Research
Researching Metabolic Diseases
Our work, funded by the NIH, the American Diabetes Association, Harvard Medical School, various foundations, and the pharmaceutical industry, has resulted in over 1100 original publications, including more than 808 in medline, more than 251 collaborative papers in the context of the Look AHEAD Study, over 350 reviews/chapters in textbooks, which have received over 176,500 citations with an H-index of more than 162 in Google Scholar. Group members have been honored with numerous prestigious awards at national and international meetings.
The Mantzoros research group conducts independent investigations and collaborates on several projects with experts from national and international institutions.
Our projects aim, among others, to:
- Investigate the etiology, underlying molecular mechanisms and pathophysiological links between obesity/adipose tissue, MASLD/MASH, diabetes, cardiovascular disease, and malignancies.
- Explore the role of promising new classes of anti-obesity medications including leptin and other peptides such as adiponectin, serotonin receptor agonists, and incretins such as GLP-1, GIP, and other incretin analogues in the treatment of obesity and the metabolic syndrome (insulin resistance, diabetes, hypertension, hyperlipidemia).
- Investigate the roles of leptin and neuropeptides in obesity as well as the mechanisms underlying their roles.
- Investigate new molecular targets for the treatment of obesity, diabetes, cardiovascular disease, and endocrine malignancies.
- Perform "proof of concept studies" incretin analogs involving leptin, GIP, GLP-1, and other incretin analogs and neuropeptide agonist administration in humans to fully elucidate their role in human physiology and disease.
Specific examples of ongoing research projects are outlined below.
Our basic research studies focus on physiological and pathophysiological regulation of novel molecules important in energy homeostasis, obesity, MASH, and diabetes, and obesity, as well as complications of the latter including cardiovascular disease and malignancies. We utilize a wide range of research methods including genomics-bioinformatics, molecular biology, and animal physiology studies to answer important questions regarding obesity, insulin resistance, and their consequences which include diabetes, cardiovascular disease, and malignancies. Our ultimate goal is to develop novel diagnostic and therapeutic strategies by better-understanding and exploiting underlying mechanisms. Our main focuses are:
- Investigate the physiology of novel hormones in the regulation of energy balance in conditions of energy deprivation (e.g. anorexia nervosa, starvation, strenuous exercise) or of energy excess (obesity, diabetes, non-alcoholic fatty liver disease) in humans.
- Identify molecular pathways related to metabolic diseases in humans using both targeted and untargeted “omic” approaches and assessing their potential as prognostic markers or therapeutic tools for obesity, diabetes, MASH, and other metabolic diseases.
- Explore the role of promising new classes of anti-obesity medications (e.g. leptin, adiponectin, serotonin receptor agonists, incretins) and of nutritional interventions (e.g. walnut consumption, coffee intake, Mediterranean diet) on appetite control using neurocognitive and neuroimaging techniques and on cardiometabolic profile through hormonal, biochemical, metabolomic and lipidomic analyses.
- Perform "proof of concept studies" in mice and humans involving leptin, GLP-1, and other incretins, neuropeptide agonist administration and PPARγ selective modulators to fully elucidate their role in human physiology and disease as well as their treatment efficacy in disease states such as obesity, diabetes and MASLD.
- Investigate the pathophysiological link between obesity and diabetes, metabolic and hormonal milieu and malignancies.
We conduct and participate in large-scale epidemiological investigations, including cross-sectional, cohort, and case control studies, in collaboration with members of the Environmental Health, Nutrition, and Epidemiology Departments of the Harvard School of Public Health as well as the Veterans Administration healthcare system and several major epidemiology universities and institutions worldwide, e.g. Karolinska Institutet and Uppsala University, the network of German Diabetes and Metabolism Centers etc.
Our research efforts have expanded to studying non-modifiable disease determinants, including certain single nucleotide polymorphisms, as well as modifiable determinants, such as diet and exercise, as predictors of adipokine concentrations and/or metabolic diseases.
Following our initial work on the role of insulin and insulin-like growth factors, we performed the first case-control and prospective cohort studies demonstrating that adiponectin is a key link between obesity/insulin resistance and common malignancies associated with obesity including endometrial, breast, prostate, renal, and colon cancers. Ongoing studies are investigating the underlying mechanisms and exploring the roles of adiponectin and other adipokines as diagnostic and therapeutic agents in these disease states. We are also involved in Mendelian Randomization studies and disease trajectory studies.
The above basic research and epidemiologic studies have provided important new information and have advanced our knowledge of human physiology and pathophysiology. The hope is that these advances will ultimately lead to therapeutic breakthroughs.
Our main focuses are:
- Clinical epidemiology studies in the areas of obesity, MASLD / MASH, diabetes, cardiovascular disease, and malignancies.
- Raising and testing hypotheses of the physiological and pharmacological role of novel compounds.
- Developing new diagnostic and therapeutic tools for the above disease states.
To understand the neuropharmacology underlying leanness and obesity, we utilize functional magnetic resonance imaging and neurocognitive testing. Our recent studies have illuminated the functional brain activation changes to food cues in response to leptin administration in lean, hypoleptinemic women. Studies examining the effects of other molecules, such as GLP-1 analogues, or centralling acting medications, such as naltrexone/buproprion or lorcaserin, which treat obesity are underway. Furthermore, we are also examining where receptors for key molecules regulating energy homeostasis are expressed in the human brain using immunohistochemistry and study their function using in vitro and in vivo techniques. Through the combination of these techniques, we will be better able to understand the mechanisms of action for these molecules and be better able to help develop future, successful therapeutics.
Our interventional studies in humans range from early phase pharmacokinetic and small scale, investigator-initiated "proof of concept" studies, to medium, and large-scale double blind placebo-controlled clinical trials, which, if positive, are later expanded into multi-center clinical trials.
Our group was the first to complete pharmacokinetic studies of leptin in humans and were the first to conclusively demonstrate, utilizing "proof of concept" studies involving leptin administration, the role of leptin in regulating the neuroendocrine response to energy deprivation in humans. We were also the first to demonstrate that low leptin levels are intimately linked with neuroendocrine abnormalities observed in the REDs or in anorexia nervosa. Further, we demonstrated that administration of leptin, in replacement doses, corrects neuroendocrine and reproductive abnormalities and improves markers of bone density in strenuously exercising women athletes with the "female triad". Leptin was recently approved by the FDA for treatment of lipodystrophy in humans.
Our clinical research studies focus, among others, on:
- The physiology of leptin in lean and obese individuals and the associations between leptin levels, pulsatile secretion of leptin, and neuroendocrine and immune function in humans.
- Randomized, double-blind, placebo-controlled trials to investigate the effect of leptin treatment in several disease states.
- Randomized, double-blind, placebo-controlled trials investigating the effects of liraglutide (a GLP-1 analogue) and novel dual and triple incretin receptors agonist; in addition to lorcaserin (a specific serotonin receptor agonist) or other centrally acting medications in lean and/or obese subjects.
- Nutritional epidemiology studies as well as controlled, randomized meal replacement weight loss studies.
- Randomized clinical trials in obese patients with diabetes, including the Look AHEAD study, i.e. a study of health outcomes in response to weight loss. In a national multi-center clinical trial, the Look AHEAD study, we examine the long-term effects of an intensive lifestyle intervention program designed to achieve and maintain weight loss by decreasing caloric intake and increasing physical activity in overweight volunteers with type 2 diabetes.
- Interventional placebo-controlled trials for the treatment of diabetes and obesity, and nonalcoholic steatohepatitis (MASH).
- Randomized placebo-controlled, Phase 3, cardiovascular outcome clinical trials on next generation weight-loss medications (Survodutide) designed to evaluate the cardiovascular safety and efficacy.
MASLD/MASH is recognized as the most common liver disease in developed countries with its incidence continuously rising in parallel to the increasing incidences of obesity and type 2 diabetes (T2DM).
- Our research has led us to authored call-to-action guidelines, opinion papers, multi-society consensus statements and editorials on the management and novel nomenclature of MASH, which are currently defining and driving research in the field, in view of the ever-increasing prevalence of MASH and its integration in clinical practice.
- We are extensively studying nutritional and other predictors of MASLD/MASH and its outcomes, as well as the underlying mechanistic pathways of steatotic and inflammatory liver disease that are influenced by nutrition across diverse population.
- We conduct comprehensive studies on the efficacy and underlying mechanism of novel potential treatments for MASH and moderate to advanced liver fibrosis, based on different mechanistic pathways (eg., elafibranor, liraglutide, empagliflozin, spironolactone) in both basic and clinical studies.
Omics technologies, the development of which has been significantly advances in the last few years, can potentially be used for further investigate the pathophysiology of MASLD, develop accurate diagnostic methods, and identify therapeutic targets. Our laboratory primarily focuses on the study of circulating transcriptomics, proteomics, metabolomics, lipidomics, and glycomics, particularly in the context of clinical trials, to better understand the biochemical snapshots of metabolic disease. We implement complex in-house statistical analyses and state-of-the-art machine learning and artificial intelligence methods to fully elucidate results and understand the intricacies of metabolic physiology and pathophysiology.
- We are performing studies on high-throughput untargeted longitudinal and cross-sectional proteomics, using the latest SomaScan technology, to discover the biochemical intricacies governing energy regulation in lean humans under leptin administration.
- We are focusing on high-throughput metabolomics and lipidomics through a multi-national endeavor to build non-invasive diagnostics for MASLD/MASH, and stages of fibrosis through advanced machine learning models in large biopsy-proven population cohorts from around the world.
- We compare and improve standard clinical markers and scores with omic-features to translate our results in meaningful and scalable algorithms or tools.
