Ulker Center Report

Nutrient, Genetic, and Metabolic Research

for

The Decade of Discovery 2015 Annual Report

1 Visionary 2 Letter from Gökhan Hotamışlıgil, MD, PhD 6 Publication Highlights 16 Q&A with Renata Goncalves, PhD 18 Q&A with Mustafa Yilmaz, PhD Candidate 20 Q&A with Benedicte Mengel Pers, PhD 22 Inaugural Sabri Ülker Fellows 27 Department of Genetics and Complex Diseases 30 Harvard T.H. Chan School of Public Health 32 Looking Forward 2

VISIONARY

The Sabri Ăœlker Center for Nutrient, Genetic, and Metabolic Research, made possible by a generous gift from the Ăœlker family, embodies the ideal of free, innovative, and continuous scientific research dedicated to eradicating the most intractable and pervasive threats to human health in the 21st century by leveraging its scientific platforms to advance nutrition and metabolism research. Our team is committed to seeking novel solutions and creating the pathways toward significant improvement in the conditions that impact all of humanity.

Our investment in the intellectual and technological advances and education in the Life Sciences will aim to promote the translation of our work into insights that will not only illuminate the mechanisms driving chronic metabolic and degenerative disorders, cancer, and longevity but also offer solutions that are applicable to large sections of society.

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LETTER FROM GÖKHAN HOTAMIŞLIGIL, MD, PhD

“ Through an interdisciplinary and collaborative framework, the Sabri Ülker Center’s aim is to integrate the revolutionary advances in Life Sciences with nutritional and metabolic research programs of global health reach.”

Gökhan Hotamışlıgil, MD, PhD Director of the Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research, Chair, Department of Genetics and Complex Diseases and James S. Simmons Professor of Genetics and Metabolism at the Harvard T.H. Chan School of Public Health

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DEAR FRIENDS,

I am delighted and honored to share with you this update on our work at the Sabri Ülker Center.

As we are faced with a global epidemic of obesity and associated chronic metabolic diseases, I believe that it is critical to focus on basic biological research that has the potential to lead to new insights and therapeutic strategies. Our goal is to be a leader at this exciting frontier where we hope to make substantial contributions to the understanding of the underlying mechanisms that connect molecular nutrients, metabolism, and disease. I am extremely grateful for the generosity of the Ülker family in supporting our dream. In the past year we are proud to have established the Sabri Ülker Center, appointed our first fellows, and produced many outstanding publications, advancing our knowledge of the connections between inflammation, cellular stress responses, and metabolic disease, gaining insight into the structural and biological changes in cells that disrupt function as a consequence of obesity. Our scientists also created new tools to aid in the search for novel therapeutics that will lead to sustainable and effective solutions against chronic metabolic diseases.

The Sabri Ülker Center is also deeply committed to providing training and learning opportunities for young scientists, and we are extremely pleased to have welcomed two young Turkish physicians to the laboratory as our inaugural Ülker fellows. In this first year of their fellowships they have already made great strides in their work towards understanding the role of cellular organelles such as the endoplasmic reticulum in metabolic disease. It is an honor to help guide their research and shape their careers, and I look forward to sharing in their discoveries. In addition, we recruited several postdoctoral fellows to embark on new avenues of metabolic research, and international interns to support their educational activities in the field of metabolism.

I hope that you enjoy reading about our initial efforts in this first year of the Sabri Ülker Center and the accomplishments of its members. The Center has already created tremendous excitement towards our ultimate dream of making meaningful contributions in the effort to eradicate human disease and suffering.

The challenges we confront are great, and the path is long and treacherous, but our enthusiasm for developing novel and far-reaching solutions to improve public health is unparalleled.

Sincerely,

Gökhan Hotamışlıgil, MD, PhD 3

Andrea Caricilli, PhD 4

UNLOCKING THE MECHANISMS driving metabolic disease is our steadfast goal. Only through sustained, vigorous, and exceptional effort will we blaze the trail of discovery.

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PUBLICATION HIGHLIGHTS

Within the Life Sciences it often takes years of hard work by a large team to generate the data to make advances and put together a body of work necessary for innovative, high-impact publications.

This year, members of the Sabri Ülker Center published several examples of our high-impact research.

A few examples are listed here and described in the following pages. I was extremely pleased by the positive response to our study published in Nature Medicine and featured on its cover entitled, “Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity.”

This project was led by a brilliant postdoctoral fellow, Dr. Ana Paula Arruda, who found that exposure to excess nutrients in obesity causes a remarkable rearrangement of intracellular organelles. Dr. Arruda, Dr. Mengel, and their colleagues showed that increased proximity of the organelles contributes to obesityinduced organelle dysfunction, insulin resistance, and fatty liver, suggesting that interventions that disrupt these connections could be therapeutic for metabolic disease.

I’m proud to share with you that one of our star graduate students, Dr. Meric Erikci Ertunc, published the culmination of her dissertation work in the Journal of Lipid Research. Her paper, “Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity,” elucidates a key aspect of the ongoing groundbreaking work within the Sabri Ülker Center. We have spent two decades studying the role of the aP2 protein in type 2 diabetes and heart disease, but only very recently made the surprising discovery that it is exported from fat tissue and can act as a hormone to influence metabolism. Dr. Erikci Ertunc studied the detailed mechanism of how aP2 is transported out of fat cells, leading to a better understanding of how this process is regulated, and suggested approaches to treat diabetes by interfering with aP2 export.

One of our ongoing primary goals at the Sabri Ülker Center is to identify new therapeutic directions for metabolic disease therapy, as perhaps best exemplified by our recent paper in Science Translational Medicine: “Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity.” This manuscript described the development of a set of tools to enable the discovery of compounds that improve the function of the endoplasmic reticulum, which is regulated by nutrients and impaired in metabolic disease. Members of the Sabri Ülker Center used these tools to identify and characterize a new chemical and demonstrated that it can be used to treat obesity and diabetes in experimental models with striking success. We were very excited by the publication of this manuscript and I anticipate many future discoveries will be made possible by these new screening tools.

Dr. Takahisa Nakamura reported in two manuscripts published in Cell Reports and Proceedings of the National Academy of Sciences, the discovery of mechanisms that control the activity of a key immunometabolic signaling molecule called PKR. We are happy to report that Dr. Nakamura successfully obtained an independent faculty position recently at Cincinnati Children’s Hospital.

Our publication of “S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction,” in Science was an important achievement toward which we had been working for several years. This work demonstrated a surprising link between inflammation and endoplasmic reticulum stress, a connection that remained unexplained for many decades. Postdoctoral fellow Dr. Ling Yang found that in the liver, obesity-associated inflammatory signals impaired the endoplasmic reticulum stress response, contributing to the development of insulin resistance and diabetes. Dr. Yang recently transitioned from the Sabri Ülker Center to start her independent research career as a faculty member, and I am thrilled to have had the opportunity to mentor her and participate in her professional development.

Finally, our perspectives on two of our main areas of work were published in Cell Metabolism and Nature Reviews Immunology on lipids and lipid binding proteins and calcium metabolism in health and disease.

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IMPACTING GLOBAL HEALTH through life sciences in the 21st century and beyond.

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PUBLICATION HIGHLIGHTS

Chronic Enrichment of Hepatic Endoplasmic Reticulum-Mitochondria Contact Leads to Mitochondrial Dysfunction in Obesity Arruda AP, Pers BM, Parlakgül G, Güney E, Inouye K, Hotamisligil GS Nature Medicine, December, 2014 Research from our group and many others has demonstrated that nutritional fluctuations and obesity are associated with dysfunction of cellular organelles including the endoplasmic reticulum (ER) and mitochondria. The ER is a vast tubular network within cells that serves as the synthetic factory for many key molecular building blocks of metabolism, while mitochondria are responsible for producing cellular energy. In obesity, the ER in liver cells is overwhelmed both because it is inundated by raw materials, and because of surrounding stress and inflammation. To make matters worse, energy supplies also diminish over time as the mitochondria fail to operate properly and start emitting additional toxic signals.

In this manuscript, two postdoctoral fellows from the lab, Ana Paula Arruda and Benedicte Mengel Pers, together with Güneş Parlakgül and Ekin Güney, led a team investigating the structural changes that occur in liver cells in obese animals. They demonstrated that there was an increase in the number of connections between ER and mitochondria through specialized structures called MAMs. Under normal conditions, these connections are few and far between, and are necessary for the function of both organelles. However, early during the course of obesity, ER-mitochondrial connectivity is increased, leading to an elevated transfer of calcium ions from the ER to the mitochondria. Although calcium is necessary for mitochondrial function, in excess it led to mitochondrial stress, with deleterious consequences for metabolism. We also found that an intervention involving a synthetic bridge between ER and mitochondria impaired mitochondrial function and made mice more sensitive to high fat diet-induced insulin resistance and diabetes.

From these findings we concluded that MAM formation may initially be an adaptive response, but in the setting of excess nutrients and obesity it turns out to be too much of a good thing, leading to functional failure of multiple organelles. Importantly, this work also identifies molecules that could be targets for future therapeutic strategies.

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Secretion of Fatty Acid Binding Protein aP2 from Adipocytes through a Nonclassical Pathway in Response to Adipocyte Lipase Activity Erikci Ertunc M, Sikkeland J, Fenaroli F, Griffiths G, Daniels MP, Cao H, SaatcioÄ&#x;lu F, Hotamisligil GS Journal of Lipid Research, February, 2015 One of the areas of focus in the laboratory has been the role of fatty acid binding proteins (FABPs) in metabolic disease. Over the last two decades, we have demonstrated that the major FABP expressed in fat tissue, called aP2, is a critical mediator of type 2 diabetes, insulin resistance, fatty liver disease, and atherosclerosis. It was commonly assumed that aP2 acted inside fat cells, and the effects we observed of aP2 inhibition or genetic deletion were due to changes in lipid metabolism.

However, a few years ago we discovered that aP2 is actively secreted from fat cells and can act as a unique hormone to alter the metabolic function of other organs. Since then, we have been very interested in understanding what drives secretion of this unusual hormone.

This manuscript is the culmination of a herculean effort from a former graduate student in the lab, Meric Erikci Ertunc, and our collaborators in the SaatcioÄ&#x;lu lab in Norway. She found that aP2 is secreted following induction of lipolysis, the process by which fat tissue breaks down triglycerides into fatty acids and releases them into the bloodstream. However, this protein lacks features of classical secreted hormones, and traditional pathways fail to explain how it is released from fat cells to act on other organs. Further dissecting the molecular mechanism, we found that lipolysis signals lead to the movement of aP2 into specialized vesicles, which are then released from the cell as exosomes. The striking biochemistry and microscopy in this publication have led to the identification of the key molecular players in this process, which could potentially lead to new ways to interfere with aP2 secretion and treat or prevent metabolic disease. We believe these insights and systems will help in the understanding of many long-lasting biomedical questions related to the role of lipids and lipid escort proteins.

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PUBLICATION HIGHLIGHTS

Phenotypic Assays Identify Azoramide as a Small-Molecule Modulator of the Unfolded Protein Response with Anti-Diabetic Activity Fu S, Yalcin A, Lee GY, Li P, Fan J, Arruda AP, Pers BM, Yilmaz M, Eguchi K, Hotamisligil GS Science Translational Medicine, June, 2015 Earlier work from our group and others showed that in obesity, the ER is unable to keep up with the demand for protein and lipid production, and that the resulting ER stress contributes to cellular dysfunction and the development of obesity and diabetes. However, efforts to translate strategies to improve ER function into clinical use for obesity and metabolic disease have had limited success, in part because of the inherent difficulty in measuring ER function in cells and hence inability to identify compounds to target ER. In this article, a team in the lab led by Suneng Fu, Abdullah Yalcin, and Grace Yankun Lee describe the development of two complementary and novel cellular assays that allowed direct monitoring of ER function in live cells. Using this platform the team characterized a unique small molecule that we named azoramide. This molecule improved ER function and was strongly protective against chemical-induced ER stress and death. In experimental obesity and diabetes, administration of azoramide dramatically improved glucose metabolism and insulin sensitivity and corrected diabetes. These results underscore the importance of ER function in metabolic disease and are an important proof of principle that these assays could be used to discover new compounds or natural nutrients with similar activity for therapeutic use. Furthermore, many other pathologies including neurodegenerative diseases involve ER dysfunction, thus this approach might be broadly useful in discovering and characterizing new medicines for a variety of diseases.

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A Critical Role for PKR Complexes with TRBP in Immunometabolic Regulation and eIF2Îą Phosphorylation in Obesity Nakamura T, Kunz RC, Zhang C, Kimura T, Yuan CL, Baccaro B, Namiki Y, Gygi SP, Hotamisligil GS Cell Reports, April, 2015 One outcome of our research in the last several years has been the concept that metabolism is inextricably linked to the immune system. We have learned that obesity is a state of low level inflammation, and that this contributes to the development of metabolic diseases. These observations have expanded greatly and grew into a new field of study called immunometabolism.

In unraveling the mechanisms for this critical biology, we have identified several important signaling nodes, one of which is a protein named PKR. PKR is activated by pathogens and nutrients, and work from our lab and others has demonstrated that it plays an important role in the development of insulin resistance and metabolic inflammation. However, how PKR itself is regulated and activated in response to nutrient stress has been unclear.

In this paper, a former postdoctoral fellow in the lab, Takahisa Nakamura, discovered that the protein partners of PKR differ in the liver of obese animals compared to lean and healthy controls.

Specifically, we found that obesity-induced activation of PKR was associated with interaction with proteins called TRBP and Dicer, and further that TRBP appeared to directly activate PKR. This was a critical insight that challenged the conventional understanding of TRBP-PKR interaction, and provided a better understanding of how cells respond to stresses and how these response systems may be manipulated and targeted to treat or prevent disease.

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PUBLICATION HIGHLIGHTS

S-Nitrosylation Links Obesity-Associated Inflammation to Endoplasmic Reticulum Dysfunction Yang L, Calay ES, Fan J, Arduini A, Kunz RC, Gygi SP, Yalcin A, Fu S, Hotamisligil GS Science, July, 2015 We know now that two important things happen with aging and obesity; multiple organs start a damaging sequence of immune responses called chronic inflammation, and the function of key cellular organelles such as the ER fail in executing their vital functions. While the mechanisms that incapacitate ER in many chronic diseases remained enigmatic, it was generally assumed that once the ER fails, inflammation ensues.

In a ground-breaking study done this year, we showed results that turned this dogma on its head. This work, led by former postdoctoral fellow Ling Yang and Ediz Calay, demonstrated that obesity-related inflammation that impairs the ER’s ability to respond to stress, leading to a crippled ER and disruption of glucose homeostasis. Specifically, we found that inflammation results in an increased level of production of a powerful gas called nitric oxide (NO), which creates a modification of a protein involved in the ER stress response called IRE-1. The modified protein was then no longer able to perform its essential pro-resolution actions, and engaged in maladaptive responses perpetuating cellular dysfunction, and generating pathological conditions such as diabetes. Remarkably, expressing an engineered form of IRE-1 that could not be modified

by NO improved metabolic control in obese animals and protected them against diabetes.

This study suggests that therapies that target inflammatory pathways including NO production could be effective strategies in the treatment of metabolic disease.

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Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes Arruda, AP and Hotamisligil, GS, Cell Metabolism, September, 2015 In this review, we present a new framework for understanding the cellular dysfunction that is a consequence of obesity and nutritional stress. Specifically, we discuss the emerging field of study that reveals a role for calcium homeostasis in integrating inflammation, organelle dysfunction, and other mechanisms that underlie the development of chronic metabolic diseases. This insight may lead to new lines of research and therapeutic approaches.

Metabolic Functions of FABPs–Mechanisms and Therapeutic Implications Hotamisligil, GS and Bernlohr, DA, Nature Reviews Endocrinology, October, 2015 Lipid metabolism and the biology of fatty acid binding proteins (FABPs) such as aP2 have been a central focus of the work in the lab and represent important areas in understanding the connections between obesity and metabolic disease. In this review, we partnered with another world expert in FABP research, Dr. David Bernlohr, to describe the original discovery of FABPs and how the field has developed to our current understanding of how these proteins are regulated and function.

Importantly, we also detail the new understanding that these proteins have extracellular actions relevant to metabolic disease, presenting new opportunities for interventional strategies.

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EXPANDING THE IMPACT

Committed to training the next generation of scientists.

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RENATA GONCALVES, PhD

“ I love to work at the bench, and the opportunity to test my ideas both in cells and in the whole organism makes me believe that what I am doing really can help make a difference in fighting human disease in the future.�

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Q.

W here were you before you joined the Sabri Ülker Center?

Q.

I just joined the Center in May 2015 for postdoctoral work.

Before that I was at the Buck Institute for Research on Aging in California, working with Dr. Martin Brand. I was interested in understanding how the mitochondria, the cellular organelle that converts nutrients into energy, generates signaling molecules called reactive oxygen species. When reactive oxygen species are overproduced, they can be toxic and contribute to the development of diseases including insulin resistance and diabetes.

Q.

Q.

W hat compelled you to join the Sabri Ülker Center?

I felt like my interests overlapped with the vision and much of the work that was currently being done in the Center–studying energy metabolism and how this is altered under pathological conditions.

Q.

C ould you describe your project?

H ow do you think your time in the Sabri Ülker Center will affect your career in the long term?

I have very high expectations for this experience! The intellectual environment in the Center is amazing. My colleagues are very bright, critical, smart, and intelligent people and I am very sure I will use the connections I am establishing here for future collaborations when I become an independent researcher. In parallel I am acquiring a broader understanding of metabolism and human health.

H ow does your work relate to global health challenges?

The proportion of humans considered obese has increased very fast in the past decades. The projection for the next 30 years is alarming since the numbers of obese individuals will more than double and carry increased risk for many other pathologies like diabetes, cancer, and cardiovascular diseases. If our work can contribute to reduce the tremendous burden of these pathological outcomes, this will represent a great impact not only on global health but also on global economics.

Our cells have these tiny structures inside them called mitochondria. For decades mitochondria were Q. W hat are you excited about for the considered the “powerhouse” of the cell because they coming year? burn the nutrients we consume and convert them into energy that is utilized for important reactions. During I am very excited about the new challenges I will face this process mitochondria also generate potentially in this project. I love to work at the bench, and the harmful molecules collectively known as reactive oxygen opportunity to test my ideas both in cells and in the species (ROS). These were once considered by-products whole organism makes me believe that what I am doing of metabolism, but more recently we have come to really can help make a difference in fighting human understand that they also play important physiological disease in the future. signaling roles. Under certain pathological conditions such as insulin resistance and type 2 diabetes, the production of ROS from mitochondria is dysregulated.

I’m trying to understand the mechanisms that lead to this, and my hypothesis is that this is related to changes in protein synthesis in the mitochondria.

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MUSTAFA YILMAZ, PhD CANDIDATE

“ My work, together with that of other people in the Sabri Ülker Center, is important for our comprehensive understanding of the changes in the pathological state of obesity, thereby potentially allowing us to develop new therapeutic approaches.”

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Q.

W here were you before you joined the Sabri Ülker Center?

Q.

I joined the Sabri Ülker Center for my PhD work.

Before that I was doing my Master’s studies in Dr. Mehmet Öztürk’s Lab at Bilkent University in Ankara, Turkey, working on liver cancer.

Q.

Q.

I’ve learned here how to first identify the most important questions that remain to be answered in the field and then try to figure out the most elegant ways to address those questions. I think that getting comfortable with this scientific approach will help me advance my career significantly after my graduate study with Dr. Hotamışlıgil.

Furthermore, I’m able to interact with an accomplished group of scientists in this environment; I think that’s influenced my understanding of the field and will help open up many new opportunities for me.

W hat compelled you to join the Sabri Ülker Center?

First and foremost, I was interested in doing research on metabolic diseases, such as obesity and diabetes, because I believe that extensive basic and translational research is needed to develop successful treatments for these growing epidemics. Second, the focus and the exceptional quality of the research done in the Center convinced me to be a part of this research group.

Q.

H ow does your work relate to global health challenges?

Chronic metabolic disease including obesity has already become an epidemic, affecting individuals’ lives and causing an immense economic burden. My work, together with that of other people in the lab, is important for our comprehensive understanding of the changes in the pathological state of obesity, thereby potentially allowing us to develop new therapeutic approaches for the treatment of the disease.

C ould you describe your project?

Obesity is characterized by an expansion of fat tissue, and this expansion is associated with numerous pathological alterations, including inflammation and dysfunction of organelles inside the cells such as the endoplasmic reticulum. Both of these mechanisms, discovered earlier in the lab, are directly linked to fat cell dysfunction and systemic perturbations. My project primarily focuses on why fat cells, as they are filled with excess nutrients, develop stress in the organelles and how they respond to it. In particular, my research aims to delineate the connection between endoplasmic reticulum dysfunction and decreased oxygen concentration in the tissue, which we already know occurs in the fat of obese humans.

H ow do you think your time in the Sabri Ülker Center will affect your career in the long term?

Q.

W hat do you hope will come out of your work?

I hope that my work will provide insights into how major pathological alterations observed in obese fat tissue are interconnected at the molecular level. This kind of insight could help us identify key regulator proteins to target therapeutically.

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BENEDICTE MENGEL PERS, PhD

“ My four years working with Dr. Hotamışlıgil are very precious to me and I believe they will affect my future in many aspects.

It has been a great adventure, especially as it was a complete change of field and direction for me.”

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Q.

W here were you before you joined the Sabri Ülker Center?

Before joining the Sabri Ülker Center I was trained in Physics and did my PhD in Computational Biophysics at the Niels Bohr Institute, University of Copenhagen, Denmark.

Q.

W hat compelled you to join the Sabri Ülker Center?

especially as it was a complete change of field and direction for me. I have learned experimental biology here, but also a new way of thinking and approaching scientific questions. This is something that I will bring with me when I leave the Sabri Ülker Center and that I believe will affect my daily work for the rest of my career.

In addition, the warm atmosphere in which such high level science is being performed, due Dr. Hotamışlıgil’s management of the Center, is an inspiration to me, and I hope I can help build and maintain this type of environment wherever I go next.

I was foremost attracted by the exciting science done in the center. Then when I visited the labs I could not help noticing the interaction between the lab members and Q. H ow does your work relate to the wonderful atmosphere, and I knew I wanted the global health challenges? opportunity to join this group of scientists.

Obesity and metabolic diseases such as type 2 diabetes are some of the greatest challenges globally. We are Q. C ould you describe your project? trying to understand what goes wrong in a cell in an obese individual or upon exposure to nutrients, hoping I am studying a protein called STIM1, which senses that we can eventually find ways to intervene in changes in calcium levels in the specialized pathological processes and prevent and treat disease. compartments of cells such as endoplasmic reticulum and can quickly work to restore levels when they fall by allowing for calcium entry into the cell. We are Q. W hat are you excited about for the specifically trying to understand how the actions of coming year?

STIM1 are regulated by nutrients and obesity, because This coming year I’m excited to finish my study about work from our lab and others has previously shown STIM1 and prepare for publication. I am sad that I will that disruptions to calcium homeostasis contribute to be leaving the Sabri Ülker Center and Boston, but also diseases such as insulin resistance, diabetes, and fatty excited to be moving back to Denmark to continue my liver disease. academic career there.

Q.

How

do you think your time in the Sabri Ülker Center will affect your career in the long term?

My four years in the Center are very precious to me and I believe they will affect my future in many aspects.

Working with Dr. Hotamışlıgil has been a great adventure

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INAUGURAL SABRI ÜLKER FELLOWS

Güneş Parlakgül, MD

Ekin Güney, MD 22

We are so delighted to have welcomed our inaugural Sabri Ülker fellows, Ekin Güney and Güneş Parlakgül into the lab this year. Both have already demonstrated their capacity for hard work and focus, and made excellent research progress.

Drs. Güney and Parlakgül are focusing on a challenging question, which aims to understand how cells and organs cope with stress and challenging exposures and how they respond to defend their functional integrity. Their particular focus is the role of nutrient and metabolic fluxes and kinetic changes that occur in cells during metabolic fluctuations and stress. Their initial work already made significant contributions to understanding the alterations in organelle structure in the context of obesity and how these alterations impair glucose metabolism in the whole body. In addition to their primary projects on organelle function and metabolism, these two budding scientists have developed an interest in another extreme condition which involves hibernation of grizzly bears. Hybernation requires dynamic and dramatic regulation of nutrition and metabolism, as the animals rapidly gain fat mass in the autumn to prepare for months of low level activity, and then transition to higher energy usage when they become active in the spring. This process has not been well studied at the molecular level, and Ekin and Güneş now have a unique opportunity to explore this fascinating process. We are hopeful that this work, in the long run, may have dramatic impact on understanding how humans use and store energy, how metabolic fluctuations are coordinated, and how these processes go wrong in obesity, diabetes, and metabolic disease.

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SCIENTIFIC FREEDOM AND SUSTAINED FOCUS are paramount to the development of significant advances in improving the quality of life around the globe.

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The excitement of launching the Sabri Ülker Center and seeing its very productive first year is further magnified by the tremendous success of the faculty, collaborators, postdoctoral fellows, and students affiliated with GCD. Under the leadership of Dr. Gökhan S. Hotamışlıgil, the GCD community has grown from a nascent core of committed faculty to a fully realized, high impact department dedicated to addressing the most critical pandemics such as diabetes, heart disease, and other metabolic disorders through integrative programs combining biochemistry, cell biology, physiology and genetics.

ACHIEVEMENT HIGHLIGHTS Each member of the GCD community has brought creativity, dedication, and purpose to solving the greatest public health challenges of the 21st century. Through the creation of new disease models and collaboration across the Life Sciences, GCD faculty have produced many outstanding publications and have been recognized by the scientific community for their exceptional contributions by distinctions. These include: Brendan Manning, PhD, Professor of Genetics and Complex Diseases and the Director of the Graduate Program Dr. Manning received the prestigious National Cancer Institute Outstanding Investigator Award.

This multimillion-dollar seven-year award provides extended funding stability, giving the most promising and productive investigators enough time and resources to continue or embark on projects of unusual potential in cancer research—and to take greater risks in their work.

Tobias Walther, PhD, Professor of Genetics and Complex Diseases Dr. Walther, who studies the formation of specialized storage compartments for lipids, is the first Harvard Chan faculty to receive a Howard Hughes Medical Foundation (HHMI) Investigator award. HHMI funds individuals rather than projects, empowering the most talented and impactful researchers like Dr. Walther and colleagues to take risks and stretch the boundaries of their work in metabolic and neurodegenerative disease.

Marianne Wessling-Resnick, PhD, Professor of Nutritional Biochemistry Dr. Wessling-Resnick, who studies iron metabolism, received the Vitamin and Mineral Research Interest Section Outstanding Investigator Award for 2015. The award recognizes Dr. Wessling-Resnick’s sustained excellence in the area of vitamin and mineral research, which is critical to the understanding of metal metabolism and in particular, genetic disorders of iron homeostasis.

Gökhan Hotamışlıgil, MD, PhD, Director of the Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research, Chair, Department of Genetics and Complex Diseases and James S. Simmons Professor of Genetics and Metabolism at the Harvard T.H. Chan School of Public Health The Endocrine Society awarded Dr. Hotamışlıgil the prestigious Roy O. Greep Award for Outstanding Research. This award was bestowed in recognition of Dr. Hotamışlıgil’s pioneering work in understanding the mechanistic basis of chronic metabolic diseases.

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Further demonstrating the success and determination of our departmental members, we are delighted that GCD faculty published many high impact publications this year. A selection of these is listed below.

The Garp Complex is Required for Cellular Sphingolipid Homeostasis Fröhlich F, Petit C, Kory N, Christiano R, Hannibal-Bach HK, Graham M, Liu X, Ejsing CS, Farese RV, Walther TC Elife, September, 2015

Oncogenic PI3K and K-Ras Stimulate De Novo Lipid Synthesis through mTORC1 and SREBP Ricoult SJ, Yecies JL, Ben-Sahra I, Manning BD Oncogene, June, 2015

Protein Crowding is a Determinant of Lipid Droplet Protein Composition Kory N, Thiam AR, Farese RV Jr, Walther TC Developmental Cell, August, 2015

Dietary Restriction Protects Against Experimental Cerebral Malaria via Leptin Modulation and T-cell mTORC1 Suppression Mejia P, Treviño-Villarreal JH, Hine C, Harputlugil E, Lang S, Calay E, Rogers R, Wirth D, Duraisingh MT, Mitchell JR Nature Communications, January, 2015.

From Cell Biology to the Microbiome: An Intentional Infinite Loop Garrett WS Journal of Cell Biology, July, 2015 CCL2 Promotes Colorectal Carcinogenesis by Enhancing Polymorphonuclear Myeloid-Derived Suppressor Cell Population and Fåunction Chun E, Lavoie S, Michaud M, Gallini CA, Kim J, Soucy G, Odze R, Glickman JN, Garrett WS Cell Reports, July, 2015 Host Lysozyme-Mediated Lysis of Lactococcus Lactis Facilitates Delivery of Colitis-Attenuating Superoxide Dismutase to Inflamed Colons Ballal SA, Veiga P, Fenn K, Michaud M, Kim JH, Gallini CA, Glickman JN, Quéré G, Garault P, Béal C, Derrien M, Courtin P, Kulakauskas S, Chapot-Chartier MP, van Hylckama Vlieg J, Garrett WS Proceedings of the National Academy of Sciences, June, 2015 Cancer and the Microbiota Garrett WS Science, April, 2015 Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness Jacobi D, Liu S, Burkewitz K, Kory N, Knudsen NH, Alexander RK, Unluturk U, Li X, Kong X, Hyde AL, Gangl MR, Mair WB, Lee CH Cell Metabolism, October, 2015 Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan Via a Catecholamine Signal Burkewitz K, Morantte I, Weir HJ, Yeo R, Zhang Y, Huynh FK, Ilkayeva OR, Hirschey MD, Grant AR, Mair WB Cell, February, 2015 Molecular Basis of Giant Cells in Tuberous Sclerosis Complex Kwiatkowski DJ, Manning BD New England Journal of Medicine, August, 2014 The TSC Complex is Required for the Benefits of Dietary Protein Restrictions on Stress Resistance in Vivo Harputlugil E, Hine C, Vargas D, Robertson L, Manning BD, Mitchell JR Cell Reports, August, 2014 Coordinated Regulation of Protein Synthesis and Degradation by mTORC1 Zhang Y, Nicholatos J, Dreier JR, Ricoult SJ, Widenmaier SB, Hotamışlıgil GS, Kwiatkowski DJ, Manning BD Nature, September, 2014 Low-dose Radiation Exposure Induces a HIF-1-mediated Adaptive and Protective Metabolic Response Lall R, Ganapathy S, Yang M, Xiao S, Xu T, Su H, Shadfan M, Asara JM, Ha CS, Ben-Sahra I, Manning BD, Little JB, Yuan ZM Cell Death & Differentiation, May, 2014 Spatial Control of the TSC Complex Integrates Insulin and Nutrient Regulation of mTORC1 at the Lysosome Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, Manning BD Cell, February, 2014

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Endogenous Hydrogen Sulfide Production is Essential for Dietary Restriction Benefits Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Treviño-Villarreal JH, Mejia P, Ozaki CK, Wang R, Gladyshev VN, Madeo F, Mair WB, Mitchell JR Cell, January, 2015 Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice Robertson LT, Treviño-Villarreal JH, Mejia P, Grondin Y, Harputlugil E, Hine C, Vargas D, Zheng H, Ozaki CK, Kristal BS, Simpson SJ, Mitchell JR Journal of Nutrition, August, 2015 Novel Pathways of Apolipoprotein A-1 Metabolism in High-Density Lipoprotein of Different Sizes in Humans Mendivil CO, Furtado J, Morton AM, Wang L, Sacks FM Arteriosclerosis, Thrombosis and Vascular Biology, November, 2015 Nramp1 and Other Transporters Involved in Metal Withholding During Infection Wessling-Resnick, M Journal of Biological Chemistry, July, 2015 The Small Molecule Ferristatin II Induces Hepatic Hepcidin Expression in Vivo and in Vitro Alkhateeb AA, Buckett PD, Gardeck AM, Kim J, Byrne SL, Fraenkel PG, Wessling-Resnick M American Journal of Physiology Gastrointestinal and Liver Physiology, June, 2015 Ferroportin Deficiency Impairs Manganese Metabolism in Flatiron Mice Seo YA, Wessling-Resnick M The Journal of the Federation of American Societies for Experimental Biology, July, 2015 Somatic Human ZBTB7A Zinc Finger Mutations Promote Cancer Progression Liu XS, Liu Z, Gerarduzzi C, Choi DE, Ganapathy S, Pandolfi PP, Yuan ZM Oncogene, October, 2015 UXT, a Novel MDMX-Binding Protein, Promotes Glycolysis by Mitigating p53-Mediated Restriction of NF-kB Activity Liu XS, Genet MD, Haines JE, Mehanna EK, Wu S, Chen HI, Chen Y, Qureshi AA, Han J, Chen X, Fisher DE, Pandolfi PP, Yuan ZM Oncotarget, July, 2015 A Novel Role of PRR14 in the Regulation of Skeletal Myogenesis Yang M, Yuan ZM Cell Death and Differentiation, April, 2015

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The overarching mission of the Harvard T.H. Chan School of Public Health is to advance public health through education, discovery, and communication.

To pursue this mission, the Harvard Chan community has identified four major threats that are the drivers of disease and suffering world-wide.

These threats are: • Old and new pandemics, including metabolic diseases • Harmful physical and social environments, including nutrients • Poverty and humanitarian crises • Failing health systems POWERFUL IDEAS FOR A HEALTHIER WORLD

For over 100 years, the Harvard T. H. Chan School of Public Health has been a leader in the transformation of public health. Together, we will address these complex threats through ground breaking science that will drive actionable policy development and empower individuals to thrive in a healthier world. The School is also unrivaled in its commitment to Life Sciences to generate impactful solutions for the greatest threats to human welfare. We are deeply grateful for and energized by the Ülker family’s visionary gift, and look forward to a decade of discovery in which the Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research will lead the field in combating metabolic diseases, offering hope to those suffering from chronic and complex diseases.

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Furkan Burak, MD 31

LOOKING FORWARD

As described in these pages, the first year of the Ülker Center has been a rewarding one, and we are excited to have launched the center and committed to maintaining the pace and quality of our work.

As I look forward to the coming year, I anticipate a year with continued effort on several fronts and hope that it will be marked by new discoveries, as the work of several of our research fellows nears completion. We are excited to share with the scientific community our advances in understanding how cells protect themselves from overloads of lipids and cholesterol. We will also be describing a potential new therapeutic direction to treat type 2 diabetes, and will reveal our surprising insights into the function of hormones derived from fat tissue.

To facilitate our progress we are working toward developing innovative cellular platforms for nutrient screening, and we have nearly completed the construction and equipment acquisition for our new microscopic imaging center. The new technology and dedicated space will enable us to visualize the structural and sub-structural changes within cells that occur in obesity, and to begin to understand how these affect metabolic processes and disease progression.

This is a unique and innovative approach in metabolic disease research, and has already been successful in expanding our understanding of how interactions between the endoplasmic reticulum and mitochondria contribute to the development of obesity and diabetes.

In addition, I look forward to organizing and hosting the inaugural Sabri Ülker Symposium on Metabolism and Life, to be held May 5-6, 2016 in İstanbul. This event will be an unparalleled opportunity for attendees to engage with and learn from the leading researchers in the field of metabolism from around the world.

I am very hopeful that this symposium will help shape the direction of future research, both in our group and by our colleagues, by exposing us to new perspectives and nucleating new ideas and collaborations.

Finally, I am perhaps most excited about the unknown and unanticipated discoveries that may lie ahead. I feel incredibly fortunate to be part of this project and that the Sabri Ülker Center is well-situated for the careful and vigorous observation and thoughtful, sustained experimentation necessary for such advances. I look forward to working with the talented scientists as we progress toward new approaches to treat and prevent metabolic disease.

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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.hsph.harvard.edu/gsh-lab/sabriulkercenter Follow us: @sabriulkerctr