Mantzoros Lab Research

Our basic research studies focus on physiological and pathophysiological regulation of novel molecules important in energy homeostasis, obesity, NASH, 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:

• Molecular pathogenesis of obesity, NASH, insulin resistance, and associated comorbidities, including cancer, cardiovascular disease, insulin resistance and type 2 diabetes
• Molecular biology, physiology, and pathophysiology of adipokines, such as leptin, adiponectin etc. in animals and humans
• Molecular biology, physiology, and pathophysiology of hepatokinas, incretins, and myokines, in animals and humans

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.

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, NAFLD / NASH, 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 medications, such as 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 "female triad" (a disease state characterized by the simultaneous presentation of disordered eating, amenorrhea, and decreased bone mineral density) 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.

Currently, we are further exploring the role of leptin in the physiology, pathophysiology, and potential treatment of several disease states, including obesity.

Examples of our current studies are presented in the projects section.

Our work, funded by the NIH, the ADA, HMS, various foundations, and the pharmaceutical industry, has resulted in over 600 original publications in medicine, more than 150 collaborative papers in the context of the Look AHEAD Study, over 230 reviews/chapters in textbooks, which have received over 86,000 citations with an H-index of more than 147 in Google Scholar. Group members have been honored with numerous prestigious awards at national and international meetings.

MASLD 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 intircacies 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.