Speech title: New molecular and architectural determinants of metabolic regulation in health and disease
James S. Simmons Chair of Genetics & Metabolism,
Director, Sabri Ülker Center for Metabolic Research
Harvard University, TH Chan School of Public Health
Assoc. Member, Harvard-MIT Broad Institute,
Harvard Stem Cell Institute, Joslin Diabetes Center
Department of Molecular Metabolism
M.D. Ankara University, Ph.D. Harvard University
Dr. Hotamisligil’s research efforts focus on the molecular and genetic basis of common and complex metabolic diseases. His research examines the identity and molecular mechanisms of adaptive response systems in health and disease with a focus on metabolism. He is an internationally recognized leader with many seminal contributions including discoveries that defined the inflammatory origins of metabolic disease which are the pillars of the field of immunometabolism. His research group identified the role of endoplasmic reticulum as a key locus of immunometabolic adaptation, identified key mechanisms that relate to ER’s metabolic functions, such as the most recent discovery of ER-bound Nrf1 as a guardian of metabolism, and identified novel lipid and peptide hormones, such as Fabkin. In more recent years, Hotamisligil has been devoting effort to explore molecular architectural determinants of metabolic function. Dr. Hotamisligil pursues interdisciplinary paths and collaborations towards development of novel preventive and therapeutic strategies against chronic metabolic and inflammatory diseases. These programs have driven several drug development platforms, some currently in clinical trials others in advanced stages. His published work has resulted in >200 scientific manuscripts which have received >80,000 citations with an h factor>110 and resulted in multiple patents.
Dr. Hotamisligil has been recognized with many fellowships and awards during his training from the Markey and Pew Foundations, and the American Diabetes Association. Dr. Hotamisligil’s scholarly recognitions include the Outstanding Scientific Accomplishment Award of the American Diabetes Association, the Wertheimer Award of the International Association of Obesity, Science Award of the Vehbi Koç Foundation, Roy Greep Award for Outstanding Research of the International Endocrine Society, the International Danone Prize, and most recently, the EASD-NovoNordisk Foundation Diabetes Prize for Excellence. Dr. Hotamışlıgil explores the intersection of art and science and his work “Molecular Architecture”, jointly with Refik Anadol, is featured at the Venice Bienale, 2021.
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Dramatic changes in diet and lifestyle put humans at odds with their environment and placed a strong burden of the adaptive mechanisms developed throughout evolution, particularly those dealing with metabolic challenges. As a result, chronic metabolic diseases became the greatest threat on human health and welfare globally without adequate preventive or therapeutic measures. Currently, only diabetes affects more than 500 million individuals and this number is expected to double in the next 25 years. This dramatic incidence points to strong evolutionary underpinnings that must be considered in understanding the mechanistic basis of the epidemic and the pursuit of effective intervention strategies.
One such evolutionary force comes from the selection of highly effective responses to low blood glucose, which presents a significant threat to survival of the species. Hence, a multitude of systems, generally known as counter-regulatory program, act on liver to promote glucose production during life threatening conditions and starvation. A critical component to this regulatory program that emanates from adipose tissue, the major energy store, is yet to be identified. In this lecture, I will present evidence that this critical adipo-hepatic hormonal axis is mediated by a novel hormone, Fabkin, that is produced in response to breakdown of triglyceride stores in adipocytes1. In the presence of chronic nutrient and energy exposure such as the case in obesity, this pathway remains constitutively active in both experimental models and in humans and leads to development of diabetes and other associated metabolic pathologies.
Regulation of molecular subcellular architecture has also emerged as a novel metabolic adaptation mechanism. We have been exploring the subcellular architecture at the nanoscale in native liver tissue and its regulation during physiological and pathological states. Utilizing multiple imaging platforms including enhanced focused ion beam scanning electron microscopy (FIB-SEM), followed by deep-learning-based image segmentation, combined with biochemical and physiological approaches, we recently completed resolution of molecular architectural organization in large volumes of intact liver tissue in an unprecedented detail2. We found that hepatic subcellular architecture undergoes massive re-organization during nutritional cycles and in obesity, characterized by marked disorganization of stacks of ER sheets and predominance of ER tubules, as well as its interactions with mitochondria. Importantly, experimental recovery of ER’s structural organization through multiple interventions resulted in improved ER function and systemic glucose and lipid metabolism. Taken together, these data demonstrate that molecular architecture is highly dynamic and regulated, integrated with the metabolic program of the cell, and critical for adaptive homeostasis in health and its disruption in disease.