweight may confound GH stimulation testing in the pediatric outpatient setting and demonstrated the degree to which increased BMI predicts reduced GH responsivity to standardized GH testing in this population. She investigated the physiological effects of GHRH1-44 and GH on endogenous GH pulsatility in healthy subjects and showed important effects of GHRH to reduce hepatic fat through augmentation of puslatile GH in HIV-infected patients, published in JAMA. This work led to an NIH-funded U01 grant with NIH to investigate the effects of GHRH on steatohepatitis. She is also investigating effects of statin therapy and insulin sensitivity in obesity.
Martin Torriani, M.D. is an Associate Professor of Radiology and holds a primary appointment in the Division of Musculoskeletal Radiology. He is an expert on the quantification of intramyocellular lipid using MR spectroscopy and pioneered the technique at MGH. He has first authored a number of critical papers in the field, including a recent Editorial on the clinical significance of racial differences in intermuscular fat in the American Journal of Clinical Nutrition. He is investigating the novel use of MR to determine the effects of inhibition of lipolysis on IMCL and PET to investigate brown fat in HIV lipodystrophy. His studies suggest a novel phenotype of fat in the dorsocervical area, characterized by a brown fat –like phenotype and expression of deiodenase-2.
Virginia (Jeanne) Triant, M.D., M.P.H. is an Assistant Professor of Medicine at Harvard Medical School and a physician in the Massachusetts General Hospital (MGH) Infectious Diseases Division. She received her MD from the Yale School of Medicine and MPH from the Harvard School of Public Health. She completed her residency in internal medicine at Brigham and Women's Hospital (BWH) and fellowship in infectious diseases at the combined Partners (MGH/BWH) Program. Her research focuses on the epidemiology of increased cardiovascular disease risk and chronic disease complications among HIV-infected patients, and she has developed a longitudinal HIV cohort with which she conducts clinical investigations. In important publications, she has demonstrated a 1.75-fold increase risk of acute myocardial infarction (AMI) in HIV-infected patients compared to non HIV-infected patients in a large healthcare network. She has also shown that CRP is increased and useful to predict AMI in the HIV population and that decreased CD4 cell count is associated with increased AMI risk.
Markella V. Zanni, M.D. is an Assistant Professor of Medicine at Harvard Medical School. Her research centers on the role of inflammation in mediating cardiovascular and metabolic risk in a variety of disease states including HIV and obesity. She has studied the metabolic activity of lipoatrophic fat in patients with HIV lipodystrophy, using 18FDG-PET/CT technology. She has also published on the effects of TNF-alpha antagonism on cardiometabolic parameters in obese subjects, and on the relationship between sCD163 (a monocyte/macrophage activation marker) and insulin resistance in normal-weight and obese subjects. More recently she has demonstrated high risk vulnerable plaque morphology among HIV-infected patients and demonstrated that the new 2013 ACC/AHA guidelines do not recommend statins for many HIV patients without traditional cardiovascular risk, but with increased high risk morphology plaque. Her recent interests center on CVD among HIV-infected women. She is also a Co-Investigator and protocol Vice-Chair for REPRIEVE (www.REPRIEVEtrial.org).
Suman Srinivasa, M.D., is an Instructor in Medicine at Harvard Medical School. Her research interests center around the mechanisms and clinical consequences of renin-angiotensin-aldosterone-system (RAAS) activation among HIV-infected patients. In her initial studies she has demonstrated increased RAAS activation in association with excess visceral adiposity among HIV-patients, using urinary aldosterone secretion and graded angiotensin-stimulated aldosterone increases in collaboration with Gail Adler at the Brigham and Women’s Hospital. She has also demonstrated that RAAS activation results in increased inflammation and insulin resistance among HIV patients and she is now assessing the effects of a mineralocoroticoid receptor blocker, eplerenone, in this population.
Sara Dolan-Looby,Ph.D, ANP-BC, received her BSN from the University of Vermont, her MSN from the MGH Institute of Health Professions, and completed her Ph.D. at Boston College in 2008. For the past 10 years, Dr. Looby has established a program of research investigating the metabolic complications of HIV among women, specifically cardiovascular disease, reduced bone density, and androgen deficiency in this population. She has published extensively in this area, and was recently awarded a K23 award to investigate the metabolic and psychological manifestations experienced by perimenopausal women with HIV. Her second project funded by the Harvard CFAR is investigating CVD risk, specifically alterations in inflammatory markers and adipokines, and their relationship to body composition among perimenopausal women with HIV. Dr. Looby lectures extensively on HIV infection in women, and is a recognized leader in this field. She is also a volunteer community educator at several AIDS service organizations throughout Massachusetts.
Katie Fitch, A.N.P. received her BA from the University of Washington and her MSN from the MGH Institute of Health Professions. Ms Fitch has conducted several studies focusing on the assessment of metabolic complications in HIV. She was named outstanding researcher in 2015 by the Association of Nurses in AIDS Care for numerous contributions. She has completed a study evaluating lifestyle modification and metformin among HIV-infected subjects with the metabolic syndrome and she has recently published in AIDS the observation that after 1 year of treatment with lifestyle modification and/or metformin, metformin had a significant effect to halt the progression of coronary artery calcification among the participants randomized to metformin. In addition she is contributing to a study evaluating eplerenone, a mineralocorticoid receptor blocker, among HIV-infected patients with increased waist circumference and impaired glucose to determine if blocking the effects of aldosterone will ameliorate cardiovascular risk parameters. In 2015, she was named as Project Manager of the Clinical Coordinating Center of REPRIEVE, a large 6500 person primary CVD prevention trial in HIV-infected patients (www.REPRIEVEtrial.org).
Meghan Feldpausch A.N.P, received her MSN from the MGH Institute of Health Professions. She is working on two studies evaluating the physiological effects of GHRH 1-44 in on steatohepatitis in HIV and obesity and statin therapy on liver fat and insulin sensitivity in obesity.
Ewelinka (Nika) Grzejka, B.S received her degree in Health Management and Policy from The University of New Hampshire. She serves as an Office Manager for the Program and coordinates all grant submissions for funding consideration. She is also responsible for managing the Program's overall financial performance including budgeting and forecasting.
Linda Pronjari, B.S. received her Bachelors of Science degree in Health Management and Policy from The University of New Hampshire.She serves as a staff assistant to Dr. Grinspoon and directs the administrative aspects of the Program.
Current Research Projects
Physiologic Effects of Long Term GHRH1-44 on Steatohepatitis in HIV Lipodystrophy
Visceral fat accumualtion in HIV lipodystrophy is associated with reduced levels of growth hormone and increased metabolic and cardiovascular disease risk. In this study, we will administer a growth hormone releasing hormone (GHRH1-44) analog to HIV subjects with increased liver fat to augment physiological reductions in GH secretion, in order to reduce visceral adiposity, liver fat and related indices of liver inflammation. This 6 month randomized, placebo-controlled, double-blind, interventional study will asses histological indices of liver inflammation and steatosis for the first time, in response to GHRH, building on prior studies demonstrating an effect using MRI assessments. .
For more information contact Dr. Takara Stanley at 617-726-5312 or 617-643-4420
Effects of Eplerenone on Insulin resistance and Inflammatory Indices in HIV-infected Patients
RAAS activation is seen in association with insulin resistance and increased inflammation in HIV-infected patients. In this randomized, placebo-controlled trial, HIV-infected patients with insulin resistance are randomized to placebo or eplerenone for 6 months with assessment of insulin resistance by euglycemic, hyperinsulinemic clamp as well as inflammatory indices.
For more information contact Dr. Suman Srinivasa at 617-726-1585
Effects of Pitavastatin on Liver fat and Insulin Resistance in Obesity
Liver fat and insulin resistance are increased in patients with obesity, a group which is often prescribed statins. However, the effects of statins on these parameters are not known. We will assess for the first time the effects of pitavastatin, a newer statin which is metabolized by glucoronidation on these parameters in obese subjects, using a randomized, placebo-controlled trial design.
For more information contact Dr. Takara Stanley at 617-726-5312 or 617-643-4420
Metabolic Effects on QUAD Therapy on Antiretroviral Naive HIV-Infected Patients
Newer information from the SMART trial suggests that antiretroviral therapy may decrease inflammation, but this hypothesis has never been tested directly in HIV. In this trial, we are assessing the effects of QUAD on arterial inflammation using FDGPET, as well as effects on cholesterol efflux and T-cell and monocyte function using flow cytometry.
For more information contact Dr. Markella Zanni at 617-724-6926 or 617-724-0248
Arterial Imaging with Tilmanocept in HIV-infected Patients
Tilmanocept is an imaging agent used in the assessment of the sentinel node in breast cancer. It binds to the CD206 receptor on activated macrophages. Histology of plaque lesions suggest increased expression of this receptor, and thus tilmanocept is being assessed as a novel imaging agent for vulnerable plaque in HIV-infected patients.
For more information contact Dr. Markella Zanni at 617-724-6926 or 617-724-0248
Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE)
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 6500 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 an anticipated 90-100 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.
For more information contact Dr. Steven Grinspoon, Katie Fitch or Dr. Markella Zanni at 617-724-9109
Randomized trial to Decrease Arterial Inflammation in HIV-infected Patients by Reducing Intestinal Gap Junctions
Arterial inflammation is increased in association with increased markers of microbial translocation. Gap junctions permit bacterial translocation in HIV, which may contribute to increased immune activation. In a novel trial, investigators in the PINM, will decrease these gap junctions and assess effects on arterial inflammation using FDGPET.
For more information contact Dr. Janet Lo at 617-724-3425 or 617-724-8070.
Recently Completed Research Projects
Physiologic Effects of Long Term GHRH1-44 in Abdominal Obesity
Obesity is associated with reduced levels of growth hormone and increased metabolic and cardiovascular disease risk. In this study, we administered a growth hormone releasing hormone (GHRH1-44) analog to obese subjects with reduced growth hormone to normalize growth hormone levels and to reduce visceral adiposity and improve metabolic and cardiac risk factors. This randomized, placebo-controlled, double-blind, 12 month interventional study demonstrated significant effects of GHRH on visceral adiposity, triglyceride levels, CRP and carotid IMT, and is the first to demonstrate the effects of augmentation of pulsatile GH in obesity.
Results Published: J Clin Endocrinol Metab. 2012; 97(12):4769-79
Effects of Statins on Inflammatory Indices in HIV-Infected Patients
HIV-infected subjects with evidence of subclinical atherosclerosis on 64 slice coronary CT angiography were randomized to atorvastatin or placebo for 12 months. The effects of atorvastatin on plaque progression and inflammatory indices were determined. Atorvastatin was shown to reduce plaque volume by almost 20% compared to an increase of 20% in the placebo-treated patients. In addition, significant effects were seen on noncalcified plaque, high risk plaque morphology and CRP.
Results Published: Lancet HIV; ePub Jan. 9, 2015.
Effects of Inhibition of Lipolysis with Acipimox on Skeletal Muscle Mitochondrial Function and Insulin Resistance
In a randomized, placebo controlled trial of obese patients with insulin resistance and abdominal adiposity, acipimox reduced free fatty acids over 6 months, and improved fasting glucose, triglyceride, adiponectin, insulin and skeletal muscle ceramide expression, but was not effective to improve mitochondrial function by P31 spectroscopy, mitochondrial density or mitochondrial oxidative phosphorylation.
Assessment of Brown Fat in HIV Lipodystrophy
In this study, the presence of brown fat was assessed in HIV-infected patients with dorsocervical fat accumulation (buffalo hump) using FDG PET and UCP-1 expression testing. Although UCP-1 expression and FDGPET uptake were not increased, a unique intermediate phenotype was demonstrated with increased DIO2 expression in association with increased energy expenditure. In a corollary study, subcutaneous adipose tissue in the dorsocervical hump was biopsied and demonstrated reduced DICER concentration, consistent with an altered metabolic phenotype.
Results Published: J Clin Endocrinol Metab. 2012;97(4):E602-7; J Clin Invest. 2014;124(8):3339-51
Assessment of RAAS Activation in HIV Lipodystrophy
HIV-infected and weight and age-matched non HIV patients underwent vigorous assessment for RAAS activation with controlled posture and salt studies. Data demonstrated increased urinary aldosterone and angiotensin stimulated aldosterone, in association with increased visceral fat in the HIV group. Stimulatory conditions for RAAS activation were associated with increased inflammatory markers, including CRP and IL-6 and reduced adiponectin.
Results Published: J Clin Endocrinol Metab. 2015;100(8):2873-82
Training is a major focus of the Program in Nutritional Metabolism. Dr. Grinspoon, Program Director has been successful in training research fellows in metabolism-related clinical research for over 20 years and received a K-24 mentoring award from the NIH in this regard. In addition, he is the Principal Investigator of a Harvard Wide Training Grant in Nutritional Metabolism. Nine recent fellows have obtained mentored, K equivalent grants (K23 or KL2/cMERIT), seven of whom, including Dr. Martin Torriani, Dr. Janet Lo, Dr. Virginia Triant, Dr. Sara Looby, Dr. Markella Zanni, Dr. Suman Srinivasa and Dr. Takara Stanley are now faculty members, investigating effects of increased intramyocellular lipid on insulin resistance in HIV-infected patients (Dr. Torriani), subclinical atherosclerosis in HIV disease (Dr. Lo), the incidence of myocardial infarction in HIV (Dr. Triant), effects of menstrual status on CVD in HIV (Dr. Looby), and effects of GHRH 1-44 on steatohepatis in HIV (Dr. Stanley), the effects of RAAS blockade in HIV (Dr. Srinivasa) and the effects of statins on MACE in HIV (Dr. Zanni). Dr. Lo has received a Masters Degree from Harvard Medical School in Clinical Investigation and Dr. Triant an M.P.H. from the Harvard School of Public Health. Two recent fellows received National Research Service Awards from the NIH to study the effects of TNF inhibition in the metabolic syndrome (Dr. Zanni) and the effects of GH and GHRH on endogenous GH pulsatility (Dr. Stanley). A prior fellow, Dr. Meininger is now currently a Director for Clinical Research in Metabolism at Merck Pharmaceuticals. Cross-training and fertilization resulting from the rich network of collaborating programs at Harvard is a strength of the Program, which facilitates interdisciplinary training in sophisticated clinical and translational nutrition research techniques through a select group of well-established Program Faculty in related fields of nutrition and metabolism research.
The Program in Nutritional Metabolism serves as the coordinating site and Dr. Grinspoon is the Principal Investigator of the Harvard Training Program in Nutritional Metabolism, an NIH-funded T32 Program. The Training Program offers two NIH-funded training slots for qualified M.D. and Ph.D.'s interested in related research fields. The Executive Steering Committee of the Grant includes Steven Grinspoon, M.D., Joseph Avruch, M.D. (MGH), Alan Walker, M.D. (MGH), Joseph Majzoub, M.D. (Children’s Hospital), Madhu Misra, M.D. (MGH), Jose Florez, M.D. (MGH), Walter Willett, Ph.D. (Harvard School of Public Health).
To Learn More about Training Opportunities, contact Dr. Steven Grinspoon, (617) 724-9109 and see T32 website.
NUTRITION OBESITY RESEARCH CENTER AT HARVARD
CALL FOR PILOT FEASIBILITY PROJECT (PFP) APPLICATIONS IN NUTRITION, OBESITY
OR RELATED RESEARCH FIELDS
(NEW AND COMPETING RENEWALS)
The Nutrition Obesity Research Center at Harvard (NORC-H) (previously known as Harvard Clinical Nutrition Research Center) will be accepting applications for new pilot/ feasibility projects as well as for competing renewals of currently funded one-year projects for the 21st year (08/01/2016-07/31/2017) of the NIH-supported NORC. Projects will be funded up to $20,000 in the first year with possibility for renewal for a second year.
The specific purpose is to find:
1. Young investigators (senior fellows* or junior faculty) established by research programs relevant to clinical research who are without NIH R01 and R21 grant support (K awardees are encouraged to apply).
2. Established scientists not currently focused on nutrition per se who wish to initiate studies of direct or indirect importance to nutrition, metabolism or obesity.
3. Established nutrition researchers with novel new projects distinctly removed from their currently funded research projects.
Applications should be in the format of an R01, including all the NIH forms and budget pages, with the text portion of the grant limited to 3-5 pages single-spaced (NIH PHS 398). For anyone planning to submit a continuation, please be certain to detail the progress you have made in the first year, as well as your plans for the proposed second year.
In addition, please suggest 3 or 4 individuals who might be able to review your application knowledgeably. These individuals can be from within or outside the Nutrition Obesity Research Center, but should not be current collaborators. Please include their full names, mailing addresses, telephone and fax numbers and e-mail address.
Please submit electronically to Ewelinka ‘Nika’ Grzejka at firstname.lastname@example.org . FOR A COMPLETE APPLICATION GO TO THE NORC WEBSITE
For any science related questions please contact Dr. Steven Grinspoon, Co-Director of the NORC and Director of the Pilot Feasibility Program at 617-724-9109
* Fellows must be in the final year of training and must have a documented commitment to a faculty appointment by a sponsoring division or department.
PublicationsView recent publications from the Program in Nutritional Metabolism. Some full text articles may require a subscription.
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Dr. Steven Grinspoon
Director, MGH Program in Nutritional Metabolism
Ewelinka Grzejka, B.S