Annual Report 2019

FIRST DECADE OF DISCOVERY

2019 ANNUAL REPORT

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Letter from Gökhan S. Hotamışlıgil, MD, PhD Publication Highlights Impact of the Center Next Generation of Scientists Message from Ashish Jha, MD, MPH Looking Forward

Primary hepatocyte (liver cells) lipids are shown in yellow.

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CHARTING THE FUTURE OF METABOLIC DISEASE

The Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research exists to advance scientific understanding of the fundamental mechanisms that govern metabolism and its intricate relationship with human health and disease. Scientists at the Center work to discover the body’s previously unknown builtin mechanisms, which can then be exploited to either promote health, prevent, or treat disease.

Advances in the basic science of metabolism as well as in analytical tools, imaging technologies, and computational power over the past decade have opened extremely exciting new avenues of exploration, creating a path to a much better understanding of both health and disease at the cellular and molecular levels. Today’s technologies even allow us to see inside a cell in real time—to observe how it responds to a particular set of conditions and understand how it functions. Never before have we been able to obtain the incredibly detailed resolution of samples, conditions, or living organisms that is needed to obtain a holistic view of the processes that govern the body’s systems of nutrient acquisition, storage, and utilization. Our aim is to utilize all these exciting approaches for better understanding of metabolism in health and disease.

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Metabolism is Life At the cellular and organismal levels, metabolic flux and balance are a requisite to move, to replicate, to repair damage, and to sustain life. Disruptions to this delicate balance are a major contributor to many diseases and aging. Thus, in some sense, metabolism is life; it is the molecular explanation of how we interact with the internal and external environment and operate as living organisms.

Proper metabolism insures robust function and health, and metabolic disturbances set the stage for chronic disease and the greatest threats to global public health. We at the Sabri Ăœlker Center are committed to investigating the molecular underpinnings of metabolism, its interactions with nutrients, and its dysregulation in chronic metabolic diseases such as obesity, diabetes, and cardiovascular diseases as well as during aging, with the long-term goal of translating the findings into new preventive and therapeutic directions and strategies to prolong healthy life.

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FIRST DECADE OF DISCOVERY

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Our Primary Target We consider endoplasmic reticulum (ER) to be the “master of organelles,” the mini-organs or functional units inside the cell that are extremely critical to a cell’s ability to monitor its metabolic environments, food and carbon sources, and what kind of stress responses it should emanate to establish balance and health.

ER is where one may find the most powerful metabolic defense mechanisms.

Consisting of a vast network of membranes that reach every part of the cell and essentially all of its functional units, the ER has become an important area of focus for the Sabri Ülker Center, relating to promising studies of chronic illnesses and successful strategies for therapeutic treatments and disease preventions.

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FIRST DECADE OF DISCOVERY

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Our Ongoing Pursuit Like Michelangelo’s statue of David, most masterpieces of art we admire are products of long periods of extremely hard work. And science is no different. First, we must master the existing knowledge and gain exposure to different fields to find the interesting things at the crossroads of these fields. Second, we must accept that our maximum level of creativity is far below the level of complexity of the human body.

Third, we must become accustomed to failure, otherwise we will not be able to learn from the creativity and complexity of biology. Only when we learn how to objectively examine the results of a carefully constructed experiment, do we have the chance to understand something uniquely interesting that we would never have been able to imagine on our own.

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FIRST DECADE OF DISCOVERY

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“ The Sabri Ülker Center is not just a physical place, but a powerful mindset—where we are able to collaborate in the pursuit of solutions to some of the most important challenges facing our world.

The Center is currently the research home to scientists from 11 different countries, representing a diverse array of religions, cultures, and lifestyles.

It is a unique place for all scientists who enter— one where identity is measured not only by the world class quality of one’s research, but also by the joy and enthusiasm one brings to the whole environment and to the pursuit of science.”

GÖKHAN S. HOTAMIŞLIGIL, MD, PhD James S. Simmons Professor, Department of Molecular Metabolism Director, Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research

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FIRST DECADE OF DISCOVERY

DEAR FRIENDS,

We are mid-way through the first decade of discovery made possible by the generosity of the Ülker family and Foundation, and I am thrilled by the continued contribution of our laboratory to the understanding of the cellular and molecular mechanisms that underlie chronic metabolic diseases. I am pleased to present you with some highlights of the work that is completed and published in the pages of this report and to share a few exciting developments that are in progress at the Center.

This year, we completed several groundbreaking projects that have been keeping us busy for many years. Chief among them is the discovery of a new hormone complex, which describes a novel endocrine axis in the regulation of beta cell responses and plays a major role in type 1 diabetes. This work was recently presented to the scientific community in several meetings and submitted for publication just before the printing of this report. We are extremely excited about this development as it opens up new possibilities that will have important implications for disease prevention. We are also approaching the finish line in our structural and imaging work related to the importance of subcellular architecture, and our collaborations with the world’s leading imaging scientists also continue at full speed. We likewise shared this work recently with the scientific community and will be reporting the first chapter of this long-lasting project in the coming months. Our work on endoplasmic reticulum responses and the inflammatory origin of obesity and diabetes has witnessed important developments. The molecular mechanism of action of the Nrf1 molecule, which was discovered at the Center as a critical regulator of metabolism through the endoplasmic reticulum is now advancing, and we discovered an exciting new mechanism that connects the dysfunction of this organelle to the adipose tissue inflammation at the molecular level. These are some examples of ongoing work in our Center.

To be the director of the Sabri Ülker Center is an honor for which I am humbled, and the Center allows our team to pursue the root causes of the diseases that pose the greatest threats to global human health.

The impact of the metabolic disease pandemic has become pervasive and the resulting burden is enormous.

If we just look at diabetes, it kills more than 5 million people a year. The burden has been increasing over the past 25 years throughout the globe so that means we still have much to do. To be successful in this journey, we continue to promote global scientific development and to engage and challenge fellows, trainees, and junior scientists and embark on collaborative studies. A major component of this effort is the annual International Symposium on Metabolism and Life. Our next Symposium program is complete and features a spectacular lineup of leading scientists and as before a terrific group of Rising Stars. We are eager to welcome you to İstanbul for this program, which will be held on June 3–5, 2020.

I am pleased to present to you this fifth annual report of our progress, recognizing that the transformative support from the Ülker family has made this possible. In this report you will read about the achievements of our current complement of researchers, the progress of our Ülker fellows, and the highlights of the year just passed.

Sincerely,

Gökhan S. Hotamışlıgil, MD, PhD 9

Cytoskeletal staining of COS-7 cells. Actin filaments are shown in red.

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PUBLICATION HIGHLIGHTS

SIGHT With novel tools and methods, as well as remarkable scientific progress on which to build, new opportunities are opening for scientific exploration at an astonishing pace. Scientists at the Sabri Ăœlker Center are using an array of exciting and powerful platforms to establish the fundamental causes of metabolic disease and generate translational tools to improve the quality of human life. This is an entirely new approach in global health, and the implications for disease prevention and treatment are extraordinary.

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PUBLICATION HIGHLIGHTS

This past year was filled with insightful studies led by members of the Sabri Ăœlker Center. We are proud to share the highlights of our newest publications with you. These studies are valuable for illustrating the important mechanisms underlying metabolic regulation and adaptation, and for opening new avenues for discovery and intervention, which we hope will bring benefits for public health and lead to preventive or therapeutic strategies in the future.

One significant report was the groundbreaking study on propionate, a chemical found in many food products and also produced by our body endogenously, and its impact on metabolic regulation. In this study, we showed that, when administered to mice, propionate triggers a hyperglycemic response, which is hormonally regulated. Our findings in animal models were translated to humans. We observed that participants who received a propionate-containing meal had increased levels of key hormones that regulate hyperglycemic responses, as well as a decrease in post-meal insulin sensitivity. In addition, in a dietary intervention trial, plasma propionate concentrations directly correlated with insulin resistance in obese participants.

These observations may have important implications for public health and should encourage further investigation on long-term exposure to different food components. Another exciting study unraveled a new mechanism by which the brown adipose tissue adapts to extreme metabolic stress, such as cold and obesity, in order to maintain endoplasmic reticulum (ER) homeostasis and cellular integrity. This mechanism, which is also involved in protecting cells against cholesterol-related damage, presents therapeutic opportunities to treat metabolic diseases. We also published a study that explored mechanisms involved in regulating calcium in the endoplasmic reticulum, the cellular compartment responsible for protein and fat production. Our studies revealed that, in obesity, this regulation is impaired, causing calcium levels to decrease below a critical threshold. This knowledge presents itself as an opportunity to correct calcium levels and interfere with detrimental effects of metabolic diseases.

These and other publications are a few examples of our collaborative efforts toward the advancement of science and a deeper understanding of metabolic regulation, supporting our ultimate goal of contributing positively to human health.

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PUBLICATION HIGHLIGHTS

Brown Adipose Tissue Thermogenic Adaptation Requires Nrf1-Mediated Proteasomal Activity Alexander Bartelt, Scott B. Widenmaier, Christian Schlein, Kornelia Johann, Renata L. S. Gonçalves, Kosei Eguchi, Alexander W. Fischer, Günes Parlakgül, Nicole A. Snyder, Truc B. Nguyen, Oliver T. Bruns, Daniel Franke, Moungi G. Bawendi, Matthew D. Lynes, Luiz O. Leiria, Yu-Hua Tseng, Karen E. Inouye, Ana Paula Arruda, Gökhan S. Hotamışlıgil Nature Medicine, March 2018

Brown adipose tissue (BAT) mediates non-shivering thermogenesis in mammals that are exposed to temperatures below thermoneutrality, an ambient environment in which basal metabolism is sufficient to maintain body temperature.

To sustain its exceptional oxidative metabolic activity, BAT consumes vast amounts of intracellular and circulating nutrients, and in doing so, it exerts beneficial metabolic effects on obesity, insulin resistance, and atherosclerosis.

During cold acclimatization BAT undergoes an adaptive process and the tissue grows in size and in total metabolic capacity. This involves both new adipocyte differentiation, as well as increased metabolic activity of existing adipocytes.

BAT is also activated by acute nutrient influx, in particular by consumption of a high-fat diet. However, chronic exposure to excessive amounts of nutrients, which occurs in obesity, results in whitening and reduced metabolic capacity of BAT in mice and humans. Because the mechanisms underlying BAT deterioration in obesity remain insufficiently understood, the identification of factors that protect thermogenic adipocytes from metabolic stress during adaptation to cold or to obesity may hold great potential toward therapeutic approaches for metabolic diseases. The dramatic metabolic changes in BAT during this adaptation not only involve dissipation of energy-rich nutrients but also de novo synthesis of new proteins, lipids, and cellular organelles. Thus, we hypothesized that cold adaptation might require novel adaptive mechanisms for increased quality control of these metabolic processes. In particular, enhanced protein production and folding, as well as protection against aberrantly modified or oxidized proteins and other metabolites may be required as adaptive mechanisms to resist the rising cellular stress. The concept of specialized molecules

and adaptive responses to achieve this challenging task is very compelling in brown adipocytes, considering their unique cellular organization of high mitochondrial and lipid content and extremely high metabolic flux, yet relatively scarce endoplasmic reticulum (ER) mass.

In this study, we showed that BAT thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identified the ERlocalized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process.

Cold adaptation induces Nrf1 in BAT to increase proteasomal activity, which is crucial for maintaining ER homeostasis and cellular integrity, specifically when cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown adipocyte-specific deletion of Nrf1 resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function, and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenous expression Nrf1 or by treatment with a proteasome activator resulted in improved insulin sensitivity.

In conclusion, we found that Nrf1 is a novel protective system of brown adipocyte function, providing increased proteometabolic quality control for adaptation to cold and obesity. These findings, along with our discovery of key metabolic functions of Nrf1 in protecting tissues against cholesterol-associated stress and damage, as well as our ongoing work in other conditions of extreme metabolic stress, suggest that Nrf1 is a critical guardian of metabolic health, presenting exciting opportunities to treat metabolic diseases in humans. We are currently pursuing these possibilities and mechanisms underlying the action of this molecule.

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PUBLICATION HIGHLIGHTS

Defective STIM-Mediated Store Operated Ca2+ Entry in Hepatocytes Leads to Metabolic Dysfunction in Obesity Ana Paula Arruda, Benedicte Mengel Pers, Güneş Parlakgül, Ekin Güney, Ted Goh, Erika Cagampan, Grace Yankun Lee, Renata L. S. Gonçalves, Gökhan S. Hotamışlıgil eLife, January 2018

Obesity is a chronic metabolic disorder. An individual’s genetic makeup may render them more vulnerable to the condition, which is further driven by overeating and sedentarism. The resulting surplus of nutrients affects the cells and organs of the body in several adverse ways. For example, excessive nutrients impair a compartment within cells called endoplasmic reticulum (ER). This compartment is where many proteins and fats are made and transported. It is also the site of many metabolic processes, and the primary storage location of calcium ions.

Many proteins need calcium ions to work properly and be secreted, including metabolic enzymes. In obesity and other metabolic diseases, the ER has reduced ability to store calcium, resulting in loss of folding capacity of proteins, ER stress, inflammation, impaired insulin action and abnormal glucose metabolism. In these conditions, in which the ER leaks calcium, there are also important implications for the function of other cellular organelles, triggering, for instance, mitochondrial dysfunction. When ER calcium is artificially increased by synthetic chemicals, ER function is restored, improving metabolic health in obese mice and humans.

Under normal circumstances, calcium levels in the ER are sensed and regulated by proteins called SERCA, IP3Rs and the STIM-Orai complex. STIM1 senses and regulates the levels of calcium in the ER. When calcium levels drop, STIM1 moves along the ER membrane closer to the cell surface and joins up with a calcium channel called Orai1. The STIM1-Orai1 complex allows calcium ions to enter the cell and replenish their levels in the ER, in a process known as store operated calcium entry.

In this study, our laboratory explored whether STIM1 expression pattern is altered in obesity and, if so, whether it contributes to the inability of the ER to maintain proper 14

calcium levels. High-resolution microscopy and biochemical techniques confirmed that STIM1 biological function is indeed compromised in liver cells from obese mice. In these cells, STIM1 was found in unusual small clusters, and was not able to move along the ER membrane when calcium levels dropped below a critical threshold. As a result of these navigational errors, STIM1 failed to couple with Orai1 at the cell surface, meaning less calcium was able to enter the cell. On the other hand, increasing the levels of expression of STIM1 in liver cells in obese mice significantly improved glucose intolerance. Further mechanistic work identified that a small sugar molecule, that is added onto STIM1 in obesity, reduces its ability to move accurately. In fact, when the expression of this sugar molecule was artificially decreased in liver cells from obese mice, STIM1 biological function could be partially rescued. Mice without STIM1 in their liver showed signs of metabolic pathologies.

Interestingly, it has been reported that cells from patients with loss-of-function mutations in Stim1 or Orai1 accumulate lipid droplets as a consequence of metabolic anomalies, which was also observed in our experiments with STIM1-deficient liver cells.

Notably, when STIM1 levels were experimentally increased in obese mice, it restored calcium levels in the ER closer to normal, and improved metabolism, with enhanced insulin signaling, glucose tolerance, and decreased lipid content in hepatocytes.

These findings show that regulating ER calcium levels via proteins such as STIM1 is essential to maintain ER function, insulin action, and systemic glucose metabolism, providing an important mechanistic insight into metabolic regulation through organelle homeostasis. Therefore, interventions to correct calcium levels may represent therapeutic promises to combat metabolic diseases.

PUBLICATION HIGHLIGHTS

The Short-Chain Fatty Acid Propionate Increases Glucagon and FABP4 Production, Impairing Insulin Action in Mice and Humans Amir Tirosh, Ediz S. Calay, Gurol Tunçman, Kathryn C. Claiborn, Karen E. Inouye, Kosei Eguchi, Michael Alcala, Moran Rathaus, Kenneth S. Hollander, Idit Ron, Rinat Livne, Yoriko Heianza, Lu Qi, Iris Shai, Rajesh Garg, Gökhan S. Hotamışlıgil Science Translational Medicine, April 2019

Propionate is a naturally occurring short-chain fatty acid (SCFA) and a potent mold inhibitor commonly found in many food products, as well as in animal feeds. It is also produced endogenously in the body. Since 1912, our understanding has been that propionate administration triggers glucose production through gluconeogenesis, a metabolic process that produces glucose from non-carbohydrate precursors, and other unclear mechanisms in the liver. However, a recent study using labeled propionate showed that gluconeogenesis accounts for only 5% of the increased endogenous glucose production observed in rats infused with propionate. Interestingly, the notion that exposure to exogenous propionate triggers hyperglycemia and hyperinsulinemia has been supported by several other studies, raising the question of what mechanisms are elicited by this SCFA to increase blood glucose. In addition to this knowledge gap, previous studies have not found a consistent observation as to whether exposure to propionate correlates to improvement or deterioration of metabolic health.

In this study, we aimed to understand how exogenous propionate triggers hyperglycemia and how it affects metabolic regulation. We showed that propionate, either administered directly into blood or in the gut, leads to increased levels of blood glucose in male and female mice.

We also observed that this rapid hyperglycemic response after propionate administration was hormonally regulated by fatty-acid binding protein 4 (FABP4) and glucagon, triggering hepatic glycogen stores to be used, releasing glucose into the circulation. This regulation was absent when mice lacking expression of either glucagon receptor or FABP4 were treated with propionate. On the other hand, FABP4deficient mice treated with recombinant FABP4 were able to respond to propionate administration, increasing their blood

glucose levels. In addition, we found that propionate-induced hyperglycemia was dependent on norepinephrine release from adrenergic neurons, stimulating glucagon and FABP4 release.

From these findings, we asked what consequences chronic exposure to propionate would have on metabolic regulation, and we found that it was associated with increased weight gain, fat mass, blood glucose, and also circulating insulin, glucagon and FABP4 levels in normal lean mice. Our findings in animal models were also corroborated by results found in humans. In a randomized, placebo-controlled, double-blinded crossover study, we evaluated the effects of propionate in a mixed meal.

Participants who received a propionate-containing meal had increased norepinephrine, glucagon and FABP4 levels, as well as decreased post-meal insulin sensitivity. Additionally, in a dietary intervention randomized controlled trial, we found that plasma propionate concentrations directly correlated with insulin resistance in obese participants. However, reduction of propionate levels was associated with improvement in insulin resistance, regardless of dietary intervention or initial body weight. In conclusion, we showed that propionate-induced increase in glucagon and FABP4 drives enhanced glucose production, likely due to glycogenolysis, which leads to increased blood glucose and insulin levels. Larger interventional studies targeting a reduction in propionate exposure and assessing metabolic and anthropometric outcomes are necessary to fully translate our findings in mice to humans.

Additionally, repeated exposure to propionate in a chronic setting, as performed in our animal models, may have important implications for public health. Given the results, propionate exposure, endogenously or exogenously, should be considered as an important regulator for metabolic health.

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PUBLICATION HIGHLIGHTS

TACI-Deficient Macrophages Protect Mice Against Metaflammation and Obesity-Induced Dysregulation of Glucose Homeostasis

12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism

by Producing the Omega-3 Lipid 12-HEPE from Brown Fat

Lunhua Liu, Karen E. Inouye, Windy Rose Allman, Adam Steven Coleman, Shafiuddin Siddiqui, Gökhan S. Hotamışlıgil, Mustafa Akkoyunlu

Luiz Osório Leiria, Chih-Hao Wang, Matthew D. Lynes, Kunyan Yang, Farnaz Shamsi, Mari Sato, Satoru Sugimoto, Emily Y. Chen, et. al., Yu-Hua Tseng

Diabetes, August 2018

Cell Metabolism, October 2019

This research publication was the result of an inter-laboratory collaboration involving our Center and the US Food and Drug Administration laboratory, directed by Mustafa Akkoyunlu, MD, PhD. In obesity, metabolically driven chronic inflammation or metaflammation within adipose tissue and other metabolic tissues is a crucial step in the development of insulin resistance and diabetes. How immune cells arrive at and regulate inflammation and the function of adipose tissue is not fully understood. Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is one of the three receptors for the TNF superfamily cytokines, which are critical mediators of inflammation. This study, using genetic models, demonstrated that mice were mostly protected from weight gain, impaired glucose tolerance, and insulin sensitivity when TACI expression was absent. This beneficial phenotype was predominantly related to alterations in macrophage responses, which favored reduced inflammatory capacity and enhanced repair function. These findings highlight the crucial role for TACI-mediated polarization of adipose tissue macrophages and subsequent metaflammation found in metabolic complications associated with obesity, presenting TACI as a novel therapeutic target against obesity-associated diseases, such as type 2 diabetes.

This research publication was the product of a multi-laboratory collaboration involving our Center and directed by Dr. Yu-Hua Tseng, Senior Investigator in the Section on Integrative Physiology and Metabolism at the Joslin Diabetes Center, Harvard Medical School, in addition to numerous other institutions. Brown adipose tissue (BAT) maintains body temperature in cold conditions by using blood glucose and fatty acids. Understanding how BAT clears nutrients, including blood glucose, is key to understand the function of this tissue and perhaps develop new therapeutic approaches to combat diabetes. This study showed that cold stress activates the enzyme 12-lipoxygenase (12-LOX) in BAT, which produces lipids that help to maintain body temperature, and characterized the lipids species that may be responsible for this action. Deletion of 12-LOX from mouse BAT inhibits the production of 12-HEPE, a 12-LOX-derived lipid that can shuttle glucose into tissues and improve glucose tolerance in obese mice. Thus, this study contributed to the knowledge about lipokines with metabolic activity and identified a novel lipid mediator.

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PUBLICATION HIGHLIGHTS

Adipokine FABP4 Integrates Energy Stores and Counterregulatory Metabolic Responses

TMEM2 Modulates ER Stress in a Non-Canonical Manner

Kacey J. Prentice, Jani Saksi, Gökhan S. Hotamışlıgil

Renata L. S. Gonçalves, Gökhan S. Hotamışlıgil

Journal of Lipid Research, January 2019

Cell Metabolism, December 2019

With the Industrial Revolution came important lifestyle changes, such as excessive food intake and diminished physical activity, contributing to an epidemic of obesity and metabolic diseases.

In this context, previous adaptive mechanisms that were used to overcome temporary exposures to nutrient excess became chronically engaged in order to circumvent prolonged exposure to nutrient surplus and alterations in metabolism. We explored the role of fatty-acid binding protein 4 (FABP4) as a key factor that is crucial for homeostasis and endurance, but maladapted in obesity or chronic stress. FABP4 is one of the most abundant proteins in adipocytes, and its role includes maintenance of adipocyte homeostasis, regulating lipolysis and adipogenesis.

FABP4 also has distinct functions in numerous cell types, including macrophages, endothelial cells, and the bronchial epithelium. Recently, studies in the Sabri Ülker Center identified FABP4 as a novel hormone produced during the breakdown of lipid stores and acts in liver and pancreas. Here, we also discussed the actions of hormonal FABP4, what is currently known about its biological activity in target cells, as well as mechanisms of secretion of this protein and factors that can influence this cellular process.

The activation of endoplasmic reticulum (ER) stress requires stress response pathways to be engaged flexibly, considering the cell type, the nature of the challenge, and the severity and persistence of the assault. The adaptive responses of the ER are generally considered to be carried out through activation of a pathway called the unfolded protein response (UPR). In this publication, we comment on recent work by Schinzel et al. (Cell, November 2019) that identified the cell surface hyaluronidase, Transmembrane Protein 2 (TMEM2), as a modulator of ER-stress resistance independent of the UPR. This study showed that TMEM2, when breaking down hyaluronan (HA) within the extracellular matrix, alters ER stress resistance independent of the canonical unfolded protein response pathways, but dependent on CD44, ERK, and p38. Since loss of ER function and proteostasis is one of the hallmarks of aging, TMEM2 was expressed in C. elegans, leading to increased longevity and pathogen resistance independent of canonical UPR, but dependent on the ERK and p38 orthologs. The key insight from this work was that other systems, in addition to UPR, may be necessary to mitigate ER stress depending on circumstances, elucidating mechanistic components of complex processes and diseases, such as aging, cancer, inflammation, and metabolic diseases.

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Colorful cell plasmid COS-7 cells in green, endoplasmic reticulum in red, and peroxisomes in purple.

THE IM 18

IMPACT OF THE CENTER

MPACT When we understand, at a mechanistic level, the basic biology of disease—how things work, how things are integrated, and how biological systems change by exposures—it will absolutely, positively transform what we know as public health.

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Work at the Center is focused on advancing basic research to address the cellular and molecular mechanisms that underlie metabolic diseases which pose the greatest threats to global human health. As scientists at the Center, one of our activities is to inform the general public to raise awareness about the importance of science and developments that may impact the community.

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COS-7 cells mitochondria in red and endoplasmic reticulum in green.

IMPACT OF THE CENTER

Eating to Excess: Metabolic Inflammation Adapted from an interview with Harvard Magazine, 2019

Similarities among diseases of metabolism and inflammation suggest that they are indeed rooted far back in developmental history. Gökhan S. Hotamışlıgil, Simmons Professor of Genetics and Metabolism at the Harvard T.H. Chan School of Public Health, has constructed his research for the past 25 years on the premise that this shared history suggests shared biological mechanisms as well. The ailments that cluster most dramatically, he points out, are “chronic metabolic diseases” such as diabetes, cardiovascular disease, stroke, Alzheimer’s, nerve degeneration, and cancer. In general, a person who has any one of these illnesses is more likely to develop the others. “This is exactly the same cluster that emerges during aging,” he says. “All of the age-related pathologies emerge in clusters of non-communicable diseases, except the latter occurs in a much shorter period of time, and earlier in the lifespan.

“That tells us that these illnesses are part of our natural history, our biological heritage,” continues Hotamışlıgil, who directs the Sabri Ülker Center. “If these two clusters emerge in two separate conditions in exactly the same way, then they must come from deeply embedded biological and developmental vulnerabilities.

One area Hotamışlıgil has focused in the past 25 years is a form of chronic inflammation, which he refers to as metaflammation, as a mechanism of metabolic disease. Hotamışlıgil says, unequivocally, “Chronic inflammation is uniformly damaging and is absolutely causal to the process, because if you interfere with it, you can reverse the pathology.” And this ability to control such diseases simply by reversing inflammation is a biological response, dating far back to the time of a common ancestor, that has been retained across diverse species of animals to the present day, he says, pointing to experimental evidence: “If you make Drosophila [fruit fly] diabetic, and then block the inflammatory response systems, you can cure diabetes in Drosophila, the same way you can reverse it in the mouse, in primates, and in humans, provided that you do it with the right tools. Of course, the higher the organism, the more complex these pathways are, so it takes more effort to define the precise mechanisms to manipulate to achieve similar impact.”

Seeking the origins of inflammation, Hotamışlıgil asks, “What is the most primordial process in the emergence of life? Metabolism.

Energy management. And then, of course, the next critical process to emerge within cells is the ability to defend. And so that brings in the immune system, which is younger than metabolism, but much older than many other systems.” In some of the simplest organisms, he points out, energy management and immune functions are packaged in the same organ, such as the fruit fly’s fat body. But even as these functions became specialized and divided among three or four organs in more complex organisms, they retained their evolutionary memory. “They share many tricks,” he says, because the “immune response is enormously expensive, energy-wise.”

The intimate relationship between the metabolic and immune systems, he believes, has been maintained because it takes “tremendous energy to mount an effective immune response.

While this link is essential to maintain health and homeostasis, abnormalities that develop over time, as in the case of obesity, carry a great risk of damage.”

The metabolic stress that is a hallmark of modern life, the stress that the body has not evolved to handle, is constant eating, he continues. When people eat, energy and nutrients enter the body rapidly, are processed, produce in turn a lot of by-products, and then

ADIPOCYTE Rough Endoplasmic Reticulum

Golgi Apparatus

Nucleus

Cytoplasm Fat Reservoir

Mitochondrion

Membrane

A fat cell, or adipocyte, is more than 90 percent triglyceride.

If the thin cell wall enclosing this droplet of fat ruptures, an inflammatory response ensues.

need to be reduced to “functional substances that are distributed throughout the body, and then disappear very quickly. Many cells and tissues actually undergo a huge amount of stress during this process,” he explains, “as they store appropriate nutrients and dispose of harmful intermediates.” Part of this process also involves mounting an immune response. “The pancreas, for example, must secrete four to five hundred milliliters of enzymes every day” to be able to manage the incoming energy load with every meal. “If you place these organs under constant stress, they start malfunctioning.”

The consequence is that “right now, one out of every 10 individuals has diabetes. One out of every four individuals has fatty liver disease.

And if you reach a certain age, one out of every three individuals will develop neurodegenerative disease.”

The metabolic stress that underlies these conditions comes from the daily imbalance between how much energy people consume and how much they need and can process in a healthy manner. The long-term consequence of overconsumption, combined with lack of sufficient expenditure, is stored energy—the accumulation of fat.

Excess body fat, especially in the wrong places, is an additional risk factor for inflammation and disease.

Clinical studies implicating stored fat as a source of inflammation have been buttressed by basic research that shows that adipose tissue—body fat—is laced with immune cells, which become more abundant with weight gain, perhaps because fat cells can secrete alarm signals that summon white blood cells. “A fat cell is almost like a primitive immune cell,” says Hotamışlıgil. “It can request the assistance of immune cells when in trouble, but if the stress continues, and the immune cells remain, they start changing their character and behavior from helpful to harmful.

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Hotamışlıgil Named to Highly Cited Research List by Web of Science, 2018 and 2019.

Cited Papers are in the Top .1%.

“Highly Cited Researchers” from Clarivate Analytics is an annual list recognizing influential researchers in the sciences and social sciences from around the world. Web of Science is the largest publisher-neutral citation index, powering global discovery and citation analytics across the sciences, social sciences, and art and humanities.

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IMPACT OF THE CENTER

ÜLKER CENTER LECTURES AND AWARDS

Gökhan S. Hotamışlıgil January 2019 Keynote Speaker, Keystone Symposium on Integrated Pathways of Disease in NASH and NAFLD, Sante Fe, NM “Metainflammation and Fatty Liver Disease” February 2019 Excellence in Immunology Lecture, Texas Southwestern Medical Center, Dallas, TX “Immunometabolic Integration in Health and Disease” Keynote Speaker, Future of Everything, New England Turkish Student Association, Boston, MA “Biology of Stress Management” April 2019 Keynote Speaker, IPPM, Adana, Turkey “ A Quarter Century in the Labyrinths of Immunometabolism” Scientific Organizer and Lecturer, Keystone Symposium Immunometabolism, Metaflammation, and Metabolic Disorders, Vancouver, Canada “ Immunometabolic Components of Age- and Obesity-Associated Pathologies” D. Harold Copp Award and Lecture, University of British Columbia, Vancouver, Canada “ Metabolic Biology of the Endoplasmic Reticulum in Health and Disease” May 2019 Opening Lecture, Summit of Science Ambassadors, Sabanci University, Istanbul, Turkey “ Leveraging Natural Defenses Against the Greatest Global Health Problems” August 2019 Keynote Speaker, 29th Annual BioCity Symposium, 30th Annual Symposium of Turku Centre for Biotechnology, Turku, Finland “ Foundations of Immunometabolism and Implications for Metabolic Health and Disease” September 2019 Distinguished Biomedical Scholars Lecture, University of Iowa Medical Center, Iowa City, IA “ The Metabolic Biology of the Endoplasmic Reticulum in Health and Disease” Morgridge Metabolism Lecture: Frontiers in Metabolism Meeting­—Mechanism of Metabolic Disease, Madison, WI “Immunometabolic Integration in Health and Disease”

October 2019 Keynote Lecture Endoplasmic Reticulum Meeting, Paris, France “ Architecture and Function of the Endoplasmic Reticulum in Metabolic Health and Disease” November 2019 Keynote Speaker, IBG Science Day, Izmir, Turkey “Architectural Regulation Is Central for Homeostasis” Mary Shorb Lecture in Nutrition, University of Maryland College of Agriculture, College Park, MD Lecture, “Endoplasmic Reticulum in Health and Disease”

Laboratory Members Lectures & Awards March 2019 Endocrine Society Annual Meeting, New Orleans, LA Dr. M. Furkan Burak presented a poster and short talk on obesity-related asthma and received the Endocrine Society Outstanding Abstract Award.

April 2019 Experimental Biology, Orlando, FL Dr. Min-Dian Li presented a project poster and short talk on the mechanisms of FABP 4 secretion and its impact on aging.

Keystone Symposium Immunometabolism, Metaflammation, and Metabolic Disorders, Vancouver, Canada Several members of the Sabri Ülker Center, Drs. Kacey Prentice, Karen Inouye, and Gürol Tunçman, presented posters on their ongoing work.

July 2019 Gordon Conference on Molecular Membrane Biology, Andover, NH Drs. Ana Paula Arruda and Güneş Parlakgül presented on ER structure and organization and received best poster award from conference organizers and the Traffic magazine.

September 2019 Islet Society Meeting, Maribor, Slovenia Dr. Kacey Prentice was invited to speak on the impact of FABP4 on pancreatic beta cells and on the progression of type 1 diabetes.

7th Helmholtz Diabetes Conference, Munich, Germany Dr. Kacey Prentice was invited to present a flash talk on the role of FABP4 in beta cell function and type 1 diabetes.

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Electron microscopic resolution of subcellular structures.

THE FU 24

NEXT GENERATION OF SCIENTISTS

UTURE The goal of the Center is to inspire a core group of brilliant scientific leaders to create a home for metabolic science and a culture of respect and collaboration that will endure. It is our dream that each scientist who trains at the Sabri Ăœlker Center will not only be transformed but will go on to transform others, creating generation after generation of world-class scholars, each striving to solve the world’s most pressing health problems.

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NEXT GENERATION OF SCIENTISTS

NURDAN DAĞTEKİN Visiting Doctoral Student, 2018–2019

Nurdan performed her thesis work at the Center, and will defend her doctoral thesis in 2020 at İstanbul University.

What were you doing before you joined the Ülker Center?

Q.

I graduated from Istanbul University Faculty of Pharmacy as valedictorian in 2014. During my undergraduate education, I was interested in both pharmacodynamics and pharmaceutical chemistry, and I decided to pursue a doctoral degree in pharmacology. I was awarded a scholarship by the Scientific and Technological Research Council of Turkey and primarily studied cardiovascular pharmacology.

Describe the project you were working on while you were here.

Q.

A t the Sabri Ülker Center, I was working on a hormone called FABP4, also known as AP2, that was discovered in the lab and has been shown by our group and others to be an important player in the pathogenesis of a wide array of diseases, such as obesity, diabetes, fatty liver disease, and atherosclerosis. I was working to understand how this hormone exerts its effect on the lung and its contribution to the development of asthma.

This will be the center of my thesis.

What drew you to want to be a part of the Ülker Center?

Q.

I wanted to work under the outstanding mentorship of Dr. Hotamışlıgil and with a group of people who are all experts in their research fields. I think what makes the Center unique is not only its tremendous success in the field, but also its supportive and collaborative environment that involves a wonderful and brilliant group of people who work together to do science.

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What do you hope will emerge from your project? What will we learn?

How will it help advance medicine, public health, or something else for the benefit of populations?

Q.

Obesity is the leading risk factor for asthma and this form of airway disease is different than other forms of asthma and does not respond to current therapeutics. Understanding the underlying mechanisms of a disease may lead us to figure out the source of the pathology in order to generate effective agents to improve human health and the quality of a patient’s life. I imagine this process as a long path that leads us to finding a cure and I hope my work will be part of an important step toward achieving this purpose.

What was most challenging about your work?

Q.

I think science is a challenge in itself with its never-ending questions. Every answer creates another question and it becomes an endless cycle that makes you feel both challenged and enthusiastic about your work. In the Hotamışlıgil Lab, all the resources that are available, and the scientists with whom you have a chance to work, make you feel free to ask any questions and really go for it! And it makes you feel more engaged in the work because this enthusiasm never fades away in such a supportive environment.

What do you find to be exciting about your work?

Q.

The human body is a puzzle that we have tried to solve for centuries. Finding just a small piece that fits and getting closer to understanding its complexity is exciting and fascinating.

I hope my work will be an important piece that will allow us to see the picture a little more clearly, give more insight into asthma pathogenesis, and allow us to help more people affected by this disease.

NEXT GENERATION OF SCIENTISTS

KOSEI EGUCHI, MD, PhD Postdoctoral Fellow, 2013–2017

Currently, Associate Medical Director, Novo Nordisk

What were you doing before you joined the Ülker Center?

Q.

I was working as a physician scientist at Tokyo University, Japan. I divided my time between doing research in disease biology in the field of metabolic diseases and atherosclerosis and practicing as a cardiologist at the University Hospital.

Describe the project you were working on while you were here.

Q.

I worked

on several projects, all of which were aimed at identifying the mechanisms of diseases that are related to metabolic syndromes. At the time I joined the Center, the lab had just discovered a novel hormone called FABP4, secreted from adipocytes, and the levels increase in obesity, contributing to the development of diabetes. One of the projects I worked on was to clarify the mechanisms that lead to dysregulation of this adipokine in obesity and how it may contribute to the development of cardiovascular diseases.

What do you hope will emerge from your project? What will we learn?

Q.

From the epidemiological studies, we know that the risk of death by cardiovascular diseases increases drastically with the increase of body mass index and presence of insulin resistance and diabetes. However, there is very little known about the mechanisms that connect these diseases. The project I focused on at the Sabri Ülker Center was designed to describe one of the important mechanisms that directly link obesity and cardiovascular diseases.

How will it help advance medicine, public health, or something else for the benefit of populations?

Q.

Since

pharmaceutical companies are rapidly incorporating cutting-edge biotechnology into medicine, our findings will be utilized directly in the prevention of cardiovascular diseases in obesity. In fact, the experiments that prove the benefits of a potential drug targeting the FABP4 molecule are already being performed in nature. There is rare mutation in humans which reduces the activity of this protein, and those that carry this mutation have dramatic reductions in their risk of cardiovascular disease.

What do you find to be exciting about your work?

Q.

I found my work very exciting for a variety of reasons. The first was that my project began from the finding of a lab member who seemed to be working on a non-related project. Because of this, it was a unique opportunity to collaborate. Second, the mechanisms of action of the molecule we are interested in are completely unexpected, at least from my perspective.

Finally, it was clear that the molecule that I was working on plays an indispensable role in the inter-organ communication both in the physiological settings and in the development of metabolic diseases.

What is your favorite memory of being in our lab?

Q.

Sabri Ülker Center is an incredibly stimulating and supportive environment. It differs from anyplace that I have worked before. Because the lab is composed of so many different people from all around the world, it was always interesting to interact with different cultures, go out for a meal, celebrate a birthday together, or attend a party at a lab member’s home.

Another great memory was the opportunity to travel with the lab to Istanbul to attend the Sabri Ülker Center Symposium on Metabolism and Life in 2016. During that trip I had the chance to visit Ephesus, which was a special trip for me.

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NEXT GENERATION OF SCIENTISTS

JANI SAKSI, PhD Postdoctoral Fellow

Where are you from?

Q.

I was born and raised in Tornio, a small city in Northern Finland only 150 km from the Arctic Circle. I completed my bachelor’s and master’s degrees in genetics and biochemistry at the University of Helsinki and earned my PhD in neurology from the same university.

What got you interested in science?

Q.

Scientific curiosity, simply. I arrived at the Sabri Ülker Center by coincidence. I published a paper from my PhD that sparked the interest of professor Hotamışlıgil who contacted me to discuss the findings I presented. The integrity and vigor with which he and his team pursue the big unanswered questions of obesity-related metabolic dysfunction combined with the truly unique environment in the Sabri Ülker Center really caught my attention. For me that is what science is all about: coming together to discuss and wonder, to collaborate, and solve problems.

What were you doing before you joined the Center?

Q.

During my PhD, the questions I was interested in centered around atherosclerosis and how in some people these arterial lesions, that are commonplace in the aging population, can lead to myocardial infarctions and strokes while others would avoid these complications despite equal severity of the disease. While screening for gene expression differences between symptom-causing and quiescent lesions we discovered that the overexpression of fatty acidbinding protein 4 (FABP4) had a major role in promoting these symptoms, while individuals carrying a mutation that reduced the expression of FABP4 were often protected from these end points.

Tell us about your research?

Q.

Currently,

I am pursuing a very exciting project that is following up on a previous discovery of the lab showing that FABP4 is a unique fat-derived hormone secreted into the

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circulation. This groundbreaking discovery has changed our perspective of how this protein functions and communicates changes in the body’s energy balance to distant organs, and how it is dysregulated during obesity. If we can understand how this communication works, we can tackle specific elements of it in order to ameliorate obesity-related metabolic diseases with precision that is otherwise difficult to obtain.

What do you hope will emerge from your project?

Q.

I am hopeful and excited about the work we are doing with FABP4, and believe it will yield answers to basic biology questions and will extend beyond this single protein to reveal novel translational avenues that could be used to prevent or even treat obesity-related metabolic complications in the future.

Why should the average person be interested in your area of scientific discovery?

Q.

Obesity is one of the most pressing health concerns of our day. The research that we are doing here at the Sabri Ülker Center has the potential to provide future solutions for people afflicted by metabolic dysfunction like type 2 diabetes.

What excites you about your work?

Q.

The most exciting aspect of my current work is related to the discovery of new obesity-related hormones that may change the way we think about and approach immunometabolic disorders.

Tell us what you like to do when you aren’t working on research.

Q.

Art is something I value very much and I enjoy cooking from scratch. I spent a lot of time around my family’s restaurants growing up, so food and presentation are important to me, as are nature and travelling.

NEXT GENERATION OF SCIENTISTS

MARTIN P. McGRATH, PhD Associate Director of Strategic Alliances, 2012–2019

Currently, Director, Alliance Research Discerna Pharmaceuticals, Inc.

Tell us about your growing up and discovering a passion for science.

Q.

I was born and raised in City Island, New York, which is a small island off the coast of the northeast Bronx. For as long as I can remember, I’ve always enjoyed learning how things work and using that knowledge to solve problems or create something new. With the support of my high school teachers, I discovered my real passion was for chemistry. After obtaining my PhD in organometallic chemistry, I started my career in the Chemical Sciences Division at Monsanto Corporate Research back when Monsanto was a diversified chemical company. Working in Corporate Research provided me the opportunity to work with many different parts of the company and obtain experience in a wide range of chemical programs. As a large part of the company’s business focus changed to pharmaceuticals, I began to focus my efforts on medicinal chemistry and drug delivery. I believe that sometimes it is the intersection of different disciplines that can provide a unique solution to scientific problems.

What path did you follow that brought you to the Ülker Center?

Q.

At Pfizer, half of my responsibilities were related to managing external collaborations with academic and biotech groups.

When Pfizer shut down the Cambridge site, I became aware of the opportunity to join the Hotamışlıgil lab to manage academic/industrial collaborations working directly with the research group from the academic side. The overarching goal of these collaborations was to bring novel diabetes and metabolic disease medicines into the clinic for testing. This was an excellent opportunity to use my experience to help the Hotamışlıgil lab succeed in this endeavor.

Tell us about Strategic Alliances.

What is most challenging about this kind of work­—what is most satisfying?

Q.

Strategic Alliances are the formal collaboration between two groups, typically academic and industrial, with the set purpose of achieving goals that neither group could achieve on their own. For example, an academic group may have a novel discovery that they would like to see commercialized, but they don’t have the resources or infrastructure to bring a product to market. An industrial group may have the infrastructure to commercialize a new product concept but not the expertise or resources to explore a new scientific area. By joining forces, the academic and industrial groups can leverage the strengths of their partner to explore new opportunities and advance new products.

What excites you about your work?

Q.

Seeing

both sides of the strategic alliance, academia and industry, achieving their individual goals and, as a result, succeeding in the strategic alliance gives me a great feeling of accomplishment. I truly enjoyed being able to use my knowledge and experience to help bridge the gap in the strategic alliance and foster the intersection of disciplines to generate new ideas and hopefully new medicines to test in the clinic and improve people’s lives.

What do you like to do when you aren’t working on research?

Q.

Outside of work, I enjoy woodworking and music. I make wood turnings and create pens out of exotic hardwoods as gifts. For the last 9 years, I have played guitar in an 8-piece jazz band that played at a number of venues in northeast Massachusetts including our Department’s Holiday Gathering at Harvard.

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INAUGURAL SABRİ ÜLKER FELLOWS

GÜNEŞ PARLAKGÜL ON ORGANELLE STRUCTURE

Organisms have a variety of mechanisms that allow them to adapt to their environment and cope with stress. However, sustained exposure to stress can result in failure of these adaptation mechanisms and lead to disease. The endoplasmic reticulum (ER) is a continuous membrane system within the cell, which plays a role in many physiological processes such as protein synthesis and folding, lipid synthesis and secretion, and calcium handling. The ER has a very complex structure and acts as a master organelle through its contact sites with other organelles. Previous work in the Hotamışlıgil lab and others has shown that within liver cells, changes to the structure and function of the ER are key events in adaptation to metabolic stress. During my fellowship, I have been studying how the ER in liver cells adapts to different nutritional and hormonal states, such as fasting and feeding, by reorganizing its structure. I am using various imaging techniques such as electron microscopy and confocal fluorescence microscopy to view ER in these different states. The recent establishment of the Sabri Ülker Center Imaging Lab has given us tremendous power to visualize these processes in a high throughput manner. Additionally, we collaborate with the world’s best laboratories to obtain the highest resolution images of liver tissue. We have also defined molecular strategies to restructure ER synthetically in the organs of mice and study the impact of these interventions.

The Sabri Ülker fellowship has provided me the opportunity to pursue my curiosity and to work on these scientific questions freely. My aim for the future is to understand the role of this organelle’s structural adaptation in the context of metabolism and metabolic disease, such as obesity and diabetes. My long-term goal is to become an independent researcher and investigate the organelle homeostasis in metabolic disease.

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3-D rendering of FibSEM data acquired from mouse liver tissue.

One of the greatest powers of science is its ability to unite people, where representatives from every nation, culture, ethnicity, religion, and lifestyle can work together for a common purpose. This is most evident in the Sabri Ülker Center, where we come together to tackle challenging questions and dream to make a positive impact on human life.

INAUGURAL SABRİ ÜLKER FELLOWS

EKİN GÜNEY ON INFLAMMATION

While inflammation is an important repair and survival mechanism, its excess presence for long periods of time is harmful. A special form of this reaction called metaflammation occurs in obesity. In my fellowship, I explored what may be a molecular mechanism that gives rise to this pathological form of inflammation in adipose tissue during obesity. Collaborating with Drs. Güneş Parlakgül and Ana Paula Arruda, we explored the role of calcium fluxes in the endoplasmic reticulum and the cause of its dysfunction and metabolic disease. Through this work, I discovered a connection between ER dysfunction and fundamental inflammatory responses. In the adipose tissue we showed that this mechanism is important for metaflammation and abnormal insulin action. I would like to combine clinical and basic science and was accepted to the University of California San Francisco’s clinician scientist program in pathology. At the Sabri Ülker Center, I learned how to be a well-rounded scientist and, most importantly, how essential it is to be excited about science and to share that enthusiasm. I bring that same excitement to my clinical life now. The principles I learned and skills I gained at the Sabri Ülker Center have helped me to connect with other scientists, be brave enough to ask challenging, novel questions about the pathogenesis of diseases, and pursue answers. I am now following my dream to become a neuropathologist. With the training I received working in the Center I am excited to work toward discoveries of better detection techniques and treatment of neurodegenerative diseases. The primary goal of scientists is to untangle biological mysteries and apply this information to advance public health. Truly novel scientific ideas can be difficult to pursue. The environment of the Sabri Ülker Center has been transformative for all of us.

Differentiated adipocytes with fibroblasts in background.

Science is the one common network of knowledge that all of us share. It has to be pursued in an honest and open-minded way. The primary goals of scientists are to understand biology, untangle the mysteries of the universe, and apply this information to advance the standards of every living being.

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ALUMNI FACULTY AND MEDICAL FELLOWSHIPS

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Alex Bartelt, PhD

Scott B. Widenmaier, PhD

MinDian Li, PhD

Assistant Professor of Cardiovascular Metabolism, Ludwig-Maxilians Universität München, Munich, Germany

Assistant Professor, Department of Anatomy, Physiology & Pharmacology, University of Saskatchewan, Saskatoon, Canada

Assistant Professor/ Principal Investigator, Chongqing Southwest Hospital, China

Amir Tirosh, MD, PhD

Feyza Engin, PhD

Kosei Eguchi, PhD

Director, Center for Diabetes Research and Endocrinology, Tel Hashomer, Israel; Assistant Professor, Harvard Medical School and Brigham and Women’s Hospital, Boston

Assistant Professor, Department of Biomolecular Chemistry and Medicine, University of Wisconsin

Associate Medical Director, Novo Nordisk, Tokyo, Japan

Takahisa Nakamura, PhD

Ling Yang, PhD

Suneng Fu, PhD

Assistant Professor, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Associate Professor, Tohoku University

Assistant Professor, Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa

Assistant Professor, Tsinghua-Peking Center for Life Science, Center for Synthetic and Systems Biology, Tsinghua University, China

Ebru Erbay, MD, PhD

Ekin Güney

Erika Cagampan

Associate Professor Cedars-Sinai Medical Center, University of California Los Angeles & Bilkent University

Pathology Residency and Physician-Scientist Program, University of California San Francisco

Medical School, University of California San Francisco

COS-7 cells in endoplasmic reticulum in green and mitochondria in red.

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“ Progress on the most pressing problems of human health require cross-disciplinary work. The generous investment by the Ülker family serves as a catalyst and has sped up scientific progress on metabolic conditions in unprecedented ways. The fruits of this investment allow the entire global public health community to more effectively tackle the metabolic disorders that are at the heart of some of the biggest health problems facing the world.”

ASHISH JHA, MD, MPH Director, Harvard Global Health Institute Dean for Global Strategy and K.T. Li Professor of Global Health, Harvard T.H. Chan School of Public Health Professor of Medicine, Harvard Medical School

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MESSAGE FROM THE DEAN FOR GLOBAL STRATEGY

The rise of metabolic diseases is threatening to erode the major progress made in global public health.

As director of the Harvard Global Health Institute, I see the impact of this troubling trend as nations rich and poor struggle to care for billions of patients, for example over 650 million with obesity and 425 million with diabetes worldwide.

The International Diabetes Federation (IDF) estimates that “1.1 million children and adolescents ages 14–19 years have type 1 diabetes mellitus. Without interventions to halt the increase in diabetes, there will be at least 629 million people living with diabetes by 2045. High-blood glucose causes almost 4 million deaths each year, and the IDF estimates that the annual global health care spending on diabetes among adults was US$ 850 billion in 2017.”

The effects of diabetes extend beyond the individual to affect their families and whole societies. It has broad socioeconomic consequences and threatens national productivity and economies, especially in low- and middleincome countries where diabetes is often accompanied by other diseases.

Through its rigorous study of the cellular and molecular mechanisms that underlie these diseases, the Sabri Ülker Center has, in its short five years, become known across Harvard and the broader scientific community as a key driver of breakthroughs and paradigm-changing discoveries. A visionary and extraordinary leader, Gökhan Hotamışlıgil has not just pioneered a new field but is putting a new class of therapeutic interventions within reach.

Sincerely,

ASHISH JHA, MD, MPH 35

LOOKING FORWARD

Diabetes and its complications represent one of the most serious challenges to public health in the 21st century. With its concomitant life-threatening complications of cardiovascular disease, renal failure, blindness, and peripheral vascular disease, type-2 diabetes can undermine underprivileged groups and emerging nations. Obesity and its complications are also major threats to human health. Currently, there are no safe and effective long-term treatments to curb the global obesity epidemic.

Our researchers are motivated by the significance of combating these challenges and, undeterred, they continue to focus on the ultimate goal of making discoveries that will expand scientific knowledge in the collaborative environment that is the Sabri Ülker Center. These past four years have been remarkable for the impact of their achievements and we celebrate their scientific and intellectual growth. In 2015, we discovered that the fatty-acid binding protein 4 (FABP4), which is naturally expressed by human fat cells, is in fact a novel hormone that greatly influences the development of diabetes, fatty liver disease and cardiovascular pathologies.

When FABP4 function is blocked, genetically or pharmacologically in mice, the animals are protected against insulin resistance and diabetes even when severely obese due to dietary or genetic interventions and remain so for as long as they live. Since then, using the resources provided by the Sabri Ülker Center and leveraging our collaborations throughout the world, we developed antibodies that target FABP4, which is pathologically elevated in humans with obesity, diabetes and cardiovascular disease, partly blocking its function in the blood.

The next step will be to investigate whether the same strategy can be applied as a therapy for diabetes and other metabolic diseases in humans. Prospects of therapeutic interventions 36

are stirring while new questions have arisen regarding communication between organs and organelle dysfunction.

As we enter the sixth year of our first decade of discovery at the Sabri Ülker Center, we look forward to welcoming you to Istanbul in June to the third annual Sabri Ülker Symposium; “Metabolism and Life.” This Symposium brings together a spectacular array of global experts exploring various aspects of metabolism and implications for health and disease states during the aging process.

The Sabri Ülker Symposium will be an unparalleled opportunity for attendees to engage with and learn from the globally recognized leading scholars in the field of metabolism from around the world. Sessions will feature presentations from renowned experts describing their innovative work to unravel the molecular details of metabolic pathways and translate these findings into real-world approaches to treat or prevent metabolic disease. The symposium will also be a great platform for young and emerging scientists to interact with established experts and for local and international scholars to build new networks. We are confident that this event will lead to new perspectives, stimulate new collaborations, and inspire future scholarly efforts.

“In science, every important breakthrough lifts the entire field as researchers are able to build on the new foundation of knowledge. This is the kind of work we’re now able to focus on because of the generosity of the Ülker family and community, and this is why I am more optimistic than ever that real progress against metabolic diseases is within our reach.”

Gökhan S. Hotamışlıgil, MD, PhD

Colorful cell plasmids. Mitochondria in green, endoplasmic reticulum in red, and cell membrane in blue.

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Harvard T.H. Chan School of Public Health 665 Huntington Avenue Building 1 Room 605 Boston, Massachusetts 02115

Visit us: www.gsh.sph.harvard.edu Follow us: @sabriulkerctr