Christos Socrates Mantzoros

Christos S. Mantzoros was born in Nafplio, Greece and graduated with MD and received 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 at the Beth Israel Deaconess Medical Center and Joslin Diabetes Center program of Harvard Medical School. He also 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 in Endocrinology, Metabolism and Diabetes as well as in Clinical Nutrition. He went rapidly through the academic hierarchy steps from Instructor to Full Professor of Internal Medicine at Harvard University within twelve years.

His work spans the entire spectrum from animal physiology and molecular biology, through observational, epidemiology studies, to physiology and pharmacokinetic interventional proof-of-concept clinical trials on new therapeutic agents important in the treatment of obesity, diabetes and other metabolic diseases in humans.[3] Dr. Christos Mantzoros is known for his groundbreaking work on leptin (see Leptin below) and adiponectin and the relationship between IGF-1 and cancer (see Epidemiology of Cancer below). Recent major contributions of his research group include the elucidation of the physiological role and potential diagnostic and therapeutic utility of several adipokines and myokines, leptin, adiponectin, in human physiology and pathophysiology.[3][4] Leptin has been approved by the Food and Drugs Administration for lipodystrophy and severe insulin resistance accompanied by hyperglycemia and hyperlipidemia.[3] His work has resulted in patents for diagnostic and therapeutic applications and has directly contributed to the development of new pharmaceuticals by major pharmaceutical companies. Currently, he and his team are utilizing various interventions (physiological, pharmacological and dietary) and tools (hormonal, neurocognitive and neuroimaging, functional MRI) to investigate the role of the human brain in regulating energy homeostasis, obesity and metabolism (See Neuroimaging Studies below).

In 2018, Dr. Mantzoros gave a Harvard Medical School Mini Med lecture to teach medical concepts to a lay audience. The lecture was attended by close to 100,000 people from all over the world through live-streaming.[5][6]

In the area of leptin, Mantzoros pioneered physiology studies, conducted clinical trials in humans, and discovered its therapeutic potential. He was the first to investigate the normal physiology of leptin in humans, including circadian rhythms and the role of leptin in fasting and with relation to body weight.[7][8][9][10][11][12] His team has published the only three studies on leptin pharmacokinetics determining leptin doses to be used in humans. Indeed, 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 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 complete normalization of hormone axes and bone density in HA as well as insulin resistance and metabolic regulation in lipodystrophy.[10][11][13][14][15][16][17][18][19][20] Additionally, he observed that functional changes in how the brain views food occur in subjects with hypoleptinemia and that these can be corrected with leptin replacement.[21] Dr. Mantzoros and his team observed that short-term metreleptin treatment enhanced activity in areas detecting the salience and rewarding value of food during fasting, while long-term treatment decreased attention to and the rewarding value of food after feeding. Furthermore, hypothalamic activity is modulated by metreleptin treatment and leptin decreases functional connectivity of the hypothalamus to key feeding-related areas in these hypoleptinemic subjects. These findings expanded the role of leptin into systemic neuroendocrine regulation.

Observing that the incidence of certain cancers increases with the rate of obesity (e.g. cancers which have been linked with obesity such as endometrial, esophageal, breast, etc.), Dr. Mantzoros hypothesized that insulin-like growth factor 1 (IGF-1) which is also found at higher levels in obesity and a growth factor might be related to the development of cancer. Indeed, he first confirmed in a case-control study that IGF-1 was linked with prostate cancer.[22][23][24] Later, he confirmed a similar link between IGF-1 and other types of cancers, including thyroid, breast, and others both in case control and prospective epidemiology studies.[25][26][27] This work opened the way for efforts to develop molecules blocking IGF-1 signaling as possible treatments for cancer, currently being tested.

Additionally, observing the links between insulin resistance, inflammation, and sex steroids with central obesity and obesity-related cancers, Dr. 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.[25][26][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] This work opened the way for efforts to develop molecules blocking IGF-1 signaling as possible treatments for cancer, currently being tested.

The Mantzoros group also demonstrated a direct effect of adiponectin and adiponectin receptors on endometrial cancer in humans and started mapping the molecular pathways downstream of adiponectin in malignancies.[35] This suggests that adiponectin regulation may be at the root of obesity-related cancers. Due in large part to this research, adiponectin receptor agonists and/or medications that increase circulating levels of adiponectin are currently being tested as a treatment for cancers related to insulin resistance and central obesity.

Dr. Mantzoros also demonstrated that following a Mediterranean Diet, which is high in whole-grain cereals and low-fat dairy products and low consumption of refined cereals, 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 lower incidence of death from cardiovascular disease and stroke.[54][55][56][57][58][59][60]

Most recently, Dr. Mantzoros has been working on the interplay of hormones and environmental factors to influence the function of brain centers important in energy homeostasis and metabolism and how these may be altered with pharmaceuticals to treat obesity. Focusing on the human brain, he studies the control of eating behaviors as they are affected in obesity in the human cortex.[61] Most significantly, he determined the role of GLP-1 in the human brain. When Dr. Mantzoros and his team examined the GLP-1 analog liraglutide in diabetic adults and found that liraglutide was decreasing activation in the brain's cortex, the area that increases control and makes individuals more attentive to what they are eating.[62] 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 tend to eat foods as a reward, such as when they are stressed. Most recently, Dr. Mantzoros and colleagues examined the serotonin 2c receptor agonist lorcaserin in obese adults and discovered that lorcaserin was decreasing 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.[63] Decreases in emotion and salience-related limbic activity, including the insula and amygdala, were attenuated at 4 weeks. In a secondary analysis, they observed that decreases in caloric intake, weight, and BMI correlated with activations in amygdala, parietal and visual cortices at baseline, suggesting that lorcaserin would be of particular benefit to emotional eaters. These studies have important implications for obesity and future therapeutics.

Metabolism: Clinical and Experimental is a biomedical journal published by Elsevier related to all aspects of metabolism. Metabolism: Clinical and Experimental publishes studies in humans, animal and cellular models. The journal, one with a long history in the field of metabolism, was in decline for several years until 2010. Dr. Mantzoros assumed the position of Editor-in-Chief for the journal Metabolism: Clinical and Experimental in 2010. Under his leadership, the journal has experienced an approximately 20% growth annually in all metrics. The journal's impact factor in 2018 was 6.513 putting it in the top 6% of endocrinology journals (average JIF percentile 94%).[64] Its cited half-life was 9.4 in 2018 placing the journal in the top 5% of its category.[64] The impact factor has been continuously increasing over the past eight years that he has been serving at the helm, from 2 to 6.5 (2018), placing the journal amongst the top 6% of endocrinology, diabetes, and metabolism journals as indexed in Journal Citation Reports. Similarly, cited half-life, or the duration an average paper continues receiving citations, has also increased significantly and in 2018 rose to be in the top 5% of endocrinology, diabetes, and metabolism.

Dr. Mantzoros consults for several companies as the head of the Mantzoros Consulting, LLC. In 2005, he co-founded Intekrin, Inc. which was later acquired by and merged with Coherus, Inc.[65] These companies are developing a number of biosimilars at several stages of clinical development in humans (one approaching FDA approval) in addition to small molecules for diseases related to insulin resistance (e.g. Diabetes, NAFLD). CHRS-131, just successfully completed Phase II trials in humans for multiple sclerosis.[66] More recently, Dr. Mantzoros has co-founded Pangea, Inc.

Dr. Mantzoros currently serves as 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 closely mentored more than 165 scientists, many of whom are now Full Professors, 1 is now a CEO of a pharmaceutical company, 2 are Chief Medical or Scientific Officers, 1 a Vice President biotechnology companies and several others are currently Assistant and Associate Professors, Executive Directors at pharmaceutical companies or clinicians.

Dr. Mantzoros, an active member of the orthodox church, has served in many roles, including teaching pro bono biomedical ethics at the Hellenic College and Holy Cross School of Theology and serving as a member of the Archdiocesan Advisory Council on Bioethics. He has also served as a board member on the Hellenic College Holy Cross (HCHC) Board of Trustees.

Christos S. Mantzoros has received several awards. Recently, he received the 2017 Obesity Society TOPS Award, the 2018 Endocrine Society's Outstanding Clinical Investigator Award, the 2018 European Society of Endocrinology highest distinction, i.e. the Geoffrey Harris Award and the 2018 American Society for Nutrition Robert H. Herman Research Award.[67][68] He has also been elected to the American Society for Clinical Investigation (ASCI).[69]