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Nutrient, Genetic, and Metabolic Research

The Decade of Discovery 2020 Annual Report


FIRST DECADE OF DISCOVERY

The Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research is dedicated to advancing and expanding scientific understanding of the fundamental mechanisms of chronic metabolic diseases and their intricate relationship with human health and disease. 2 6 8 11 18 21 22 23 24 2

Letter from Gökhan S. Hotamışlıgil Sabri Ülker Advanced Imaging Lab Sabri Ülker Physiology Lab Publication Highlights Next Generation of Scientists Center Welcomes Affiliated Faculty Community Engagement Ülker Center Lectures Celebrating 25 Years of Hotamışlıgil Lab


WHY IS COMMUNITY SO IMPORTANT IN WHAT WE DO? We utilize our scholarly network to generate meaningful connections to build scientific knowledge as a community that collaborates, combines, compounds, and builds on our collective experience.


“In science, every contribution is valuable and paves the way for important breakthroughs. Milestone discoveries lift the entire field as researchers around the world start building on top of this new foundation of knowledge. From a metabolic perspective, this is the kind of work we have been aspiring to and are now able to focus on at the Sabri Ülker Center, and this is why I am more optimistic than ever that collectively we can make real progress against the most dangerous diseases.”


FIRST DECADE OF DISCOVERY

DEAR FRIENDS, This past year has been extraordinary and disorienting for all of us. COVID-19 has profoundly altered so much, from activities at home and in our lab in Boston to the lives of our collaborators, alumni, friends, and families worldwide. We witnessed the suffering and mourned the loss of human life around the world. In these uncertain and tumultuous times, I have been so heartened by and appreciative of the ways that members of our scientific community have strengthened international solidarity and remained united in search of new solutions. Compared to many, we have been fortunate to be able to withstand the challenges and contribute to the effort to ease the suffering. For the first time in its 25-year history, we even needed to temporarily close our laboratory. I am proud that despite these challenges, our lab managed to quickly develop a protocol to maintain its activities and, to the best of our ability under the circumstances, has continued to contribute to the understanding of the cellular and molecular mechanisms that underlie metabolic diseases and their implications for the current global crisis. I am pleased to share with you this sixth annual report of our progress including some important scientific developments, publication highlights, profiles of some of our newest lab members and two new affiliated faculty members, and the highlights of the Center over the past year. We are continually grateful for the support of the Ülker family, which has made all of this possible during these turbulent months. There is a tremendous value in studying a process as fundamental as metabolism. The COVID-19 pandemic demonstrated, once again, that studying diseases that emerge from metabolic problems, such as obesity and diabetes, is of such critical importance as these problems constitute the most important risk factors for disease progression, severity, and death from the Sars-CoV-2 virus. We are now engaged in collaborative efforts to explore the impact of metabolic and immunometabolic responses to the virus and implication of central regulators of these processes on COVID-19. We are also exploring new experimental models and translational tools that might aid in our understanding of COVID-19 and its short- and long-term complications. During this year, the generosity of the Ülker family made it possible for us to establish the new Sabri Ülker Center Physiology Laboratory, featuring state-of-the-art and expanded technologies to study metabolism, in vivo. We also improved our Imaging Lab, and initiated efforts to expand our imaging and analytical capabilities and collaborations. We also completed our first important large-scale study using these platforms. Finally, through a Harvard initiative called Lab 1636, we embarked on an academia-industry alliance to advance one of our fundamental discoveries for clinical applications against diabetes. To be successful in our ongoing fight against the greatest threats to global human health, we continue to promote global scientific development. A major component of this effort is the annual international Symposium on Metabolism and Life. Though postponed from our planned offering in 2020, we will be excited to welcome you all to join our Symposium program in May 2021 and hope that this day will mark a celebration of not only science but also a return to a sense of normalcy and health in our personal and professional lives.

Gökhan S. Hotamışlıgil, MD, PhD Director of the Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research James S. Simmons Professor of Genetics and Metabolism at the Harvard T.H. Chan School of Public Health 3


ASPIRING TO MAKE AN

IMPACT


...BY DARING TO ASK “WHAT IF?” We strive to dive deeper into basic science—to better understand the fundamental molecular mechanisms of metabolic control—in order to discover unique paths to follow and address the causes of chronic metabolic diseases, and ultimately, to develop novel therapeutic concepts.


SABRİ ÜLKER ADVANCED IMAGING LAB

SOLVING STRUCTURAL AND ARCHITECTURAL QUESTIONS (at the molecular scale) The establishment of the Sabri Ülker Advanced Imaging Lab has given us power to visualize how metabolically critical cells and their organelles, such as endoplasmic reticulum and mitochondria, adapt to different nutritional, hormonal, and stress states.

Imaging is a vital component of life sciences research that allows scientists to observe and quantify the intracellular and intercellular events at various space and time scales. The Sabri Ülker Advanced Imaging Lab (SAIL) possesses instrumentation that was acquired with the generous support of the Ülker family. Their financial support has enabled us to image live and fixed biological samples, such as cell lines and metabolic tissues, under different nutritional conditions—all in high resolution. We are able to capture information such as cell morphology, lipid content, organelle abundance, distribution, localization, motility, and interaction. More specifically, we have imaged hepatocytes, adipocytes, and pancreatic cells and were able to determine the effect of nutritional stress in endoplasmic reticulum (ER) and mitochondria dynamics and interaction in high spatio-temporal resolution. Additionally, we were also able to measure intracellular calcium dynamics in the different cellular compartments such as cytosol, mitochondria, and ER. These measurements enabled us to discover a dysfunction in calcium signaling in cells such as hepatocytes that is a key problem that occurs in obesity. The SAIL enables collaborations with other research programs that would not otherwise be possible. For example, Dr. William Mair’s lab studies the effect of aging in organelle dynamics in cellular models and also in Caenorhabditis elegans (C. elegans), a free-living transparent nematode about 1.5 mm in length. The microscopic capacity offered by our imaging lab created new research opportunities for his team. Additionally, our imaging technology capacity will allow us to collaborate with new faculty members, such as Dr. Nora Kory, who is now affiliated with the Sabri Ülker Center. She will be utilizing high-resolution microscopy to ask interesting questions that explore mitochondria form and function in aging and metabolic diseases. Previous work in the Hotamışlıgil Lab has shown that within liver cells, changes to the structure and function of the ER are key events in adapting to metabolic stress. We are now investing in even higher capacity and resolution instrumentation,

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which will give us tremendous power to visualize how the organelles in liver cells adapt to different nutritional and hormonal states, such as fasting and feeding, by reorganizing its structure. Drs. Ana Paula Arruda, Güneş Parlakgül and Hatoon Baazim are now embarking on similar analysis on one of the most challenging of cells, the adipocytes, and the adipose tissue to explore their subcellular architecture and its regulation under metabolic and nutritional challenges. We are also working and planning to further expand our imaging, computational, artificial intelligence, machine learning, and visualization capacities in the near future.

(Top) The imaging platforms at the Sabri Ülker Advanced Imaging Lab allow scientists to study the molecular events in cells and tissues over time. Live cell imaging enables visualizing the localization, interaction, and abundance of molecules such as proteins and lipids during metabolic processes. (Bottom) This microscope is equipped with a fluidic injection/ pump system for delivering various chemicals and agents during imaging. It allows us to determine calcium dynamics in the cells.


Cos-7 cell showing endoplasmic reticulum (in red), mitochondria (in green), nucleus (in blue), and peroxisomes (in purple). This cell line has been widely used to study organelle communication and other cell biology questions regarding subcellular organization.


SABRİ ÜLKER PHYSIOLOGY LAB

IMPACT OF IN VIVO MODELING “If anything has changed over the years, now more than ever, we do not just focus on cell-based work or animal physiology, but rather we strive to present a complete story from the cellular level to whole-body physiology.” Karen E. Inouye, PhD

The partnership between Dr. Hotamışlıgil and Dr. Inouye goes back more than ten years, prior to her joining the lab in 2010. Dr. Hotamışlıgil was her academic advisor during a postdoctoral fellowship at Novartis Institutes for Biomedical Research. After completing her fellowship Dr. Inouye spent some time working in industry and focused on in vivo animal studies. In reflecting on her career path, Dr. Inouye noted, “It didn’t turn out to be what I was looking for in a career, and so I began the search for a new position. I was interested in getting back into research and using my skills in metabolic physiology. After some time looking for positions, I came across an ad for the position in the Hotamışlıgil Lab. Gökhan was looking for someone to run the department’s metabolic physiology core, which included using high-end metabolic physiology equipment, mouse imaging systems, and performing advanced in vivo techniques, such as glucose clamp studies in mice, in which I had extensive experience. I felt this position was a perfect fit for my skills and research interests, and was excited at the prospect of working in a lab that was at the forefront of metabolism research.” The Sabri Ülker Physiology Lab has a full complement of state-of-the-art small animal physiology instrumentation that Dr. Inouye uses to support the research of the members of the Center, in addition to colleagues throughout the Longwood Medical area.

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SABRİ ÜLKER PHYSIOLOGY LAB

This instrumentation includes: n

High-resolution microCT scanner, GE, for mice and rats.

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Perkin Elmer IVIS Spectrum In Vivo Imaging System for in vivo imaging of bioluminescence and fluorescence signal in live mice to monitor conditions such as inflammation, atherosclerosis, vascular disease, arthritis, and cancer.

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SCIREQ Flexivent for measurement of respiratory mechanics in live mice.

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EchoMRI and DEXA instruments for measurement of lean and fat mass, and bone density in live mice.

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Blood pressure and heart rate monitoring platforms for awake mice or rats.

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Multi-lane treadmill with adjustable speed and incline, for performing exercise and related metabolic studies in mice and rats.

A major upgrade to our ability to conduct sophisticated research in live mice, while also providing them with better living conditions, has recently been made possible by an additional generous gift from the Ülker family. We were able to replace our 8-cage metabolic cage apparatus with the most advanced, 16-cage Sable Promethion Core System. Metabolic cages are an essential tool for measuring oxygen consumption and carbon dioxide production in mice, thus allowing monitoring of the effects of genetic alterations, diets, and treatments on energy expenditure and fuel utilization. Our new system has higher capacity and many upgrades. Mice are in a temperature- and light-controlled cabinet that allows the study of metabolism at different temperatures or light conditions. The system monitors their activity, measures food and water intake and body weight, and has running wheels for measuring oxygen consumption and carbon dioxide production during exercise. Food access doors allow for fasting or feeding at specific times of the day, or feeding fixed amounts of food. A separate treadmill unit allows for energy expenditure measurements during exercise at different speeds and inclines. Due to the very high sensitivity of the gas analyzers of this system, we can house the mice in standard size cages, and still get accurate oxygen and carbon dioxide measurements. The mice are housed in cages that resemble their home cages, with bedding, and food and water dispensers similar to their normal housing conditions, thus minimizing stress and improving the accuracy of measurements. This “homecage” system also allows us to house the mice in the Sable System for longer periods, and therefore provides greater flexibility for the types of experiments we can perform. The newest technology in the Sable System is the 13C/18O stable isotope analyzer that now allows us to measure metabolism of 13C- and 18O-labeled substrates we administer to mice, through their expired breath. We are also able to administer these substrates intravenously through Instech infusion and blood sampling tethers attached to the mice

“I think animal research has always played an important role in our goal to understand biology. Although a lot can be learned from in vitro cell culture experiments, in the end, to understand physiology, studies in animals are necessary to understand how genetic alterations and treatments affect the whole body.” Karen E. Inouye, PhD that can be ported through the cage lids. This will allow for measurement of fuel metabolism during steady-state infusion experiments, while at the same time measuring whole-body energy expenditure. Assistant Professor Dr. Tony Hui, a newly appointed Ülker Center affiliated faculty member, focuses on understanding metabolism with a quantitative and systems approach to examine metabolic fluxes in whole organisms. With the Sable system, he has opportunities to further his pursuit of quantitative modeling research to determine metabolic fluxes—the most fundamental functional property of metabolism. We are also adding telemetry capabilities to both our metabolic cage system and other experiments and use implanted probes for continuous measurement of body temperature, activity, blood pressure, and heart rate. Telemetric measurement of body temperature is important for cold exposure studies, so that we can continuously monitor the temperature responses of mice without any handling. We are also actively working on integrating one of the newest and exciting telemetry technologies to continuously monitor blood glucose levels. This will be a big advance in metabolism research, as glucose levels in mice can be impacted by handling of the animals during measurement. In addition, measurement of glucose levels at fixed-time intervals can miss critical data that can be obtained from continuous monitoring.

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GENERATING INSIGHT BY FOCUSING ON THE UNKNOWN We are drawn to fill the gaps in the unknown, to gain understanding by exploring uncharted territory with new ideas, methods, tools, and collaborations.


PUBLICATION HIGHLIGHTS

Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism Amir Tirosh, Gurol Tuncman, Ediz S. Calay, Moran Rathaus, Idit Ron, Abdullah Yalcin, Grace Yankun Lee, Rinat Livne, Sophie Ron, Neri Minsky, Ana Paula Arruda, Gökhan S. Hotamışlıgil Cell Metabolism, December 2020 (online) and January 2021 (in print) https://doi.org/10.1016/j.cmet.2020.11.009

This study demonstrates that regulation of intercellular communication is a critical component of tissue adaptation to metabolic stress. In the liver tissue of obese mice, Cx43, a ‘building block’ of network of channels between adjacent cells, is increased in both amount and activity under endoplasmic reticulum (ER) stress, a common insult in obesity and diabetes. Such an increase in Cx43 results in increased communication between cells, allowing cell-cell transmission and propagation of stress signals. Upon such cell-cell transmission between neighboring cells, the ER stress-naïve cells also become ‘stressed’ and dysfunctional, and further aggravate the liver impairment at the level of the tissue. Increase in Cx43 under ER stress conditions in hepatocytes, leads to abnormal Cx43-mediated intercellular communication. The increased cell-cell coupling allows transmission of harmful signals from ‘stressed’ to neighboring stress-naïve ‘bystander’ cells, resulting in impaired ER function and insulin resistance. Blocking Cx43 in hepatocytes prevents this transmission and protects the cells from overnutrition-induced stress, ER dysfunction and metabolic problems. Endoplasmic reticulum (ER) stress and dysfunction is an important mechanism in the pathophysiology of obesity-associated metabolic pathologies such as insulin resistance and diabetes. While some of the cellular events linking ER stress and insulin resistance are well characterized, how an organ coordinates its adaptive response to stress, and the role of communication between its cellular constituents remains unclear. Increased gap junction (GJ)— intercellular communication, primarily involving connexin Cx43, plays a key role in the maladaptive tissue response to various stresses and has been implicated in the pathogenesis

of atherosclerosis and neurodegenerative diseases, which, like obesity, are characterized by chronic low-grade inflammation and ER stress. In this study we demonstrate that in hepatocytes, ER stress results in increased expression of Cx43 mRNA and protein, and in increased GJ-mediated cell-cell coupling. Co-culture of ER stressed donor cells with ER stress-naïve recipient cells resulted in intercellular transmission of stress signals leading to impairment in the ER function (‘bystander response’). The propagation of ER stress required cell-cell contact, and genetic suppression of Cx43 prevented the transmission of ER stress from donor to recipient cells. In accordance with the in vitro cellular model, we observed that diet-induced obesity resulted in hepatic ER stress and upregulation of Cx43 in the liver. Remarkably, mice lacking Cx43 specifically in the liver were protected from HFD-induced liver ER stress, insulin resistance, glucose intolerance and NAFLD. Importantly, hepatocytes from HFD-fed mice were able to transmit ER stress to intact hepatocytes from lean mice in a Cx43dependent manner. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling may cause tissue propagation of ER stress. This novel maladaptive response to over-nutrition exacerbates ER stress in the liver, promoting fatty liver disease and impairing whole-body glucose metabolism. Given the strong evidence that increased ER stress in obesity plays a key role in the pathogenesis of metabolic dysfunction, interfering with Cx43-mediated cell-cell coupling in hepatocytes may block tissue propagation of ER dysfunction and thus represent a novel approach to alleviate fatty liver disease, systemic insulin resistance and abnormal glucose homeostasis.

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PUBLICATION HIGHLIGHTS

Cardiolipin Deficiency in Barth Syndrome Is Not Associated with Increased Superoxide/H2O2 Production in Heart and Skeletal Muscle Mitochondria Renata L.S. Goncalves, Michael Schlame, Alexander Bartelt, Martin D. Brand, Gökhan S. Hotamışlıgil FEBS Letters, October 2020 https://doi.org/10.1002/1873-3468.13973

Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in the gene tafazzin (taz). Taz is an enzyme important for the remodeling of cardiolipin, a phospholipid uniquely localized in the mitochondria. The loss of cardiolipin in the mitochondrial membranes causes severe heart and skeletal muscle disease. The production of mitochondrial oxidants has been implicated in the cardiomyopathy in BTHS and in many other conditions of metabolic pathology. In general, oxidants are examined as one entity, although in the mitochondria, eleven different sites can produce these oxidant molecules at significant rates. Which of these sites generate oxidants at excessive

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or abnormal rates in BTHS and in most metabolic diseases is unknown. In this study, we measured the mitochondrial oxidants production from each of these sites in the heart and skeletal muscle of a mouse model of BTHS, the tafazzin knockdown mice (tazkd). Despite manifesting the disease’s symptoms, we did not find differences in mitochondrial oxidant production between the tazkd mice and their normal wild type littermates. Therefore, our study raises questions about the involvement of mitochondrial oxidants in BTHS pathology and illustrates the importance of detailed, individual examination of oxidative species.


PUBLICATION HIGHLIGHTS

Aberrant Ca2+ Homeostasis in Adipocytes Links Inflammation to Metabolic Dysregulation in Obesity Ekin Güney, Ana Paula Arruda, Güneş Parlakgül, Erika Cagampan, Nina Min, Yankun Lee, Lily Greene, Eva Tsaousidou, Karen E. Inouye, Myoung Sook Han, Roger J. Davis, Gökhan S. Hotamışlıgil BioRxiv, October 2020 https://doi.org/10.1101/2020.10.28.360008

Chronic metabolic diseases including obesity, insulin resistance, diabetes, and atherosclerosis are the greatest threats to human health. The importance of proper metabolic balance has also become vividly apparent during the COVID-19 pandemic and they present the most important risk factor for disease severity and death. A key mechanistic link between these disease states comes from the immunometabolic dysregulation that is a central characteristic of metabolic pathologies. Earlier studies in our group demonstrated that chronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes. While the importance of chronic metabolic inflammation, or metaflammation, for metabolic disease is well established, there are important gaps in the mechanisms by which metabolic stress or obesity initiates and propagates this abnormal immune response, particularly in the adipose tissue. Also unclear is the integration of various known stress and inflammatory signals to impact metabolic properties of adipocytes. In this work, we show that in adipocytes, altered regulation of the intracellular calcium handling is a key, adipocyte-intrinsic event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. This discovery was inspired by the

observation that in the context of metabolic stress and obesity, there is an abnormal increase in the expression and activity of a calcium channel called IP3R in adipocytes. We also showed that inflammation, either induced by cytokines in cells or by obesity in mice, is responsible for this abnormality. The increased expression of IP3Rs results in increased cytosolic calcium signaling and impaired insulin action. Interestingly, the link between these mechanisms involved activation of a stress signaling enzyme called JNK, which we have shown in earlier studies to be critical to systemic insulin resistance and glucose intolerance. When JNK activity is blocked, the obesity-induced abnormal increase in IP3Rs can be prevented in both adipocytes in culture or in adipose tissue. Finally, we tested whether directly targeting this mechanism can be used to prevent obesity and associated pathologies. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic calcium is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte calcium homeostasis may offer new therapeutic opportunities against metabolic diseases, including human obesity.

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PUBLICATION HIGHLIGHTS

High Resolution 3D Imaging of Liver Reveals a Central Role for Subcellular Architectural Organization in Metabolism Güneş Parlakgül, Ana Paula Arruda, Erika Cagampan, Song Pang, Ekin Güney, Yankun Lee, Harald F. Hess, C. Shan Xu, Gökhan S. Hotamışlıgil BioRxiv, December 2020 https://doi.org/10.1101/2020.11.18.387803

The functional diversity of the cells allows responses to changing environment and proper adaptation and survival. In particular, certain metabolic cells, such as hepatocytes, exhibit a wide array of metabolic functions, and in addition to very high capacity for protein production and secretion, they can alter glucose and lipid metabolism to adapt to environmental and nutritional challenges. These, of course, include physiological responses, such as feeding and fasting, and pathological alterations such as the case in obesity and associated metabolic problems. In hepatocytes, this rich functional repertoire is accompanied by a very complex and pleitrophic constellation of architectural features of the subcellular structures. Whether and how these structural features are regulated during metabolic challenges and whether they themselves are a determinant of metabolic output is not understood and represents a critical area of investigation in the field. In this study, we have conducted a deep exploration of the subcellular architecture of organelles in liver tissue, in the native environment of hepatocytes and related architectural regulation to function. In order to obtain a detailed 3D information of the endoplasmic reticulum’s (ER’s) structural organization and morphology in a hepatocyte under physiological and pathological states, we utilized enhanced Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) imaging, a technique that has the highest spatial resolution and the advantage of large tissue imaging. Using this approach, we were able to image, segment and quantify intracellular

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organization of intact liver volume, containing around 20 full or partial hepatocyte volumes. These platforms allowed us to visualize inside and through the organellar constellations of the liver cells. Our analysis included 22,035 tissue sections, annotations and segmentation of 16TB of information using machine learning and neural networks in a volume of 935,495 cubic microns containing 1.82 trillion voxels. This work was possible through a multidisciplinary collaboration and the talented graphic art team of Refik Anadol Studios for the construction of video tours inside the cells at an unprecedented resolution. Through this analysis, we observed that obesity, which is a well-established condition of organelle dysfunction in experimental models and in humans, leads to a striking remodeling of ER structure with a marked alteration in ER sheets and tubules. We also substantiated these findings with an array of biochemical and fluorescence imaging approaches. We then tested whether re-structuring of the ER closer to its native configuration could be achieved through the use of membrane shaping proteins and examined the functional consequences in vitro and in vivo. These experiments provided striking results and showed that by simply regulating structure, the function of the ER can be restored in obesity at a cellular level with systemic repercussions. Experimental restoration of ER sheets in obesity resulted in marked improvement in systemic metabolic homeostasis. Hence, subcellular architecture is a critical rheostat of metabolic function and its regulation is a key determinant of health and disease.


PUBLICATION HIGHLIGHTS

BRIDGING KNOWLEDGE THROUGH COLLABORATION The Unfolded Protein Response Regulates Hepatic Autophagy by sXBP1-Mediated Activation of TFEB

Adipocytes Promote Interleukin-18 Binding to Its Receptors During Abdominal Aortic Aneurysm Formation in Mice

Zeyuan Zhang, Qingwen Qian, Mark Li, Fan Shao, Wen-Xing Ding, Vitor A. Lira, Sophia X. Chen, Sara C. Sebag, Gökhan S. Hotamışlıgil, Huojun Cao, Ling Yang

Cong-Lin Liu, Jingyuan Ren, Yunzhe Wang, Xian Zhang, Galina K. Sukhova, Mengyang Liao, Marcela Santos, Songyuan Luo, Dafeng Yang, Mingcan Xia, Karen E. Inouye, Gökhan S. Hotamışlıgil, Guanyi Lu, Gilbert R. Upchurch, Peter Libby, Junli Guo, Jinying Zhang, Guo-Ping Shi

Autophagy, June 2020

European Heart Journal, July 2020

Defective autophagy and endoplasmic reticulum stress contribute to obesity-associated metabolic dysfunction, although the mechanisms linking these pathways remain completely understood. In this study, systematic examination of the targets of these pathways pointed to the regulation of a transcription factor, TFEB, a master regulator of autophagy and lysosome biogenesis. Collectively, our data provide novel insight into how two organelle stress responses are integrated to protect against obesityassociated metabolic dysfunction.

It is well recognized that obesity is a risk factor of abdominal aortic aneurysm (AAA) but the mechanisms remain enigmatic. In this study, a mechanism is proposed through the increased binding of IL18 to its receptors demonstration of regions enriched in adipocytes or adjacent to perivascular adipose tissue. Two additional adipokines, leptin and FABP4 were also essential in regulating these interactions demonstrating a critical role for adipose tissue inflammation and adipokines in driving vascular abnormalities such as AAA in obesity.

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CREATING A GLOBAL COMMUNITY THROUGH

SCIENCE


...BY PREPARING FOR THE FUTURE In our ongoing fight against the greatest threats to human health worldwide, metabolic diseases, we continue to support global scientific development through supporting young scientists and by bridging knowledge gaps through our research and collaborations.


NEXT GENERATION OF SCIENTISTS

BENJAMIN GARFINKEL, PhD Postdoctoral Fellow

Q. What

brought you to the knowledge that a career in research is something you wanted to pursue?

This is a great question. In fact, a scientist was the one thing I knew as a child that I did not want to be when I grew up. My father was a scientist, and I wanted to rebel. However, when the time came to choose a major in school, I somehow found myself naturally pulled into life sciences. My initial exposure to scientific research was as an undergraduate student in the lab of Professor Joseph Orly at the Hebrew University of Jerusalem in Israel, and as is often the case, my original project rapidly evolved into new and exciting directions. By the time I graduated, I was hooked.

Q. Did

you have particular hurdles, barriers, or challenges along the way?

The first major hurdle that I encountered on my scientific journey was my father’s diagnosis with pancreatic cancer and his passing a few months later. This occurred during my first year as an undergraduate student, just as I was preparing to start work in a lab. This was a significant blow, as my mother had also died of cancer eight years earlier. I think that this personal close encounter with untreatable illness acted to further solidify my resolve to work in biomedical research. On a more day-to-day level, I believe that a scientist’s career is fraught with challenges simply by virtue of the unpredictable nature of working with experiments. More than once I have found myself having to accept that a hypothesis I was excited about proved to be utterly wrong. However, this means that when I get things right, it’s extra sweet!

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Q. What

attracted you to join the Hotamışlıgil Lab at the Sabri Ülker Center?

I had heard great things about the Hotamışlıgil Lab from colleagues in Israel when I was looking for a top-notch lab doing metabolic research for my postdoc. It was recommended to me as an excellent place to perform cutting-edge research at the interface between metabolism and immunology, a field in which I was interested in developing. I interviewed at a number of leading labs in the Boston area, but thankfully I had no difficulty in choosing. The research being performed in all of these labs was unique and fascinating, but in none of them did I encounter the lab culture that permeated the Hotamışlıgil Lab. Even as a candidate, I felt so welcomed that I wanted to return as soon as possible. Q. Are

there particular scientific questions that motivate you?

There are many, and they are constantly changing. Throughout my career so far, I’ve allowed myself to be led by my experimental results from question to question. I approach scientific research like a scavenger hunt— each time I solve a riddle, my reward is another riddle, another challenge. This is exhausting, but never boring! At the moment, I am driven by the question of how the pancreas copes with the immense burden of producing large amounts of digestive enzymes every morning when we wake up. Paradoxically, making so much protein can be harmful for the pancreatic cells, and I am trying to elucidate the defense mechanisms utilized by these cells to allow us to continue eating and digesting peacefully.


NEXT GENERATION OF SCIENTISTS

HATOON BAAZIM, PhD Postdoctoral Fellow

Q. What

brought you to the knowledge that a career in research is something you wanted to pursue?

There wasn’t a particular moment of revelation for me. I was an explorative and adventurous child and liked reading and watching documentaries. Over time, biology became the topic that engaged and fascinated me the most, particularly molecular biology. Conceptualizing biology on a molecular level engages an almost abstract level of thinking and it heightened my awareness of the dynamic nature of life. Each cell, each molecule, can seem to take on a life of its own. It really changed the way I think about the world around me.

Q. Did

you have particular hurdles, barriers, or challenges along the way?

I was born and raised in Saudi Arabia’s capital, Riyadh, where I did my undergraduate studies in Biochemistry. I then moved to the west coast of Saudi to pursue a master’s degree in Bioscience. For my doctoral studies, I moved to Vienna. There were of course several challenges that I had to overcome to be where I am now, many were cultural. I come from a very well-educated family who’s always supported me. But, it was understandably difficult for them to cope with my choice to leave the family nest on my own as a single woman and live so far away from home. In the end, my family believed in me enough to continue their support, and I try my best to make them proud. Being from a minority, perhaps even a minority within minorities, both at work and in everyday life comes with its own set of challenges. It can be very difficult to not have a community with whom I share a language and a true understanding of my culture with all its nuances. Moreover, there are many

misconceptions and prejudices that people have about Arabs and people from the Middle East that can lead to behaviors and comments that can be very alienating or sometimes offensive.

Q. What

attracted you to join the Hotamışlıgil Lab at the Sabri Ülker Center?

I knew of Dr. Hotamışlıgil as one of the world’s leading figures in immunometabolism. I was very impressed by the scientific rigor of the research done in his lab and the range of experimental approaches and the elegance of how molecular mechanisms were linked to physiology and vice versa. The lab members bring together a very solid and diverse range of expertise and work in a very collaborative manner, creating a wonderful social atmosphere. I was quickly able to connect with many of the lab members on a personal level. I could really not ask for better colleagues.

Q. Are

there particular scientific questions that motivate you?

My research interest focuses on understanding the regulatory principles by which the adipose tissue responds to infection and influences pathophysiology and immune responses. I’m particularly interested in examining infection models in which the adipose tissue undergoes excessive depletion of its energy stores, such as the case during anorexia and cachexia. There are many aspects of the adipose tissue biology that we do not yet understand, making it a very rich ground for exploration, both functionally and architecturally, that I plan to pursue.

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NEXT GENERATION OF SCIENTISTS

THE COMMITMENT TO THE FUTURE OF SCIENCE As part of our commitment to provide opportunities for young scientists who are early in their careers, the Center brings in research assistants who have completed their bachelor’s degrees and are interested in pursuing additional training that would lead to further education. Dr. Lisa Rickey is an outstanding example of one such research assistant who went on to become a physician.

Q. What

brought you to the knowledge that a career in medicine is something you wanted to pursue?

My journey to become a physician began at an early age. My love for physiology and the human body was first sparked in a 7th grade biology class when we learned about the circulatory system—such an elegant system design with a complex and dynamic role in the body. Because of this, for a time I thought I would become a cardiac surgeon! Over time my interests expanded to include education and advocacy, and I sought to intervene on health early to (hopefully) alter the trajectory of illness over a lifetime. Altogether, with a natural affinity for our tiniest humans, I found my calling in Pediatrics. Q. Did

you have particular hurdles, barriers, or challenges along the way?

The decision to pursue a career in medicine, although it felt very natural, was not one I made lightly. I often questioned if the path I had set myself on at the age of 11 was the one I truly wanted to follow. In fact, I actively searched for an alternative career that would spark the same excitement in me; I failed miserably. As a woman in medicine, I knew there would be sacrifices that I would be asked and required to make for my career. Fortunately, I have been lucky to have incredible mentors and role models along the way that have helped me to navigate the challenges I have faced during my career thus far. Q. What

attracted you to join the Hotamışlıgil Lab at the Sabri Ülker Center?

I was drawn to the Hotamışlıgil Lab’s mission to explain the disease mechanisms in diabetes, obesity, and metabolic syndrome, which are such significant public health crises.

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LISA M. RICKEY, MD Hotamışlıgil Lab Alumna, Currently Hospital Medicine Fellow, Boston Children’s Hospital, Harvard Medical School

I was especially excited to learn from a group with so many basic as well as clinical scientists who provided a clinical context to our basic science work and did so in such a wonderful collaborative and inclusive atmosphere. As a young research assistant bridging my career into clinical medicine, it was an incredible experience to participate in the translational efforts of the Hotamışlıgil Lab team to search for solutions to these complex and pervasive diseases. Q. Are

there any particular scientific questions that motivate you? My research interests have now transitioned to a clinical setting where I am focused on quality improvement in patient safety. Specifically, my research focus is to improve early recognition of clinical decompensation in hospitalized children with acute illnesses and to improve our systems for escalation of care in those circumstances.

THE PATHWAY TO SCIENCE

In 2020, two of our research assistants began similar pathways—Carla Julieta Dominguez Gonzalez matriculated at Duke University School of Medicine and Lily Greene at the Geisel School of Medicine at Dartmouth.


NEXT GENERATION OF SCIENTISTS

SABRİ ÜLKER METABOLIC RESEARCH CENTER WELCOMES NEW FACULTY Dr. Kory’s laboratory combines functional genomics, metabolite profiling, imaging, cell biology, and biochemistry approaches to address these questions at the molecular and physiological levels and determine how mitochondrial transport is altered in disease. The goal of Dr. Kory’s laboratory is to use mitochondrial transport proteins as tools to interrogate metabolic and signaling pathways to understand how mitochondria perform their roles in maintaining metabolic homeostasis.

NORA KORY, PhD Assistant Professor, Molecular Metabolism Sabri Ülker Center

Nora was born in Heidelberg, Germany. She received her BSc and MSc degrees in Chemistry and Biochemistry from Ludwig-Maximilians University in Munich. During her PhD at Yale University, she focused on mechanisms determining lipid droplet protein composition. Her postdoctoral studies with David Sabatini at the Whitehead Institute for Biomedical Research, and Massachusetts Institute of Technology led her to use functional genomics to identify and investigate the role of mitochondrial metabolite transporters in metabolism. Dr. Kory is the recipient of a Pathway to Independence Award from the National Institutes of Health.

Dr. Hui’s research focuses on understanding metabolism with a quantitative and systems approach. Specifically, he integrates isotope tracing, mass spectrometry, and quantitative modeling to determine metabolic fluxes in important animal models. Fluxes are the most fundamental functional property of metabolism. Their systematic quantification holds the potential to understand important metabolic diseases. With this approach, Dr. Hui will focus on diseases with altered energy metabolism, including obesity and cachexia, with the longterm goal of revealing the mechanisms of body weight control and developing treatment strategies for these diseases. Dr. Hui received a BSc and an MPhil in Physics, both from Hong Kong Baptist University, and a PhD in Biophysics from the University of California, San Diego. He completed postdoctoral work in the Lewis-Sigler Institute for Integrative Genomics at Princeton University. Dr. Hui is the recipient of a Pathway to Independence Award from the National Institutes of Health.

TONY HUI, PhD Assistant Professor, Molecular Metabolism Sabri Ülker Center

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COMMUNITY ENGAGEMENT

EXTENDING OUR IMPACT BEYOND THE BENCH It’s not always easy for students to imagine the realities of a career in academic research or for adults to keep up with the rapidly changing world of scientific research. Drs. Garfinkel and Tsaousidou take time to engage with communities through mentoring and learning opportunities.

Sharing science and research through publications is only one way the Hotamışlıgil Lab works to address important issues in public health. Contributions from research have the potential to significantly impact the quality of health and life. Sharing the discussion and exploration of science and research has another benefit—building bridges to connect with different groups in our community. Members of our lab—Benjamin Garfinkel, PhD and Eva Tsaousidou, PhD—have been engaging with the young student and senior communities, extending our impact beyond the bench. For each of them, being able to share their scientific understanding is a gift not only to those with whom they interact, but also to them as ambassadors of knowledge from the Sabri Ülker Center. Over the last three years, Dr. Garfinkel has been organizing lectures for senior citizens on scientific topics, such as “The Involvement of Our Immune System in Heart Disease”. Dr. Garfinkel has spoken to a number of senior communities in the Boston area, as well as groups of volunteers in projects such as the Boston ABCD Foster Grandparents program. “I believe,” he said, “that especially these days, a major issue for senior citizens is loneliness, and feeling left behind. So, I thought that they may be interested in an opportunity to gather together and learn something that is cutting edge from a Harvard scientist.”

“It was a great experience. Dr. Tsaousidou responded with great willingness and gave important information about the science she advocates. Our students were thrilled with her immediacy and communication skills. Excellent scientist and human being” General High School of Skiathos

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COMMUNITY ENGAGEMENT

ÜLKER CENTER LECTURES Gökhan S. Hotamışlıgil January 2020 Grand Rounds Lecture, Thomas Jefferson University Philadelphia, Pennsylvania “Architectural Regulation of Endoplasmic Reticulum in Health and Disease” Keeping up with the rapidly changing world of scientific research can be overwhelming to a lay audience. Dr. Garfinkel strives to break complex ideas into manageable concepts, accessible to a lay audience. Providing these talks onsite, in the various communities where seniors live, allows for a comfortable, familiar atmosphere that encourages better understanding. One of the community center coordinators, Laura Baber, shared that, “it is so engaging and fulfilling for those living in our [assisted living] community as they age to be connected with what is happening in science. Having the personal connection with Dr. Garfinkel makes it so special too.” Another scientist from the Sabri Ülker Center, Eva Tsaousidou, PhD, is a member of a virtual mentoring platform, 100mentors, built to connect students to researchers and experts around the world. This program aims to empower students at an early stage to be proactive and help them to decide their own future career path by exposing them to scientists from many countries. Through this platform, Dr. Tsaousidou has been invited to give lectures in her area of expertise to a number of grade school groups. It is not always easy for students to connect with a scientist or imagine the realities of a career in academic research. “So,” Dr. Tsaousidou says, “my goal is twofold. First, to answer scientific questions that they might have and could be harder for them to find the truth on their own. And to serve as an example of a female scientist from a modest socioeconomic background who reached for her dreams, showing them it is not impossible to find one’s path.” From her own experience, Dr. Tsaousidou realized that early mentoring is important, that it is essential to provide students with information about career paths even before they decide what to study. A mentor can be vital to success. Learning from a mentor’s experience can help prepare individuals for challenges they may face and also offer a chance to build their confidence by providing support. Science requires hard work, dedication, and most importantly, perseverance. Dr. Tsaousidou notes that she, “was blessed to have excellent mentors throughout my scientific life, and now I am excited to be in a position to give something back to the community and next generation of scientists!”

May 2020 Open Public Colloquium, Kadir Has University Istanbul, Turkey “Energy and Defense in Biological Systems”

August 2020 International AIM eSymposium on Metabolism, Center of Biomedical Research Excellence at the University of New Mexico School of Medicine Albuquerque, New Mexico “Organelle Structure and Function in Metabolic Adaptation”

October 2020 Keynote Speaker, European Atherosclerosis Society 88th Congress Geneva, Switzerland “Foundations of Immunometabolism and Implications for Metabolic Health and Disease”

November 2020 90th Anniversary Symposium of the Sigrid Jusélius Foundation Helsinki, Finland “Organelle Function in Metabolic Homeostasis

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CELEBRATING 25 YEARS OF THE HOTAMIŞLIGİL LAB

25TH ANNIVERSARY OF HOTAMIŞLIGİL LAB In the earliest days of my career, my close friend and mentor, Dr. Armen H. Tashjian, Jr., instilled in me that excellent science is paramount for advancement. In order to tackle the greatest public health problems, we need to start with basic science; we need to understand the mechanisms, to model them, and to translate them, in order to eventually resolve them. It is this model that has provided the foundation for my work from the beginning: to understand, model, and translate scientific problems to make meaningful connections and build scientific knowledge and community, and dream solutions to improve the well-being of humans. This idea of developing deep scientific understanding and community building has driven my efforts from the beginning and is what I hope to inspire in the members of my lab and in our Center. The last 25 years have been full of amazing and lifechanging experiences, discoveries, challenges, failures, and some advancement toward our goals. The most gratifying aspect of this quarter century, however, has been the

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privilege of working together with a large group of young scientists, participating in their training and advancement, and witnessing their tremendous contributions to the science of metabolism and immunometabolism in many parts of the world. In science, we celebrate diversity and inclusion and we unite around a common goal to solve the most intractable problems and make a positive contribution to human experience. This year especially brought to us all a uniquely challenging and demanding set of circumstances and an enormous level of stress and emotional turmoil. However, our lab, members of our Center, the scientific community, and the world are once again united and have worked diligently to support one another for the benefit of global health. I am grateful for the last two and a half decades and for the support and engagement of the community of brilliant scientific minds that we have built and look forward to the promise of what we will create that advances our progress, with the hope of welcoming healthy days in the very near future.


Nutrient, Genetic, and Metabolic Research

Nutrient, Genetic, and Metabolic Research

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 NUTRIENT, GENETIC, and METABOLIC RESEARCH Follow us: @sabriulkerctr

Profile for sabriulkercenter.harvard

Annual Report 2020  

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