# Christos Socrates Mantzoros

Christos Socrates Mantzoros is a Greek-born American internist-endocrinologist, teacher, and researcher. He is a professor of medicine at Harvard Medical School and an adjunct professor at Boston University School of Medicine. He is the chief of endocrinology, diabetes, and metabolism at the VA Boston Healthcare System, where he is the founding director of human nutrition at Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School. He is editor-in-chief at the Metabolism: Clinical and Experimental journal.

## Biography

He was born in Nafplio, Greece. He earned an MD and a DSc from the University of Athens Medical School. He completed a residency in internal medicine at Wayne State University and a fellowship in endocrinology, metabolism, and diabetes, as well as clinical nutrition at the Longwood Training Program (Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, and Joslin Diabetes Center) of Harvard Medical School. He received master's degrees in clinical epidemiology from the Harvard School of Public Health and clinical investigation from Harvard Medical School. He is board-certified in internal medicine and endocrinology, metabolism, and diabetes, as well as in clinical nutrition. He was made full professor of internal medicine at Harvard University.

## Research

Mantzoros's research interests have included animal physiology and molecular biology, observational epidemiology studies, and clinical trials treating obesity, diabetes, and other human metabolic diseases. Mantzoros is known for his work on leptin, adiponectin, and the proglucagon family of molecules, as well as the relationship between insulin-like growth factors (IGFs) and cancer. Leptin has been approved by the United States Food and Drug Administration for treating lipodystrophy and severe insulin resistance accompanied by hyperglycemia and hyperlipidemia. His work has resulted in patents for diagnostic and therapeutic applications and has contributed to pharmaceutical companies' development of new pharmaceuticals. Currently, he and his team are utilizing various interventions (physiological, pharmacological, and dietary) and tools (physiological, hormonal, neurocognitive and neuroimaging, functional MRI) to investigate the role of the human brain and peripheral organs in regulating energy homeostasis, obesity, and metabolism and associated comorbidities, e.g., diabetes, NASH, cardiovascular diseases, and malignancies.
In 2018, Mantzoros gave a Harvard Medical School Mini Med lecture to teach medical concepts to a lay audience. The lecture was attended by nearly 100,000 people worldwide through live-streaming.

## Leptin and Adiponectin

Mantzoros conducted physiology and pharmacokinetic studies in leptin, ran clinical trials in humans, and investigated its therapeutic potential. He was among the first to investigate the normal physiology of leptin in humans, including circadian rhythms and the role of leptin in fasting, neuroendocrine regulation in humans, and concerning body weight. His team has published studies on leptin pharmacokinetics, determining leptin doses to be used in humans. His research broadened the understanding of the neuroendocrine function of leptin on body weight, energy homeostasis, gender differentiation, immunology, and the interaction with other hormones, such as thyroid-stimulating hormone and sex steroids. Observing that extreme leanness, hypothalamic amenorrhea (HA), and lipodystrophy were conditions of hypoleptinemia, he piloted clinical trials to test the efficacy of leptin to treat these conditions, showing that leptin replacement in patients with HA and lipodystrophy resulted in normalization of hormone axes and bone density in HA as well as improvements in insulin resistance and metabolic regulation in lipodystrophy. Additionally, he observed that functional changes in how the brain views food occur in subjects with hypoleptinemia, which can be corrected with leptin replacement. Mantzoros and his team observed that short-term metreleptin treatment enhanced activity in areas detecting food's salience and rewarding value during fasting. In contrast, long-term treatment decreased attention to the rewarding value of food after feeding. Furthermore, hypothalamic activity is modulated by metreleptin treatment, and leptin reduces functional connectivity of the hypothalamus to key feeding-related areas in these hypoleptinemic subjects. These findings expanded the role of leptin from that of a hormone regulating energy expenditure to one important in systemic neuroendocrine regulation. Mantzoros's team subsequently focused on physiology studies to explore and elucidate determinants of adiponectin levels in the circulation and the physiological role of adiponectin in humans.

## Proglucagon derived peptides

More recently, Mantzoros' interest has been directed towards the physiology and clinical significance of GIP and the proglucagon-derived peptides, including endogenous GLP-1, glucagon-like peptide-2, glucagon, oxyntomodulin, glicentin, and major proglucagon fragment, which play a significant role in metabolic homeostasis and weight regulation. Among other physiology and interventional studies, Mantzoros published a randomized control trial that showed that the administration of the GLP-1 analog liraglutide to overweight/obese individuals leads to downregulation of other proglucagon-derived molecules; this suggests that normalizing the decreasing levels of several of these molecules may provide additional metabolic and weight loss benefits in the future.

## Neuroimaging studies

Mantzoros has been working on the interplay of hormones and environmental factors to influence the function of essential brain centers in energy homeostasis and metabolism and how these may be altered with pharmaceuticals to treat obesity, with a focus on the control of eating behaviors as they are affected by obesity in the human cortex. Mantzoros and his team examined the GLP-1 analog liraglutide in diabetic adults and found that liraglutide decreased activation in the brain's cortex, increasing control and making individuals more attentive to their eating. This suggests that individuals on liraglutide find highly desirable foods less appealing and that the medication might prove an effective weight loss therapy for people who eat foods as a reward, such as when stressed. Short-term treatment with GLP-1RAs decreases activation in the insula, putamen, caudate, and orbitofrontal cortex (areas of the reward system), which may lead to lower energy intake and may thus contribute to weight loss; however, the impact of GLP-1RAs on brain activity disappears during long-term treatment, which may also explain the eventual weight-loss plateau observed with these medications. Furthermore, Mantzoros and colleagues examined the serotonin 2c receptor agonist lorcaserin in obese adults and discovered that lorcaserin decreased activation in the attention-related parietal and visual cortices in response to highly palatable food cues at 1 week in the fasting state and in the parietal cortex in response to any food cues at 4 weeks in the fed state. The decrease in emotion—and salience-related limbic activity, including the insula and amygdala, was attenuated at 4 weeks. In a secondary analysis, they observed that decreases in caloric intake, weight, and BMI correlated with activations in the amygdala, parietal, and visual cortices at baseline, suggesting that lorcaserin would benefit emotional eaters. Mantzoros' team performed the first neuroimaging study investigating the association of blood concentrations of oxyntomodulin, glicentin, and GIP with brain activity in response to food cues. Findings showed that fasting blood levels of GIP were inversely associated with the activation of attention-related areas (visual cortices of the occipital lobe and parietal lobe), oxyntomodulin and glicentin with reward-related areas (insula, putamen, caudate for both, and additionally orbitofrontal cortex for glicentin), and the hypothalamus when viewing highly desirable as compared to less desirable food images.

## Non-alcoholic fatty liver disease and steatohepatitis

In addition to his work on obesity and diabetes, recognizing the rising burden of NAFLD, which currently affects approximately 30% of Americans, Mantzoros has focused on the pathophysiology of the disease and the development of diagnostic, prognostic, and therapeutic tools. Regarding pathophysiology, the Mantzoros group has linked NAFLD to central obesity and the hormones leptin and adiponectin as well as low skeletal mass and skeletal tissue hormones, including activins, follistatins, irisin, the quality of the diet and the protective role of the Mediterranean diet. The Mantzoros team, using the techniques of omics and supervised learning, has developed novel models utilizing a top-down approach (instead of the usual candidate molecule approach) i.e.metabolites, lipids, hormones, and glycans that can diagnose the presence of NASH, NAFLD or healthy status with high accuracy, as well as a model that can diagnose liver fibrosis using lipids. He has further focused on the emerging role of antidiabetic and other medications necessary in metabolism suggested to be used on the background of medical nutrition and lifestyle modification therapy for the treatment of advanced NASH. For these reasons, Mantzoros has proposed a new name and classification for this disease: DAFLD/DASH (Dysmetabolism Associated Fatty Liver Disease / Steatohepatitis), placing it as an umbrella diagnosis under a pathophysiology-based subclassification of fatty liver disease (FLD). Mantzoros, representing the Endocrine Society, has participated in the working group that published the "call to action" paper inviting primary care physicians and subspecialists to prepare for the epidemic of this prevalent condition and to contribute to screening, diagnosing, and treating it in their clinics. This working group subsequently published the 2021 guidelines on diagnosis and treatment.

## Epidemiology of cancer

Observing that the incidence of certain cancers increases with the rate of obesity (e.g., cancers linked to obesity, such as endometrial, esophageal, breast, etc.), Mantzoros hypothesized that insulin-like growth factor 1 (IGF-1), which is also found at higher levels in obesity and is a growth factor, might be related to the development of cancer. He first confirmed in a case-control study that IGF-1 was linked with prostate cancer. Later, in case-control and prospective epidemiology studies, he confirmed a similar link between IGF-1 and other cancers, including thyroid and breast. This work opened the way for efforts to develop molecules blocking IGF-1 signaling as possible treatments for cancer, which are currently being tested.
Additionally, observing the links between insulin resistance, inflammation, and sex steroids with central obesity and obesity-related cancers, Mantzoros expanded this research to the molecule adiponectin, hypothesizing that abnormalities in this molecule, caused by abnormal fat deposition in the abdomen, were upstream of all other hormonal and inflammatory abnormalities above. First performing physiology studies in rodents and later in human case-control and prospective cohort studies, his team demonstrated the link between adiponectin and several types of cancer, including breast, colorectal, thyroid, prostate, and others. This work opened the way for efforts to develop molecules blocking IGF-1 signaling as possible treatments for cancer, which are currently being tested.
The Mantzoros group also demonstrated a direct effect of adiponectin and adiponectin receptors on human endometrial and other cancers and started mapping the molecular pathways downstream of adiponectin in malignancies. This suggests that adiponectin regulation, upstream of insulin resistance and IGFs, could be at the root of obesity-related cancers. Due to this research, adiponectin receptor agonists and/or medications that increase circulating adiponectin levels are currently being tested as treatments for cancers related to insulin resistance and central obesity.

## Mediterranean Diet

Mantzoros demonstrated that following a Mediterranean Diet leads to improved levels of adipokines like adiponectin, which decreases insulin resistance and inflammatory factors like c-reactive protein and thus leads in the long-term to a lower incidence of death from cardiovascular disease and stroke.

## Metabolism: Clinical and Experimental

Metabolism: Clinical and Experimental is a biomedical journal published by Elsevier that covers all aspects of metabolism, including studies in human, animal, and cellular models. The journal was in decline for several years until 2010, when Mantzoros assumed the position of editor-in-chief. Since then, the journal has experienced a growth of more than 20% annually in all metrics, and its impact factor has more than quadrupled (current IF: 13.93). The impact factor and cite score (4-year impact factor) has placed Metabolism: Clinical and Experimental in the top 3% of endocrinology, diabetes, and metabolism journals. Its cited half-life, or the duration an average paper continues receiving citations, was 9.4 in 2018, placing the journal in the top 5% of its category. The 2022 journal cite score was 16.5.

## Translation of science into tangible clinical benefits

Mantzoros heads Mantzoros Consulting, LLC, which consults for several companies. In 2005, he co-founded Intekrin, Inc., which was later acquired by and merged with Coherus, Inc. These companies are developing several biosimilars at various stages of clinical development in humans (one is approaching FDA approval) and small molecules for diseases related to insulin resistance (e.g. Diabetes NAFLD). CHRS-131 completed Phase II trials in humans for multiple sclerosis.

## Teaching and mentoring

Mantzoros is the chief of endocrinology, diabetes, and metabolism at the VA Boston Healthcare System and the director of the Human Nutrition Unit at Beth Israel Deaconess Medical Center. He teaches at Harvard Medical School and Boston University School of Medicine. He has mentored more than 175 scientists.
Mantzoros, an active member of the Eastern Orthodox Catholic Church, has held many roles, including teaching pro bono biomedical ethics at the Hellenic College and Holy Cross School of Theology, serving on the Archdiocesan Advisory Council on Bioethics, and serving on the Hellenic College Holy Cross (HCHC) board of trustees.

## Awards

Mantzoros has received awards:
* 2021 Korean Society of Nutrition Award co-administered with the American Society for Nutrition
* 2020 Gerald Reaven Distinguished Leader in Insulin Resistance Award by the World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease
* 2020 American Society for Nutrition E.V. McCollum Award
* 2018 American Society for Nutrition Robert H. Herman Research Award
* 2018 European Society of Endocrinology Geoffrey Harris Award
* 2018 Endocrine Society's Outstanding Clinical Investigator Award
* 2017 Obesity Society TOPS Award
Other (selected) Awards include:
* Frontiers in Science Award by the American Association of Clinical Endocrinology
* Novartis Award in Diabetes and Metabolic Diseases by the American Diabetes Association
* Lilly Award by the North American Association for the Study of Obesity (the Obesity Society)
* Mead Johnson Award by the American Society for Nutrition
* HypoCCS award in Paris, France
* Wilhelm Friedrich Bessel Award by the Humboldt Foundation of Germany
* Outstanding Investigator Award by the American Federation of Medical Research
* Hygeia award by the New England Hellenic Medical and Dental Association
* Berson Award Lecture by the American Physiological Society (FASEB)
* BIDMC and Harvard Medical School award for Excellence in Mentoring

## Honorary titles

* Four honorary PhDs from medical schools
* Three honorary professorships from medical schools
* Six visiting professorships from medical schools
* The Clinical Nutrition Laboratories of the International Hellenic University have been named the "Christos Mantzoros Clinical Nutrition Laboratories"
* Mantzoros has been elected a member of the American Society for Clinical Investigation
* Mantzoros has been elected a Fellow of the American College of Physicians and the American Association of Clinical Endocrinology