The Program in Nutritional Metabolism
Explore This Research Program
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:
- Investigation and demonstration of the effects of leptin administration to restore normal gonadotropin function in severe undernutrition
- Demonstration of the effects of TNF inhibition on inflammatory markers in the metabolic syndrome
- Demonstration of the potential feedback effects of GH on ghrelin in normal human physiology and caloric deprivation
- Recognition of the mechanisms, cardiovascular consequences and treatment strategies for insulin resistance in HIV-infected patients with fat redistribution and acquired lipodystrophy.
- Demonstration of the altered regulation of GH secretion with excess visceral adiposity and the potential utility of hypothalamic GH secretogogues to restore normal GH physiology and improve excess visceral adiposity
- Effects of novel GHRH secretagogue to reduce visceral and liver fat in HIV lipodystrophy
- Novel effects of lipolytic blockade strategy on metabolic endpoints in obesity
- Researchers in the Program in Nutritional Metabolism published over 100 articles in peer-reviewed journals since 2007, including publications in JAMA, the Annals of Internal Medicine and The New England Journal of Medicine.
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
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.
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., Anne Klibanski, 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.
If you are interested in donating to the Program in Nutritional Metabolism, please contact Dr. Steven Grinspoon, Director of the MGH Program in Nutritional Metabolism by phone at 617 724-9109 or via email at firstname.lastname@example.org.
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Massachusetts General Hospital Development Office
125 Nashua Street, Suite 540
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Please reference Dr. Grinspoon and the Program in Nutritional Metabolism
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