2020 Physiology Matters

2020 Molecu lar & I n te g ra ti ve Physi o l o g y

PHYSIOLOGY MATTERS

When Science Meets Art: "Take a minute to marvel..."

Arranging Fat: UM Bioartography pg.8

Contents

Spotlight On Research pg. 06

Partners In Scientific Discovery & Responsible Research pg. 14

Too Much And Not Enough pg. 16

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Physiology Matters

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From The Chair

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Physiology By The Numbers

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Arranging Fat: UM Bioartography

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A Closer Look at Lipodystrophy

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MS In Physiology

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Louis G. D’Alecy Professorship Of Physiology

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MIP's Secret Weapon

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Fat Cells As Heroes

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Physiology 415: Leading By Teaching

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Metabolomics

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Postdoctoral Fellows Spotlight

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When Tears Flow In Science

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Big Shoes To Fill

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Hello From The Other Side

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PhD Graduates

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In Memoriam

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William H. Howell

Meet The Editors Becky Schill is a 3rd year post-doctoral fellow in the laboratory of Dr. Ormond MacDougald. Becky’s research is focused on the role of glucocorticoids in bone marrow adipose tissue expansion following caloric restriction. Her work has also recently expanded to using single-nuclei RNA sequencing to profile the transcriptome of bone marrow adipocytes in hopes of better understanding the role of these adipocytes in bone health and overall physiology. Outside the lab, Becky enjoys baking, gardening and spending time with her 1 year old son, Jake.

Carolyn Walsh is a 1st year postdoctoral fellow in the lab of Dr. Ormond MacDougald. She is investigating the mechanisms that cause lipodystrophy, a rare disease in which patients lose their adipose tissue. When she’s not at work, she enjoys biking, reading, yoga and spending time with loved ones.

Jess Maung is a 1st year rotating Molecular and Integrative Physiology PhD student. Her research interests involve obesity, diabetes, adipose tissue biology, and sex differences in disease. Jess is from Portland, Oregon and graduated from Union College in upstate New York in 2018. She is passionate about equity and inclusion in STEM, and in her free time loves to play tennis, go camping, and bake bread.

Sarah Lawson has been working in the department of Molecular & Integrative Physiology for 16 years, in an Administrative Assistant position. In her time outside of work, Sarah enjoys volunteering within her community, spending time with family and running to and from various activities with her daughters, Olivia and Emily.

Zeribe Nwosu is a 3rd year postdoctoral fellow in the laboratories of Dr. Costas Lyssiotis and Dr. Marina Pasca di Magliano. His work focuses on understanding how pancreatic cancer cells ‘feed’ and how the surrounding immune cells influence the tumor feeding and growth processes. His research goal is to identify ways to block the tumor nutrient ‘supply chain’ in order to achieve effective treatment for pancreatic cancer patients. Outside the lab, he likes to play soccer and to follow news and politics.

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From The Chair Dear Readers, Greetings from the beautiful city of Ann Arbor.

As the seasons change, I have been reflecting on the remarkable ups and downs of the last twelve months. Last spring, we were in a near-total lockdown with only essential research taking place on campus. Our students were sent home, and all our teaching activities were conducted online. In the Fall, thanks to the painstaking work of many staff members and academics throughout the university, we welcomed back cohorts of both PhD and MS students. We adopted both in-person and online teaching and resumed research, while containing the spread of coronavirus. It was impressive to see how our faculty hastened the integration of emerging technologies for teaching and running their research programs remotely. I am extremely proud of how the University of Michigan Physiology Family looked out for one another and the various ways we as biomedical scientists are contributing to the global effort to combat COVID-19 and other diseases.

This past year, our two main objectives have been to protect the health of our faculty, scientists, students, trainees and staff, while protecting our missions of research and teaching. Although it has been a difficult year, and many of us have suffered in myriad ways, many achievements have been made. We have learned new ways of working remotely, implemented asynchronous pedagogic techniques, and have engaged with more alumni than ever before. We must hold on to those insights as we return to normalcy.

The pandemic has had devastating consequences for our national society and for the world. Historians and social scientists are arguing about the profound consequences of the SARS-CoV-2 pandemic and how societies might be affected in the future. There is, however, something that cannot be denied: ideas once imagined as long-term projects are now treated as achievable aims! Early on, there was much doubt over the prospect of a vaccine; it can take over 10 years to develop an effective vaccine. However, now, in the span of just 10 months, we have six working ones. The scientific successes in our fight against SARS-CoV-2 and COVID-19 are renewing hopes around long-elusive goals of treating diseases we once considered impossible to cure. The same creative catalyst that saw the vaccine rolled out at breakneck speed without compromising the rigorous analysis is active across our academic enterprise. I am glad that research groups at University of Michigan are actively working collaboratively to combat SARS-CoV-2 and investigate the physiological mechanisms of COVID-19; this includes some of our laboratories in the Department of Molecular & Integrative Physiology.

While navigating the pandemic, we have continued to prioritize efforts to remain one of the top physiology departments in the world through outstanding contributions to research, education and service. Accordingly, there is much more to be thankful for as we continue to develop the Physiology at Michigan. For example, we have regained our status as the top NIH funded physiology department in the nation. Further, in the 2020 edition of PHYSIOLOGY MATTERS, we

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transferred the editorial control of our newsletter to graduate students and postdoctoral fellows, thus giving them the unique opportunity of interacting with members of the Physiology family. Reflecting on these developments, I am very excited and optimistic about the future.

As a department, we will continue focusing on the well-being of our trainees, faculty and staff as we start slowly transitioning back to full-time, in-person research and educational activities over the next year. If you wish to support our philanthropy efforts, we are asking for your contributions in two areas. The first is our Physiology Annual Fund, which allows us to direct resources where they are most needed as we emerge from COVID-19. The second is our MS, PhD and Postdoctoral Education Funds, which enables us to support our domestic and international students from all backgrounds and working in any area of physiology.

On a personal note, I want to thank all members of the Physiology family for the support over the last four years of service as interim department chair. After a national search for the permanent chair of our department, Dr. Marschall Runge (Dean, Medical School) and Dr. Steve Kunkel (Vice Dean for Research, Medical School) has given me the privilege to serve as the permanent chair of our department. I am humbled and grateful to all of you for your support throughout this process and will do my utmost best to carry the enormous responsibility that comes with the Chair’s office.

It is impossible to overstate the full historical importance and consequence of serving as the chair of a department that has been in existence since 1882. Physiology at Michigan has played a central role in nurturing generations of physiologists through its research, mentoring and education, and service opportunities. Together, we will continue recruiting exceptional faculty, developing new research and educational programs, and pioneering initiatives to advance and promote the careers of all our department members. The department has been effective because of its large, active and engaged membership at all levels, from undergraduate researchers just starting to emeritus faculty members, alumni and friends.

I am delighted to continue to work with you and share the responsibility of championing our department’s history as well as its future, so that successive generations may inherit the grit, collegiality and substance that has made our department what it is today.

Yours faithfully,

Santiago Schnell Chair, Department of Molecular & Integrative Physiology John A. Jacquez Collegiate Professor of Physiology

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Spotlight On Research

CENTRAL AUDITORY CONTROL Pierre Apostolides, PhD

Decades of research show that the central auditory system is not simply organized in a linear, hierarchical manner, but rather contains many feedback loops: “high-level” brain regions such as the auditory cortex send information back down to almost every auditory circuit in the midbrain and brainstem, which are "low-level" brain regions important for encoding raw sound features such as amplitude and frequency. By contrast, the auditory cortex is generally thought to encode behaviorally relevant, abstract sound features, such as a speaker's voice in a noisy environment. Consequently, it has long been suspected that descending cortical pathways are important for auditory cognition, such as following a conversation at a cocktail party. However, their precise role in hearing remains quite speculative. We are adCIRCADIAN dressing this knowledge gap using high resolution microscopy techBIOLOGY niques in behaving mice. These approaches quite literally enable Lei Yin, PhD us to see the activity of specific descending auditory pathways The molecular clock system governs circadian as mice learn and engage in auditory-guided behaviors. Our rhythms of physiological activities in humans. Malfuncresults are therefore shedding light on a critical yet poorly tioning of circadian rhythms in modern society has been imunderstood facet of the central auditory system. More plicated in the pathogenesis of many chronic human diseases, broadly, similar descending cortical pathways are including diabetes, fatty liver diseases, cancer, and atheroscleroseen across all sensory systems, like vision and sis. However, how circadian dysfunction contributes to the onset and olfaction. These studies thus lay the concepprogression of these chronic diseases remains largely unknown. The tual groundwork to understand a general current research programs in my laboratory focuses on (1) the function principle of mammalian sensory perand regulation of liver (hepatocyte) circadian clock in metabolic homeoception and higher-order brain stasis and stress responses using both diet-induced non-alcoholic liver integration. disease and alcoholic liver disease models; (2) uncovering novel regulators of the stability and degradation of key clock proteins in the liver. One of our major findings is that the hepatocyte circadian clock protects mice against alcohol induced liver steatosis (fatty liver disease) and hepatocyte injury (Hepatology 2018). We also discovered critical roles ELIZABETH of the circadian protein CRY1 in gluconeogenesis WEISER CASWELL and fructose-induced lipogenesis (Diabetes DIABETES INSTITUTE 2018; Metabolism 2020). We believe In June 2020, the University of Michigan received a that elucidation of the molecular transformative gift of $30M from University of Michigan clock actions under pathological Regent Ron Weiser to establish a state-of-the-art institute conditions will help prevent or focused on diabetes and related disorders. The Elizabeth treat chronic metabolic Weiser Caswell Diabetes Institute (EWCDI) is named to honor liver diseases.

Regent Weiser’s daughter, a leading advocate for type 1 diabetes.

The purpose of the EWCDI is to provide leadership, coordination and resources to accelerate diabetes-related clinical care, research and education at the University of Michigan (U-M). By integrating innovative diabetes care with world class clinical research and informatics infrastructure, the EWCDI is well positioned to advance clinical care and research at an extremely high level. The institute is also fully committed to the training and mentorship of trainees, faculty and staff who are dedicated to the treatment of and research on diabetes, diabetic complications, obesity and other metabolic disorders. Director Martin G. Myers, Jr., MD, PhD, and Managing Director Dorene Markel, MS, MHSA, provide the Elizabeth Weiser Caswell Diabetes Institute with the organizational and administrative leadership to support and coordinate the many diabetes related programs at U-M. The EWCDI unites with other diabetes programs and educational facilities at the local, regional, national and international levels. The Institute performs outreach to connect with patients, families and the community to increase the impact and visibility of diabetes related programs at U-M and to assist in the design of new programs ensuring a holistic approach to caring for those with diabetes. By supporting rigorous science and its integration with patient-centered clinical care, the Elizabeth Weiser Caswell Diabetes Institute leads the way to prevent, treat and cure diabetes, its complications and related metabolic diseases. To learn more about the Elizabeth Weiser Caswell Diabetes Institute visit www.

MichiganDiabetes.org.

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Arranging Fat: UM Bioartography

Callie A.S. Corsa, PhD Scientific Writer, JB Ashtin; Former Postdoctoral Fellow, Molecular & Integrative Physiology

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ave you ever looked through the microscope and been amazed at what you saw? As scientists who do this routinely, we may take it for granted, but microscopic images are often complex, intriguing, and beautiful. The UofM BioArtography program was developed to collect artistic scientific images and share them with the greater public community to spark curiosity and spread scientific knowledge.

In 2019, during my postdoc in the lab of Dr. Ormond MacDougald, I was analyzing several H&E-stained slides from various organs while phenotyping a novel mouse model we developed when I noticed something very strange under the microscope. These mice had almost no body fat (white adipose tissue), very few adipocytes in their bone marrow, and very abnormal brown adipose tissue, so we also took a close look at their skin to see if the dermal adipose tissue was affected. Consistent with our hypothesis, we saw a huge reduction in the number of dermal adipocytes in these mice. As I looked closer, I also noticed some very strange characteristics in the layers of the skin.

The dermis and epidermis were significantly thicker compared with control mice, and the hair follicles were huge and abnormally shaped.

This mouse model was created to mimic the most common inherited partial lipodystrophy, familial partial lipodystrophy type 2 (FPLD2). FPLD2 is characterized by a progressive loss of adipose tissue and the development of lipodystrophy-related diabetes and non-alcoholic fatty liver disease. FPLD2 is known to be caused by mutations in the LMNA gene, but the traditional methods that researchers use to study a disease caused by genetic mutations in people – looking at what happens to cultured cells or mice with those same mutations – hasn’t worked well with FPLD2. Examinations of cultured cells with dysfunctional or absent LMNA have yielded conflicting results (1), (2), and a LMNA mutation that causes dramatic disease in humans produces very mild effects when overexpressed in the fat cells of mice.(3) In order to study this condition in mice, we created an entirely new mouse model in which an important functional region of the LMNA gene was deleted specifically in adipocytes.

The lipodystrophic phenotypes observed in these mice beautifully mimicked the human FPLD2 adipose tissue

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loss, but why would the skin be severely affected when the genetic deletion was only targeted to adipocytes?

The subcutaneous white adipose tissue from these mice also had a very strange morphology, with the appearance of dense fibrotic tissue between the cells and mild hyperplasia of the mammary epithelial cells.

We consulted multiple pathologists to figure out what was happening in the tissue, but none of them could explain what we saw – though they all agreed it was incredibly odd. We still have no idea what caused these strange phenotypes in the skin, but it made for some very interesting images!

By sharing this image, we would like to promote awareness of rare diseases and the lack of available therapies, along with showcasing the beauty of the microscopic world. The next time you’re looking through the microscope, take a minute to marvel at the beautiful details you’re viewing, and consider sending a few of your images to UofM Bioartography! • 1. Boguslavsky et al., Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 15(4): 653-663, 2006.

2. Oldenburg et al., Deregulation of Fragile X-related protein 1 by the lipodystrophic lamin A p.R482W mutation elicits a myogenic gene expression program in preadipocytes Hum Mol Genet 23(5): 11511162, 2014.

3. Wojtanik et al., The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation J Lipid Res 50(6): 1068-1079, 2009.

Visit http://www.bioartography.com to view a collection of art for purchase. Please use discount code MIP at checkout for 15% off, valid through 6/30/21.

A Closer Look at Lipodystrophy Carolyn M. Walsh, PhD Postdoctoral Fellow, Molecular & Integrative Physiology

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ot being able to put on adipose tissue (commonly called “fat”) regardless of how much you eat or how little time you spend on the treadmill sounds pretty great to a lot of people. That’s exactly what happens to patients with lipodystrophy, but unfortunately, it isn’t as much fun as you might imagine. Having too little adipose tissue leads to many of the myriad metabolic complications that also result from having too much adipose tissue, including insulin resistance, high blood lipids, liver problems, and diabetes(1). Scientists hypothesize that since people with lipodystrophy aren’t able to store excess energy from food in their adipocytes, i.e., fat cells, lipid ends up accruing in their pancreas, muscles, and liver, just like it might in an obese person. Perhaps, researchers think, the problem has less to do with the amount of fat stored, and more to do with having it accumulate in the “wrong” places.

Some forms of lipodystrophy cause patients to lack essentially all adipose tissues starting at birth or early infancy, whilst other forms, called partial lipodystrophies, are milder and result in loss of adipocytes only in certain parts of the body.

Even though this disease is considered quite rare, with all lipodystrophies combined occurring in roughly 1 in 7000 people(2), medical practitioners have been familiar with it since at least the 19th century and have determined many of the causes of lipodystrophy, including inherited

or spontaneous genetic mutations, infection, autoimmune disorders, and treatment with certain drugs.

Precisely how patients with lipodystrophy lose their fat cells is still unknown, and there is no treatment or cure for the disease itself. At present the most that doctors can do is to manage some of patients’ symptoms with drugs like metformin to control blood sugar, statins for excess levels of blood lipids, and metreleptin to replace an important circulating hormone normally secreted from adipose tissue(1). Members of the MacLab, as the MacDougald lab is affectionately known, are now scrutinizing the FPLD2 mouse model intensely to determine exactly adipose tissue loss occurs in these animals. They have also joined forces with Dr. Elif Oral, a world-class physician specializing in lipodystrophy, who sees patients from all over North America here at U-M. The team hopes that uniting the MacLab’s fat tissue savvy with Dr. Oral’s clinical expertise will allow them to discover new therapies that dramatically improve quality of life for people with lipodystrophy.

The group is particularly excited by the possibility that their insights into LMNA functions in cells and tissues will eventually help not only lipodystrophy patients and their loved ones, but people with diseases caused by other mutations in the LMNA gene such as muscular dystrophies and accelerated aging disorders. Four hundred million diabetes sufferers may stand to benefit, too. Recent advances in scientists’ ability to look for genetic changes in broad sections of the population have led experts to suggest that far from being vanishingly rare, subtle lipodystrophy may be both common and a key driver of type 2 diabetes pathology(1), meaning that a deeper understanding of LMNA biology could lead to therapeutic advances for these patients as well. • 1. Lim et al., Lipodystrophy: a paradigm for understanding the consequences of “overloading” adipose tissue Physiological Reviews Online: DOI: 10.1152/physrev.00032.2020, 2020.

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The M.S. in Physiology Program: Navigating COVID-19

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imely preparations and continuing flexibility allowed the M.S. Program in Physiology leadership team to navigate the challenging (and memorable!) 2020 calendar year within the ongoing COVID-19 pandemic. Beginning the week of March 2, 2020, Program Directors, Drs. Amy Oakley and Isola Brown; Coordinator of Advising, Dr. Peggy Zitek; and Program Administrator, Folaké Graves, began preparations for the possible transition of program courses and activities to an online format. Program leadership utilized a portion of the weekly seminar class on March 11th, 2020, to both discuss the imminent transition to an online format and conduct a demonstration of the BlueJeans video conferencing software in advance of student presentations scheduled for the following week. During this activity, students and program leadership were informed electronically of the University’s decision to cancel classes on March 12 and 13 and transition to an online class format for the remainder of the Winter 2020 semester, effective Monday, March 16th, 2020. Talk about timing!

The end of seminar class that day was marked not only by the previously scheduled in-person Alumni Gap Year Panel and pizza party (with appropriate safety protocols for food distribution), but also burning questions from the students such as “What will the rest of the academic year look like?” and “Will this be our last time seeing each other in person?” Program leadership’s timely and advanced preparations allowed them to answer some of the students’ questions and ensured the smooth transition of PHYSIOL 592: Integrated Neuroscience, PHYSIOL 610: Translational and Pathophysiology, and PHYSIOL 605: Professional Development Seminar to an online platform. PHYSIOL 704: Peer-Facilitated Capstone Development, a new M.S. program course, was also developed during the Winter 2020 term, and offered (for the first time) virtually in Spring 2020. Capstone oral presentations in the Spring and Summer 2020 terms were hosted remotely, and this “new normal” provided some benefits: It was much more convenient for family members and friends from both within and outside the state of Michigan to attend, an option that was more challenging when pre-

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sentations were only offered in-person.

Non-class activities offered virtually in Spring and Summer 2020 included Peggy Zitek’s American Medical College Application Service (AMCAS) workshop (previously offered in-person each year in early May), and a newly-created online presentation covering the Association of American Medical Colleges’ Video Interview Tool for Admissions (AAMC VITA) assessment, offered in August 2020. Despite the (relatively) smooth transitions of courses and workshops virtually, technical and other difficulties associated with online formats still existed: Key among them was the struggle to continue community building within the 2020 cohort due to the loss of in-person academic and social activities, in particular, the M.S. Program’s annual Celebration Dinner.

A virtual trivia night provided the 2020 cohort with the opportunity to catch-up and enjoy a fun moment together, easing some of this social loss.

The difficulties of community building were also present as the 2020-2021 school year commenced and

the current cohort of students matriculated. Program leadership again worked to find creative and safe ways for students to learn and interact, both virtually and in-person. Program orientation was held in-person, according to University-provided social-distancing and health guidelines, and was a noteworthy opportunity for students to meet and interact with each other and program leadership.

Current program student, Amanda Victory, shared that “Going into the school year amidst the COVID-19 pandemic felt really uncertain at first; however, having held our orientation in-person helped break the ice when it came to organizing Zoom study sessions and hangouts. It was nice to put an actual face to the virtual one, even if the mask did cover most of it!” Socially-distanced, in-person sessions of the weekly seminar class, PHYSIOL 605, in the Fall 2020 term, were helpful to some program students. Amanda, again, shared that “…our weekly in-person seminars were a huge help in getting me motivated and excited to enter back into academia, as well as in maintaining my stamina on the days I had to study from home.”

tivities provided opportunities for students to develop networks and communities within their cohort. According to Taryn, “This was super helpful because it allowed me to establish support systems that were essential to my success and well-being over this past semester. ...

Additionally, I was not hesitant to reach out to these friends with any questions, concerns, or even if I needed to have a little vent session to release my frustrations. Especially in this virtual environment, I was so appreciative of the friends that showed me compassion and kindness throughout this past semester.”

The support students offered each other was mirrored

by Program Directors Drs. Oakley and Brown during weekly virtual student office hours in Fall 2020. Additionally, Peggy harnessed her vast previous experience conducting mock interviews and advising appointments via Facetime, to continue those aspects of the program seamlessly (with the exception of occasional WiFi glitches). The Fall 2020 Alumni Panel was another highlight of the semester, as a virtual format allowed a broader range of former students to participate in this event. For example, one panelist attends an outof-state medical school and two other panelists are 4th year medical students who are notoriously busy and would otherwise not have been able to travel to Ann Arbor for an in-person panel. As we have moved into the Winter and Spring 2021 terms amidst the continuing COVID-19 pandemic, the M.S. Program team continues to support students in learning, networking, and community building, while maintaining their health and wellness. •

Safe, in-person meetings were not possible for some program social and non-academic activities, which are crucial for community building among student cohorts.

“Community building was definitely a big challenge this past semester,” says current program student, Taryn Hayes. Student-coordinated events, such as a virtual happy hour at the beginning of the school year and socially-distanced study groups, helped to alleviate some of these challenges. Additional program-hosted activities organized in the Fall 2020 term included a virtual Friendsgiving, online trivia nights, and a virtual spirit day in support of program student and Wolverine football team co-captain, Andrew Vastardis. These ac-

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Louis G. D’Alecy Professorship of Physiology Liangyou Rui, PhD Louis G. D'Alecy Professorship of Physiology

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n January 30, 2020, the Department of Molecular and Integrative Physiology celebrated the inauguration of the Louis G. D’Alecy Collegiate Professorship in Molecular and Integrative Physiology and the installation of Liangyou Rui, Ph.D. as the first Louis G. D’Alecy Chair. Dr. Rui joined the U-M faculty in 2002 and has risen through the academic ranks in the Department of Molecular and Integrative Physiology, while also maintaining strong interactions with and appointments in the Department of Internal Medicine-Gastroenterology and Hepatology. Dr. Rui has a long history of commitment to obesity and metabolic disease research.

His laboratory is dedicated to determining the mechanisms underlying obesity, type 2 diabetes, and fatty liver disease. To combat these diseases, Dr. Rui explains, it is imperative to understand disease development at both the molecular and the physiological (integrative) levels. Obesity arises from body energy imbalance. When energy intake (food intake) exceeds energy expenditure, excess energy is stored in fat, leading to obesity. The brain, particularly the hypothalamus, controls food intake and energy expenditure, thereby determining fat mass and body weight. Fat secretes a hormone called leptin. Leptin promotes weight loss by suppressing food intake and increasing energy expenditure. Leptin exerts its antiobesity action by activating its receptor LepRb in the brain. Counterintuitively, leptin therapy fails to reduce body weight in most obesity cases, because obesity patients develop resistance to leptin. In search of factors sensitizing leptin responses, Dr. Rui identified the protein SH2B1. In cell cultures, his team found that SH2B1 directly enhances leptin signal transduction. In mice, ablation of SH2B1 causes morbid obesity, type 2 diabetes, and fatty liver disease, resembling the symptoms of human obesity. These innovative findings have inspired investigations of human SH2B1. Genomewide association studies (GWAS) confirm that SH2B1 mutations are causally linked to obesity and metabolic syndromes in humans. Dr. Rui and his colleagues further discover that SH2B1 in LepRb neurons directly increases the ability of leptin to stimulate sympathetic nerves projecting to fat, particularly thermogenic brown fat and beige fat. This work defines a novel SH2B1/

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L to R: Dr. Liangyou Rui (Louis G. D'Alecy Professor, MIP), Dr. Santiago Schnell and Dr. Loius D'alecy (Professor Emeritus, MIP)

sympathetic nervous system/fat axis that combats leptin resistance and obesity. Dr. Rui’s findings of the SH2B1/leptin signaling axis and the SH2B1/sympathetic nervous system/fat loop provide a framework for the future investigation of brain control of body weight and metabolism at the molecular level.

It has been long known that obesity is associated with chronic inflammation. Many cytokines induce insulin resistance, a hallmark of type 2 diabetes, linking inflammation to metabolic disorders. Notably, blood glucose levels are determined by a balance between insulin (decreasing blood glucose) and glucagon (increasing glucose levels). Dr. Rui and his team have identified NF-κB-inducing kinase (NIK), an inflammatory molecule, as a critical mediator between inflammation and aberrant glucagon actions. Liver NIK is highly elevated in obesity and increases the ability of glucagon to stimulate liver glucose production, thereby exacerbating progression of diabetes. In addition to regulating liver metabolism, Dr. Rui has also examined NIK actions in liver injury, inflammation, regeneration, and fibrosis, and has established a pivotal role of NIK in liver health and disease. Importantly, Dr. Rui and his collaborators have been designing novel therapeutic NIK inhibitors, aiming to develop new therapies for type 2 diabetes, nonalcoholic steatohepatitis (NASH), and alcoholic liver diseases using NIK inhibitors.

Recent research highlights a fundamental role of epigenetic reprogramming in health and disease. Histone methylation and acetylation profoundly influence gene expression, thereby shaping cell identity and functional states. Slug and Snail1, two related transcriptional regulators known to be involved in cancer metastasis,

control gene expression by recruiting various epigenetic enzymes that catalyze histone modifications at target promoters/enhancers.

Dr. Rui and his group unveil, for the first time, Snail1-elicited epigenetic reprogramming in white adipose tissue (WAT). Snail1-based epigenetic modifications inhibit expression of lipolytic gene Atgl, thus restraining lipolysis. Impaired Snail1 epigenetic activity increases lipolysis, resulting in increased lipid trafficking from WAT to the liver and fatty liver disease. In hepatocytes, Dr. Rui’s team found that Slug directly stimulates expression of lipogenic genes and de novo lipogenesis by an epigenetic mechanism, contributing to l (Chair, MIP) fatty liver disease. In the brain, Slug-based epigenetic reprogramming influences energy balance circuitry activity and obesity development.

Of note, small molecule inhibitors of Snail1/Slug associated epigenetic enzymes have been developed to treat cancer. Dr. Rui’s findings raise an intriguing possibility that these inhibitors may be repurposed to treat metabolic disease.

Brown fat and beige fat have emerged as new targets for obesity treatment. Brown and beige fat are highly active in metabolism and burn glucose and fatty acids to produce heat, thereby conferring health benefits. Importantly, obesity is associated with decreased brown/beige fat in humans. Brown/ beige fat reactivation is an appealing strategy for combating obesity and metabolic disease. Exposure to cold temperature is the most potent physiological stimulator for brown and beige fat. Cold exposure stimulates the sympathetic nervous system which activates brown and beige fat. Interestingly, drinking alcohol also activates the sympathetic nervous system.

Dr. Rui discovered that drinking, like cold exposure, robustly activates brown fat and beige fat. The brain senses alcohol and activates the sympathetic nervous system/fat axis. Remarkably, inactivation of brown and beige fat dramatically augments fatty liver, liver injury, inflammation, and fibrosis upon drinking. Mechanistically, brown and beige fat burn fatty acids and block lipid trafficking into the liver, thus alleviating alcoholic fatty liver disease. Additionally, brown and beige fat also secrete various factors that protect against hepatocyte injury and death. Of note, modest drinking has been widely believed to provide some health benefits. Dr. Rui’s findings indicate that recruitment and activation of brown and beige fat may explain drinking benefits. Hence, Dr. Rui’s findings provide a scientific foundation for a new strategy to

treat alcoholic liver disease by therapeutic activation of brown and beige fat.

In addition to his research, Dr. Rui has been strongly committed to facilitating career development opportunities for his trainees and junior faculty. Dr. Rui diligently guides his students and postdoctoral fellows in their research projects, and provides critical mentorships in paper and grant writings. Many of his trainees have successfully obtained highly competitive, prestigious awards, including F31 Ruth L. Kirschsterin National Research Service Award from the NIH (Ph.D. students), F32 Ruth L. Kirschsterin National Research Service Awards (postdoctoral fellows), American Heart Association (AHA) Postdoctoral Fellowship Awards, Travel Grant Awards from the American Diabetes Association (ADA), and Travel Grant Awards from the Endocrine Society. Many of his previous trainees have successfully developed their own independent research careers both in academic institutions and in industry settings. On his naming as the first Louis G. D’Alecy Collegiate Professor, Dr. Rui says, ‘Being named the inaugural Louis G. D’Alecy Collegiate Professor was overwhelming. I am truly honored and hope that I can live up to the exceptional example that Dr. D’Alecy continues to demonstrate for scientific discovery and professional citizenship’.

Dr. Louis G. D’Alecy was a full professor when Dr. Rui joined the faculty in the department. When he was a Ph.D. student in the Department of Physiology, Dr. Rui even had Dr. D’Alecy’s as an instructor for his classes. Dr. Rui’s daughter, Crystal Rui, who obtained her M.D. from the UM Medical School, also took Dr. D’Alecy’s courses.

Dr. D’Alecy has had exceptional scholarly achievements and superior records of teaching, mentoring, and service, and served as an inspirational role model for Dr. Rui. With respect to Dr. D’Alecy’s exceptional example, Dr. Rui states, ‘Since my earliest days in the Department, Dr. D’Alecy has been a role model as both a creative and careful scientist and a committed and compassionate mentor’. The kind support of the family, friends and colleagues of Dr. Louis G. D’Alecy ensures that Dr. D’Alecy’s legacy will be honored in perpetuity.

Through a generous endowment, the Louis G. D’Alecy Collegiate Professorship will ensure that the research programs of deserving scientists at the University of Michigan Medical School will be supported for years to come. •

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Partners in Scientific Discovery & Responsible Research Amy Puffenberger ULAM Staff

As one of the nation’s oldest and most-recognized animal medicine programs, the Unit for Laboratory Animal Medicine (ULAM) has provided veterinary care to all animals housed at the University of Michigan for over 50 years. The proper care of laboratory animals involves attending to a wide range of physical and behavioral needs. This includes the provision of clean, appropriately lighted and well-ventilated housing, the ability to exercise, environmental enrichment, proper nutrition, and veterinary health care. ULAM’s dedicated team of laboratory animal care professionals, composed of licensed faculty veterinarians; veterinary residents; veterinary, husbandry, and research technicians; trainers; and research support staff provide aroundthe-clock animal care for the entire U-M research community. In addition to overseeing the standards of care for all animals on campus, ULAM also offers a variety of specialized research support services and a comprehensive training and education program for research personnel.

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rom life-saving drugs to vaccines, advancements in organ transplantation to cancer therapies, laboratory animals have played, and continue to play, an essential role in the development of nearly every major scientific breakthrough in human and animal medicine.

Some of these discoveries, including the feline leukemia vaccine, flea control methods, and diagnostics and treatments for diabetes and cancer, have benefited companion animals as well as animals in the wild.

These advances would not have been possible without the use of laboratory animals.

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In calendar year 2020, ULAM supported a total of 32 Principal Investigators (PIs) from U-M’s Department of Molecular & Integrative Physiology.

This included animal husbandry and housing in 12 different buildings across campus, accounting for approximately 9% of the University’s total animal population. While many of these studies are still ongoing, numerous others were published throughout the year. ULAM is especially proud to have supported Physiology Department research teams with the following studies from the past year: • Unlocking the Secrets of Brown Fat – In two separate studies published in Nature Communications and Science in March 2020, Liangyou Rui, Ph.D., and Ling Qi, Ph.D., both with the Department of Molecular & Integrative Physiology, used mouse models to explore the biology of brown fat and its implications for weight loss and obesity-related diseases.

• High Blood Pressure Linked to Baroreflex in Rats – In October, Daniel Beard, Ph.D., Feng Gu, Ph.D., and their team from the Department of Molecular & Integrative Physiology described a newly observed phenomenon in the way blood pressure is maintained

in certain rats in a paper published by JCI Insight. This observation may reveal a new cause of hypertension and could offer clues about which therapies patients may respond to.

• The Link Between Obesity and Puberty – Carol Elias, Ph.D., professor of molecular & integrative physiology and obstetrics & gynecology at the U-M Medical School, and her team published a study in the journal iScience which examined two important regions in the brain to try and understand how leptin influences pubertal timing. The mouse study identified genes connecting the onset of puberty to the remodeling of specific brain sites.

• Investigational New Therapy Prevents Onset of Dravet Syndrome Symptoms in Mice – Lori Isom, Ph.D., chair of U-M’s Department of Pharmacology and professor of molecular & integrative physiology, and her team have spent several years tracing the

developmental pathway of Dravet syndrome, a debilitating genetic disease that causes intractable seizures and can lead to sudden death. Based on the encouraging findings of the team’s mouse study, published in Science Translational Medicine in August, a clinical study has been launched to begin evaluating STK-001 in children and adolescents with Dravet syndrome.

These studies represent only a small sample of the myriad projects currently underway at the University of Michigan and would not be possible without a collective commitment to achieving the highest standards of humane and compassionate animal care. ULAM is honored to partner with the U-M research community in its pursuit of innovative scientific advancements to benefit both human and animal health. •

MIP's Secret Weapon: Chuck Norris?

Elizabeth Wagenmaker Laboratory Technician, Molecular & Integrative Physiology

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here is a poster hanging in the laboratory next to mine that depicts how specific groups of lab members view each other: undergraduates see the postdocs as rolling in cash, grad students see a screaming PI, postdocs see grad students as small children poking an electrical outlet with a metal knife, etc. The one that always puts a knowing smile on my face is how lab technicians see each other: as Chuck Norris. That’s right, the butt-kicking action star that has spawned a thousand memes depicting his badassery; one of my favorite science-related ones being “the periodic table is incomplete because only Chuck Norris knows the element of surprise.”

Like Chuck Norris, lab technicians have to possess - and be adept at - a multitude of skills. We also have to be quick on our feet because on any given day, we are acting as researchers, administrators, air traffic controllers, wish-granting genies and, yes, sometimes even therapists. It is not unusual for us to be filling many roles at once. Unlike Chuck Norris, we may not quite know everything but we do serve an important purpose in maintaining the lab’s “history.” As students and postdocs come and go, it is often the technicians that provide continuity and stability within a lab. We are frequently some of the most visible representatives of the department when it comes to forming working relationships with labs outside of Molecular and Integrative Physiology (MIP) as well as other university support staff. Additionally, many lab technicians working in MIP hold graduate degrees, have research interests of their own, and publish regularly, all of which significantly contributes to the research goals of the lab and the department as a whole. So, just as with Chuck Norris, lab technicians are like Swiss Army knives: we have many important functions, we are great problem solvers and we come in handy! As a result, we truly are MIP’s secret weapons in the optimal functioning and success of the department.

Physiology Matters

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Too much and not enough: Hypoxemia and pulmonary capillary blood flow in COVID-19

Andrew Marquis PhD Student, Molecular & Integrative Physiology and Daniel Beard, PhD Carl J Wiggers Collegiate Professor of Cardiovascular Physiology, Professor of Molecular & Integrative Physiology

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espite the robust academic and industry research efforts across the globe, there are still many gaps in our understanding of the pathology of severe acute respiratory syndrome coronavirus 2 (SARS CoV2). Arguably the most concerning symptom of severe SARS CoV-2 infection is hypoxemia—inadequate oxygen delivery to the body’s tissues. Hypoxemia in Coronavirus disease 2019 (COVID-19) has been compared to Acute Respiratory Distress Syndrome (ARDS), a form of respiratory failure characterized by the rapid onset and widespread inflammation throughout the lungs. This impairs the lungs’ ability to exchange oxygen and carbon dioxide, also resulting in hypoxemia. In ARDS, abnormal ventilation is typically explained by a decrease in lung compliance, or the ability of the lungs to stretch and expand. The primary treatment involves mechanical ventilation with low volumes, low pressures, and supplementary oxygen.

While at first glance it may appear that COVID-19 causes ARDS, critically ill COVID-19 patients requiring mechanical ventilation surprisingly tend to have normal lung compliance. So, if COVID-19 patients are suffering from hypoxemia but they do not have reduced lung compliance, what then is the mechanism underlying their hypoxemia?

Efficient gas exchange in the lungs requires effective matching of airflow and blood flow—referred to as

ventilation-perfusion (V/Q) matching. Because V/Q ratios are influenced by gravity, a patient’s posture can influence their V/Q ratios. Indeed, moving a patient into a prone position (laying face down), has been shown to improve V/Q matching and oxygenation in critically ill COVID-19 patients. V/Q matching is physiologically regulated through hypoxic pulmonary vasoconstriction (HPV). HPV is a regulatory mechanism where in response to low oxygen in the alveolar space of the lung, upstream pulmonary arteries vasoconstrict, redirecting blood flow away from areas of the lung that have poor oxygen supply. In ARDS, fluid accumulation in the alveoli and alveolar walls can prevent gas exchange, resulting in poorly oxygenated blood returning to the left side of the heart. HPV counteracts this effect by limiting blood flow through poorly ventilated or fluidfilled alveoli. Yet in COVID-19 patients with severe hypoxemia, lung imaging via chest CT suggests that their alveoli remain well aerated while severe capillary microthrombosis is present. We hypothesize that the hypoxemia observed in COVID-19 is possibly explained by dysregulated pulmonary capillary blood flow distribution. In simpler terms, some pulmonary capillaries have too much blood flow, while others have not enough. Some studies have suggested COVID-19 disrupts normal HPV function. Combined with the obstruction of blood flow by microthrombi, this could create a perfect storm to disrupt the normal pulmonary

Figure 1: Schematic of our multi-scale multi-physics model of ventilation-perfusion matching. Block (A) illustrates the whole-lobe vascular network model. Black lines represent blood vessels, and colored regions represent discrete zones of perfusion. Block (B) shows how the mechanics of each vessel segment is represented as an equivalent circuit. Intravascular pressure (Pv) and flow into the vessel (qin) are state variables; inlet pressure (Pin) and flow out of the vessel (qout) are the initial conditions at boundaries for a given vessel segment; outlet pressure (Pout) is an algebraic constraint; alveolar pressure (Palv) is a dynamic pressure source; and hydraulic resistance (R), inertance (L), compliance (C), and vessel wall resistance (RD) are anatomical parameters calculated from the geometry of the vessel segment (length and radius) and can be modulated by vasoregulation (purple boxes). Block (C) depicts a representative gas exchange unit. Gases flowing through the capillary tube are exchanged with an alveolar compartment. Block (D) portrays the oxygen-sensitive vasoregulatory mechanism hypoxic pulmonary vasoconstriction (HPV). Hypoxia in the alveolar space induces conducted vasoconstriction. Conducted vascular responses are spatially propagated upstream through the endothelium - these responses modulate the values of the anatomical parameters (R, C, and RD) in the arterial network.

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Figure 2: Effect of HPV and uniform vasoconstriction on regional perfusion, V/Q matching, and oxygen flux. (A-C) Leftmost column of networks are without regulation from HPV, middle column of networks are with regulation from HPV, and the rightmost column of networks are with uniform vasoconstriction. The black scale bar is 1000 um. (A) Perfusion in the capillary compartments; (B) Ventilation-perfusion (V/Q) ratios in the capillary compartments; (C) Oxygen flux in the capillary compartments. (D-G) Blood flow, RBC transit times, V/Q ratios, and oxygen flux expressed as probability densities. (D) Distribution of flow; (E) RBC transit times normalized to mean transit time; (F) Distribution of V/Q ratios; (G) Distribution of oxygen flux.

capillary blood flow distribution.

Despite decades of research, we still do not understand how HPV affects the distribution of blood flow throughout the lungs. Moreover, the molecular governing pathways underlying HPV remain elusive. To understand how HPV influences pulmonary blood flow distribution at the system level and to analyze the role of HPV in disease, we have developed a multi-scale multi-physics computational model of V/Q matching in rat lungs (Figure 1). The major components of our model are: (a) morphometrically realistic pulmonary vascular networks; (b) a tileable lumped-parameter model of vascular fluid and wall mechanics; (c) oxygen transport accounting for oxygen bound to hemoglobin and dissolved in plasma; and (d) an empirical model of HPV based on conducted vascular response mechanics.

Model simulations predict that HPV functions to match perfusion to ventilation by more evenly distributing capillary blood flow throughout the organ. This homogenizes the distribution of V/Q ratios. Moreover, a more homogenous distribution of V/Q ratios leads to a more homogenous distribution of regional alveolarcapillary oxygen flux and thus increases whole-organ oxygen uptake (Figure 2). Simulation with regulation from HPV increases the venous outflow oxygen tension from 81 mmHg to 100 mmHg, a favorable outcome.

This is in contrast to the uniform vasoconstriction

simulation where venous outflow oxygen tension decreased slightly to 78 mmHg. Our model represents a flexible platform to understand many diseases states characterized by blood gas derangements such as collapsed airways, asthma, pulmonary fibrosis, thromboembolic diseases, and COVID-19. The significance of this model is that it can capture function/dysfunction at a variety of observable and unobservable scales. We are currently working to compare the effects of a single large acute pulmonary embolism (PE) versus a large number microthrombi.

Much like COVID-19, acute PE frequently results in hypoxemia. While the lethal threat of not having enough oxygen in a patient’s blood is certainly an obvious similarity between these two disease states, the optimal therapeutic strategy to treat each condition are different.

For acute PE, current clinical guidelines recommend a surgical approach to remove the thromboembolism as a primary intervention. For many microthrombi, this approach is exceptionally challenging or infeasible due to the limitations of current technology such as the size of intravenous catheters. Our model may also have more practical use for diagnostic purposes. For example, perhaps microthrombi alter the red blood cell transit time distribution in a manner that is wholly distinct from large acute PE and healthy controls,our model could potentially be used to predict how to differentially diagnose these conditions. •

Physiology Matters

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Fat Cells as Heroes:

Harnessing Adipose Tissue to Treat Obesity Alexander Knights, PhD Postdoctoral Fellow and Carolyn M. Walsh, PhD Postdoctoral Fellow, Molecular & Integrative Physiology

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hen it comes to adipose tissue, the “white” adipocytes (fat cells) get most of the attention.

They’re well-known for their role in storing excess energy from food intake in the form of lipids and releasing it when it’s needed by other parts of the body. “Brown” or “beige” adipocytes, on the other hand, actually expend energy themselves by producing heat in a process known as thermogenesis. This remarkable ability has long made them an exciting target for researchers interested in metabolic diseases: figuring out how to activate thermogenic adipocytes so that they burn off more energy is seen as a highly promising treatment for obesity. Despite their potential, scientists to date have had limited success with harnessing these cells for therapeutic purposes.

Things took a turn in 2018, when Jun Wu’s lab in the University of Michigan’s Molecular and Integrative Physiology Department published a paper in Nature Medicine(1) reporting the discovery of a new signaling pathway for this coveted process. Adipose tissue is composed not just of adipocytes, but of various other cell types including immune cells. The Wu lab found that these adipose-resident immune cells can secrete a molecule called acetylcholine, which then goes on to promote energy expenditure by driving thermogenesis in beige adipocytes. However, it was unclear exactly which immune cell was responsible for secreting acetylcholine, and the lab has since focused on unmasking the culprit as well as elucidating the mechanisms that underlie this novel pathway.

Dr. Alexander Knights, a postdoctoral fellow who hails from Australia, was up to the challenge. He used a fluorescent molecule linked to the enzyme responsible for synthesizing acetylcholine, which meant that his cells of interest – those that produced acetylcholine – were much easier to identify, since they all expressed green fluorescent protein (GFP). Dr. Knights found that multiple types of immune cells from the adipose tissue synthesized acetylcholine. Therefore, to narrow his candidates down further, he took mice whose acetylcholine-producing (or “cholinergic”) cells expressed GFP and exposed them to cold temperatures. Cold exposure is well-established as a stimulus that increases

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thermogenesis, so Dr. Knights knew that the cholinergic cells important for kick-starting the thermogenic program should respond. Sure enough, when he examined GFP-expressing cells from the adipose tissue of cold-exposed mice, he found that only one population had increased: the macrophages, a type of immune cell involved in a wide variety of inflammatory processes.

What’s more, knocking out the enzyme response for acetylcholine synthesis in the macrophages, but not other types of immune cells, left the adipose tissue impaired in its ability to effectively activate thermogenesis in response to cold exposure, underscoring the importance of cholinergic macrophages in this pathway.

Dr. Knights and his colleagues also found that cholinergic macrophages depended on a particular type of receptor called the β2-adrenergic receptor for synthesis and secretion of acetylcholine. These findings are especially promising given that previous attempts to harness the potential of thermogenesis for the treatment of obesity relied on another receptor, the β3-adrenergic receptor, which resulted in problematic cardiovascular side effects. The β2 receptor is an alternative target that may provide a more effective and safe strategy to activate thermogenesis and promote energy expenditure via the macrophage-adipocyte cholinergic signaling axis identified by the Wu lab.

Alex doesn’t regret moving from the other side of the world for his postdoctoral work. Although he was originally drawn to work with Dr. Wu because of her expertise in adipose tissue-resident immune cells, he says that he’s also benefited immensely from the scale of University of Michigan’s research enterprise, which has enabled him to collaborate widely with other investigators and expand his professional network. Support from the Michigan Life Sciences Fellowship, a program that provides a generous salary, funding for independent research and a tight-knit community, hasn’t hurt either. These benefits have given Alex the flexibility to pursue his own scientific interests and a level of financial security that lets him relax and focus on his work.

Something else Dr. Knights can teach you that you might not have known? Australia’s population is only 25 million, but in terms of land mass, it’s about the same size as the contiguous United States. “It’s big,” explains Alex. • 1. Jun, H. et al. Nat Med. 24, 814–822 (2018)

Physiology 415:

Learning By Teaching

Nupur Das, PhD Research Investigator, Molecular & Integrative Physiology and Kelsey Temprine, PhD Postdoctoral Fellow, Molecular & Integrative Physiology

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hysiology 415 (Laboratory Techniques in Biomedical Research) was launched in the winter semester of 2017 under the leadership of postdoctoral program director Dr. Yatrik Shah with two distinct, yet interdependent goals: 1) to train aspiring scientists and physicians in molecular biology techniques through a masters-level methods course in molecular and translational physiology and 2) to offer postdoctoral researchers and graduate students in the Physiology department a training opportunity in pedagogic methods. The course would be entirely designed, developed, and taught by trainees.

Since its inception, Physiology 415 has integrated cutting-edge research techniques with fundamental concepts in human and animal physiology to create a unique hands-on course in molecular biology. Principally designed for students headed towards advanced degrees in biology and the health sciences at the University of Michigan and beyond, it covers a wide range of molecular methodologies including DNA/RNA extraction, molecular cloning, genetic manipulation, chromatographic and mass spectrometric analysis of protein, metabolomics, animal cell culture, and physiological study of genetic and pharmacological animal models. The course changes year to year depending on the interests and expertise of the postdoctoral and graduate instructors involved. Together these instructors form a teaching team that develops the course curriculum, designs teaching methodologies, grades

the exams, and holds office hours, while the MIP administration provides the logistic and administrative support in the form of teaching materials and reagents.

Each class lasts 3 hours and includes both lecture and interactive lab components relevant to a specific topic (e.g., techniques in RNA biology) with special emphasis on hands-on training in benchside research, troubleshooting, protocol optimization, and data analysis.

Overall, Physiology 415 has been very successful in developing a congenial teaching atmosphere, and enrollment has increased consistently over the last 5 years.

As for the postdoctoral and graduate instructors, the experience is highly rewarding. Dr. Charlotte Vanacker, an MIP postdoc who taught the course for three consecutive years, says it was, “One of the most valuable opportunities I have ever had”. Last year when the COVID-19 pandemic hit in the middle of the semester, the Physiology 415 team successfully transitioned from the normally hands-on course to a virtual format on a very short notice. This year, with the pandemic still ongoing, great support from our students and U-M is allowing us to continue with the online format (which makes use of virtual lab simulations and breakout rooms for small-group discussions) with a record number of enrollments! Physiology 415 instructors gratefully acknowledge Folaké Graves and Professor Shah for their support and guidance along the way to making the program as successful as it has been. We look forward to seeing how the course continues to evolve over the next 5 years! •

Physiology Matters

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Metabolomics:

Decoding Cellular Metabolism Zeribe Nwosu, PhD Postdoctoral Fellow, Molecular & Integrative Physiology and Costas Lyssiotis, PhD Assistant Professor, Molecular & Integrative Physiology

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very cell coordinates a complex network of enzymatic activities through which it obtains and utilizes nutrients or degrades and exports waste products. Metabolism enables cells to maintain a physiologic balance between nutrient utilization and waste removal. No cell can survive or grow without metabolism and without it, key functions such as cellular respiration, signaling and migration would grind to a halt. On the other hand, aberrant or excessive metabolic activities promote diseases such as cancer, diabetes and obesity.

Understanding how cells manage nutrients and waste products is important in formulating strategies to diagnose, treat, and monitor diseases.

Measuring and interpreting metabolic pathway activities, albeit fascinating, is challenging. This is because several factors influence cell metabolism and these include cell growth and metabolic rate, physicochemical properties of the metabolites, nutrient access, to name a few. For instance, most rapidly proliferating cells accelerate metabolism to sustain their growth needs and eliminate toxic waste products. Such cells complete certain metabolic reactions at extremely fast rate and maintain some metabolites at a low level. In addition, several metabolites are inherently unstable. Metabolic pathways are also intricately connected – one pathway’s waste can become another pathway’s substrate, which can make it hard to accurately measure such metabolites. These variables constitute an exciting conundrum, which metabolomics attempts to solve.

In the last two decades, metabolomics has evolved as the state-of-the-art method for decoding metabolic activities in cells. Metabolomics is the study of metabolites and biochemical reactions at a holistic scale (‘high-throughput’). Typical metabolomics instrumentation includes a chromatography coupled to a mass spectrometer, which altogether improves analytical sensitivity even for extremely low metabolites. Metabolomics also enables the simultaneous measurement of hundreds to thousands of metabolites in biological specimens. This high throughput advantage enables a global insight into how cells react to various perturbations such as nutrient starvation or treatments.

Two major metabolomics approaches are employed to facilitate discoveries. These are either untargeted or targeted metabolomics. In the untargeted metabolo-

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mics, thousands of metabolites are detected without the need for a prior knowledge of the metabolite species. This enables an expansive possibility to extract metabolites in a retrospective fashion, hence extending the boundaries of novel discoveries. However, this approach is labor-intensive, time consuming, and requires expertise given the high likelihood of metabolite misidentification. On the other hand, targeted metabolomics is applied for detecting a well-curated list of metabolites of known physicochemical properties. This enables an expedited turnaround time that can prove useful in research, especially where the researcher is interested in few specific metabolites or pathways. On the downside, a targeted approach is limited in scope.

Another interesting aspect of metabolomics is stable isotopes tracing. In this approach, metabolites carrying isotopically labelled carbon or nitrogen are provided to cells via culture growth media or injected into in vivo models. After a predetermined time, samples are collected, processed, and analyzed by mass spectrometry, which then elucidates the pathways through which the cell channel and use the labeled metabolites. This provides a cutting-edge approach for monitoring cellular use of a given metabolite. Computational biology and mathematical modeling approaches also offer an additional iteration of metabolomics, namely, metabolic flux

analysis (MFA). With MFA, a metabolic pathway activity can be predicted with great precision based on results from mass spectrometry.

Metabolomics has enabled the identification of metabolites with powerful control on cellular behavior. For instance, metabolites such as glucose and glutamine feed into various pathways to drive cancer cell growth; methionine, tryptophan and arginine alter immune function in favor of cancer cells, while others such as succinate and 2-hydroxyglutarate are considered ‘oncometabolites’ due to their potential to induce cancer properties. Recent metabolomics work from our laboratory has shown ‘tricks’ used by cancer cells, including the attenuation of anti-tumor immunity by starving

T-cells of methionine and the dampening of chemotherapy via nutrient exchange with macrophages. In clinical diagnostics, metabolites are also very reliable biomarkers, e.g., glucose is used in monitoring diabetes, while urea and creatinine are useful indices of renal function in patients. Other utilities of metabolomics include in monitoring the effect of a treatment on biochemical profiles, detection of inborn errors of metabolism and a breadth of research questions such as determining the effect of a treatment or gene knockout on cancer cell metabolic pathways. In conclusion, metabolomics is fast becoming a mainstay approach in research and precision medicine, and with an extending breadth of applications, and is an important toolkit for driving research in our department. •

The Postdoctoral Fellows Spotlight

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he Molecular and Integrative Physiology department has a vibrant postdoctoral community, involving researchers on various aspects of physiology and diseases, including diabetes, obesity, cancer, and cardiovascular disease. Under the guidance of Dr. Yatrik Shah (MIP Postdoc Program Director), our postdoctoral fellows hold monthly seminars, annual symposium, and undergo periodic assessment of their individual development plan (IDP). MIP Postdoctoral fellows come from various countries and states across the US and have been successful in receiving funding from various agencies, including the National Institutes of Health (NIH) F/T programs, American Heart Foundation, American Diabetes Association, etc.

• Funding Source: Michigan Postdoctoral Pioneer Program (3 years) Dr. Zeribe Nwosu is from Nigeria and obtained his PhD from the University of Heidelberg, Germany. He is a postdoctoral research fellow at the Rogel Cancer Center, U-M, under the joint mentorship of Dr. Costas Lyssiotis and Dr. Marina Pasca di Magliano. Dr. Nwosu studies metabolic alterations in pancreatic cancer and tumor-immune interaction, with the goal of identifying potential therapeutic opportunities for patients.

• Funding Source: Michigan Institutional Research and Academic Career Development Award (IRACDA) Program (3 years) Dr. Sonya Wolf-Fortune obtained her PhD from the University of Michigan in Immunology. She is a postdoctoral research fellow in Dr. Katherine Gallagher’s lab. Dr. Fortune studies the role of keratinocytes in shaping the macrophage inflammatory profile in diabetic wounds in order to develop novel targets for treatment.

• Funding Source: Michigan Life Sciences Fellowship (3 years); Pediatric Endocrinology T32 (1 year) Dr. Carolyn Walsh is from Michigan and obtained her PhD from the University of California at Berkeley.

She is a postdoctoral research fellow at the North Campus Research Center and is mentored by Dr. Ormond MacDougald. Dr. Walsh studies mechanisms of adipocyte loss in lipodystrophy. She and her colleagues hope that their work will lead to improved understanding of and treatment for lipodystrophy and atypical diabetes.

• Funding Source: American Diabetes Association Postdoctoral Fellowship (3 years) Dr. Zhangsen Zhou is from China and obtained his Ph.D. from Chinese Academy of Sciences, Shanghai, China. He is a postdoctoral research fellow in Dr. Ling Qi's laboratory.

Dr. Zhou studies the role of ER-associated degradation (ERAD) in adipocytes.

Physiology Matters

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,

When Tears Flow In Science Daniel Michele, PhD Professor, Molecular & Integrative Physiology

son dissertation celebrations for our students who had spent years to reach the promised land of being awarded a PhD. But it was the personal stories and meeting one-on-one with struggling students that took me to the brink of tears. As an alumni of MIP, this was not the graduate school experience that I fondly remember, nor the positive environment we had worked so hard to create for our students in our graduate program. In that Zoom meeting, there was a minor debate about a sensitive topic related to the graduate program, and the dam finally broke. Full-on water works.

I

am not what you would describe as an overly emotional person. But the first time that I remember, I cried in my office…in a Zoom meeting…in front of my colleagues.

Going into my final year as graduate program director, I was feeling pretty good. After 2 years on the job, I knew most of the answers about the minutia of Rackham rules and graduate program policies without asking the past director, Sue Moenter, or Student Services Representative extraordinaire, Michele Boggs. Although I am horrible with names and still call my kids by my dogs’ names sometimes, the graduate students’ names, their mentors, and their dissertation research topics were locked in my memory and rolled off my tongue. With many students, unexpected friendships have formed. But who could predict what would happen in 2020? A global pandemic, a mandatory halt of nearly all research for months, stark reminders of the impact of racism in society and our workplaces, and political divisiveness that ended in a riotous mob inside the US Capitol shocked us all.

To say that this past year was a challenge to our graduate program and our students is an understatement.

The fear in the present and uncertainty for the future for our students and mentors were palpable. The isolation and loss of social gatherings made the whole experience even worse. The work as graduate program director immediately took me down new roads for supporting students’ needs that stretched me thin.

Particularly disappointing for me was the loss of in-per-

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I turned off my camera and collected my thoughts.

When I returned, the tone of the meeting had changed, and my colleagues in the meeting lifted me up with personal encouragement and collective support. The experience in the meeting was a reminder of what was indeed positive throughout 2020. The MIP community mobilized itself in support of each other and support of our graduate students. Essential employees maintained critical reagents on behalf of entire labs. Students found new and creative ways to share and learn new skills and make progress on their research from home. Mentors provided needed social support with virtual game nights and happy hours. Mental health was prioritized. Staff continued to provide support services from home, often from their kitchen tables.

Of course, I will be happy to never experience “another 2020” again in my lifetime. I am reminded however that there is another time where tears often flow in science, which is the closing remarks of students at their dissertation defense. A whole other deck of slides is typically unveiled at the end, to cover the thank yous to supportive mentors, the lab mates who contributed to the student’s project, the friends that made graduate school an enjoyable journey, pets who were acquired along the way, and key family members who never waivered in their support despite not understanding what a physiology is. The community of support that enables any individual’s success in graduate school, or any endeavor including being a graduate program director, is often large. MIP fortunately has no shortage of that support for each other. A few tears may flow in science, but most of the time they are good tears. •

Big Shoes to Fill Susan Brooks, PhD Graduate Chair & Professor, Molecular & Integrative Physiology

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fter several years in the co-pilot seat, observing as Dan Michele expertly and effectively steered the ship of our MIP PhD program, I took over as Graduate Program Director on January 1, 2021. I want to take this opportunity to recognize Dan’s exceptional dedication to our program. Importantly, I must acknowledge his unequivocal commitment to and advocacy for our students. I am continually awed at his ability to balance the needs and concerns of individual students with the best interests of the group and the greater good of the Program and Department. The integrity, sincerity, and grace with which Dan addresses head on the many challenges experienced by students, mentors and colleagues while also never missing an opportunity to celebrate their successes, big and small, provide an example that we should all strive to emulate. I know that I will, as I attempt to fill his very big shoes.

The personal, academic, and professional trials brought to bear by the many tumultuous events of the past year have demanded that we employ great creativity to maintain the quality of our instruction and mentorship, the productivity and well-being of our current students, and our historically enviable record recruiting outstanding new students. Under unprecedented conditions, I believe that collectively we have demonstrated spectacular success. Despite the requirement for only remote interactions, all eight of our first year students were advanced to candidacy, and we welcomed seven new PIBS students with a primary interest in MIP who have been engaged in the virtual classroom and in both virtual and in-person research rotations.

Although disappointed by our inability to offer customary celebratory events that are so well deserved, seven students virtually defended their PhD dissertations and have moved on to post-graduate opportunities. We have maintained our traditions of candidate seminars and held our annual Research Symposium that included an absolutely exceptional slate of Davenport Research Award presentations that would rival anything one might see at a national or international meeting.

Finally, we executed two recruitment weekend “visits” with applicants from every corner of the country. We are still awaiting the results of our efforts in terms of acceptances of our offers, but I believe we did a Zoomtacular job of displaying the collegiality and concern of our Michigan MIP family. Regardless of what the fu-

ture holds for reestablishing more “normal” day-to-day lives, I remain committed to maintaining our family feel, while also striving for a climate of inclusiveness and equity for all our students.

A year ago, I could not have imagined that today we would still be working from home, teaching remotely, staffing labs at limited capacity, and unable to gather as a Department, graduate program or even as a lab group. While we are still facing a long road back to a new normal, we have emerged from the darkest, coldest days of this winter, and we have done so with a greater appreciation for the importance of sharing a smile and a story and supporting each other. I look forward to a beautiful Michigan spring and summer filled with increased opportunities for engagement and excellence in research training along with some long-awaited and well-deserved face time (not FaceTime). Additional unforeseen challenges will undoubtedly come our way, and I am reassured knowing that Dan, with his vast experience and insight, is only a phone call away and will always have my back. I hope our students will learn to trust that I have theirs, and if I can in even a small way foster an MIP PhD experience for them in which memories of celebrating shared accomplishments and gratitude for our caring community outweigh the difficulties and trials, I will consider it job well done. •

Physiology Matters

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Hello From the Other Side: Reflections on a PhD Completed Devika P. Bagchi, PhD Molecular & Intgrative Physiology

and global health implications of studying obesity and because the lab environment and mentorship style was the right fit for me. Ultimately, my thesis work focused on the role of the Wnt signaling pathway in adipocyte function and its implications for obesity and metabolic disease – not remotely related to neurodegenerative disease research. In making this first big decision in graduate school, I learned an important lesson: if you are flexible in following your passions, new and previously unknown avenues will reveal themselves.

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hen we collectively look back on the year 2020, it will undoubtedly be with an overarching sense of personal and communal loss: so many lives and livelihoods lost, careers and personal goals indefinitely put on hold, and the feeling that time passed both interminably slowly and in the blink of an eye. Amidst it all, I hope we also remember the brief moments of lightness, human kindnesses, and personal successes, however that looked for each of us.

For me, 2020 was the year that I successfully earned my PhD - three letters soon to follow my name that will forever represent a years-long quest for knowledge and purpose. As I reflect on my journey, it is not lost on me that my experiences, lessons learned, and successes have been shaped largely by the individuals and larger communities that have supported and nurtured me along the way. By sharing some of the key experiences that helped me to thrive during my time in MIP, I hope to pay forward the investments made in me to the next generation of departmental graduate students.

As an aspiring physician-scientist, I initially chose to pursue my PhD in the Department of Molecular & Integrative Physiology because I hoped to gain an interdisciplinary understanding of the molecular and systemic underpinnings of human disease. Given my neuroscience background, I originally intended to study neurodegenerative disease, which had touched my family.

However, I ultimately found myself drawn to the lab of Dr. Ormond MacDougald, both for the important public

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During my time in MIP, I have experienced firsthand the rigorous training graduate students receive, not only in scientific research, but also in presentation, teaching, and leadership skills, all of which are critical for future success no matter your career trajectory, from academic science and medicine to industry to medical writing and beyond. As students, we are integrated seamlessly into a community of faculty members, staff, and fellow trainees who treat us as colleagues on an equal footing.

Beyond the impact on scientific advancement, this emphasis on collaboration and interdisciplinary research fosters a uniquely creative and collegial environment, perfect for the development of budding scientists.

As I dove headfirst into the trenches of my graduate work, I was also delighted to find myself surrounded by a community that was not only scientifically rich, but one that was endlessly supportive and ready at a moment’s notice to help me pursue all my goals, scientific and otherwise. Community engagement and outreach had long been a passion of mine, and I watched firsthand as the department supported efforts to establish and grow Science Education & Engagement for Kids (SEEK), a student-led organization that aims to bridge local gaps in access to science education by providing hands-on lessons and close mentorship to kids in local low-resource, high-needs schools. Doing my small part to give back to the local community has been one of the most fulfilling parts of graduate school, and I feel so fortunate to be part of a department that actively encourages students to chase their various passions. This brings me to another lesson I learned firsthand: in MIP, “if you can dream it, you can do it” is not just an ideal, it is a reality.

Graduate school is a transformative experience in so many ways. Personally, I still have much to discover about becoming a physician-scientist, but my thesis work has given me a new lens through which to view human disease and a unique framework with which to think about the underlying pathophysiology and appropriate therapeutic interventions for my patients. And as this chapter of my training closed, so many of the people I had the opportunity to learn from and grow along-

side over the last few years sat alongside me on Zoom and cheered me on as I, dressy on top and sweatpants below, shared all of the scientific and personal discoveries I’ve made along the way. So, my parting words to all the students coming after me: if you let it, MIP will become like a home to you, nurturing and supporting you through this grand adventure that you’re embarking on. And to all the faculty, staff, and friends who truly became like family to me, thank you. •

CONGRATULATIONS 2020 PhD Graduates JON DEAN

DEVIKA BAGCHI

Jimo Borjigin Lab

Ormond MacDougald Lab

“The Role of the Prefrontal Cortex in

“Investigating Roles of Wnt Signaling in Mature Adipocyte Function”

Regulating Level of Consciousness”

JACOB JOHNSON

MEGGIE HOFFMAN

Scott Pletcher Lab

Howard Crawford Lab

“Circadian Rhythms, Light, and Social Perception: Sensory Regulation of Lifespan in Drosophila”

“The Role of Tuft Cell Gustatory Signaling in Pancreaticobiliary Disease”

ALLISON HO KOWALSKY

JEFF PHUMSATITPONG

“Defining and Characterizing Cell Signal Transduction in the Sestrin2 Pathway”

“The Effects of Corticotropin - Releasing Hormone (CRH) on Gonadotropin-Releasing Hormone (GnRH) Neurons in Female Mice”

Jun Hee Lee & Santiago Schnell Labs

Suzanne Moenter Lab

NATALIE WARSINGER-PEPE

Yukkiko Yamashita & Jun Wu Labs

“PrefeNatrential Expression of Ribosomal DNA Loci and Its Implications in the Divergence of Species”

Physiology Matters

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In Memoriam:

James Beaumont 1979- 2020

J

ames N. Beaumont was born on August 21, 1979 in Detroit and grew up in the Sterling Heights area. He attended Michigan State University and received his B.A., Business Administration, from the Broad School of Business.

James experienced employment on each coast at Harvard Medical School and UCLA before joining us here at the University of Michigan, 2013-2020. His skills were put to use in many areas in our department; processing MTAS/ UFAs, completing space & equipment surveys and processing lab orders. One staff member referred to him as the "Procurement Dude", as he processed over 5,000 orders per year!

James contritubed so much more to our department than his work skills and knowledge. His co-workers fondly remember Girl Scout cookie sales for his nieces, Trader Joe's treasures brought in to be shared and games selected and sent home for their children to enjoy. His greatest loves were that of his family, friends and his beloved cats. Professor Costas Lyssiotis, PhD shares, "I am so very glad that I knew James and that I could call him a friend. He was such a kind, smart, creative, talented and decent man. He somehow seemed to know everyone in Ann Arbor, and he had all the best takes. His love of biking was exceeded only by his love of board games. He is one of a few that could keep up in the 'department of the unexpected', and I'll forever hold onto my memories of his quirky personality." •

James Beaumont with researchers Howard Crawford, Costas Lyssiotis and Marina Pasca di Magliano

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Physiology Matters

William H. Howell:

Third Professor of Physiology at the University of Michigan (1889-1892)

H

enry Sewall recommended William H. Howell, his junior John Hopkins colleague, as his successor when has had to resign as professor of physiology on account of his tuberculosis in 1889.

Starting from almost nothing, Sewall had gradually accumulated equipment for teaching and research.

When Howell arrived in Ann Arbor he found five Du Bois-Reymond induction coils, two rotating cylinders with clockwork for smoked-paper recording, one Ludwig kymographion for registering blood pressure, a Browning spectrograph, a Thompson's galvanometer, a Roy-Gaskell heart tonometer, Zeiss microscopes, and machine and woodworking tools. With these Howell could mount a full demonThe William H. Howell Lab stration course in physiology for medical students and resume research. Like Sewall, Howell also gave a course in physiology for students in the Literary Department who intended to become teachers of biology or psychology, and for them a required laboratory course was provided. There is some evidence that laboratory work was also required for medical students in Howell’s third and last year at Michigan.

At Michigan Howell continued the work on hematopoiesis he had begun at Johns Hopkins. He found that in the early embryo red blood cells are formed in many tissues and in the second half of embryonic life in the liver, spleen, and bone marrow. After birth they are formed only in the bone marrow, but in profound anemia the spleen may resume production. The nucleus of the red blood cell is lost by extrusion, but in severely anemic animals a large fragment of nuclear material, now known as the Howell-Jolly body, persists until the cell disappears.

Like Sewall, Howell had student assistants in his teaching and research. One Literary Department student and one medical student earned masters’ degrees helping him demonstrate that it is the inorganic salts of plasma, not the proteins, that maintain the beat of the heart. The medical student demonstrated that proteins are not consumed by the beating heart over a period of fourteen hours. Again working with students, Howell attempted to determine the nature of conduction by a cooled segment of nerve in a nerve-muscle preparation.

In 1892 first-year medical students at Harvard were required to do one hundred laboratory exercises in physiology, and Henry P. Bowditch, professor of physiology at Harvard, needed help. He hired Howell away from Michigan, but he could keep him only a year. Newell Martin resigned just as the Johns Hopkins School of Medicine opened, and Howell returned to Johns Hopkins as its first professor of physiology. Much later at a festive occasion in Ann Arbor Howell said: “It is true that when I was called to another position I accepted, and severed my connections here in an easy and friendly way. I have since come to recognize that, so far as I was concerned, this separation was effected without proper consideration, for I have not found elsewhere better opportunities for work nor any pleasanter or more stimulating environment for living.”

Source: Horace W. Davenport (1999) “Not Just any Medical: The Science, Practice, and Teaching of Medicine at the University of Michigan, 1850-1941”, University of Michigan Press, pages 61 and 62. •

Physiology Matters

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Give Online Thank you for your support!

Please explore giving options below.

W

e hope our successes this past year makes you proud of the University of Michigan Department of Molecular & Integrative Physiology. Our philanthropy funds play a key role in strengthening our department, faculty, and trainees. We hope you will play part and join many others in supporting Molecular & Integrative Physiology by making a gift to the funds below.

Bishr Omary Physiology Postdoctoral Awards & Symposium Fund Your gift will be used to support Molecular & Integrative Physiology postdoctoral career development in a variety of ways that include postdoc recognitions, the annual symposium, a named lectureship in conjunction with the annual symposium, postdoc travel and small grants, and other postdoctoral career development activities.

Donate online at https://www.giving.umich.edu/give/335629 Graduate Education Fund in Physiology Your gift will propel the development of future biomedical researchers currently enrolled in the Molecular & Integrative Physiology PhD Program. These individuals are studying the mechanistic basis of human diseases such as cancer, diabetes, and obesity. Donate online at http://victors.us/mipgraduate John and Margaret Faulkner Lectureship You will be supporting an annual lectureship by a prominent invited speaker selected by the students and faculty in honor of John and Margaret Faulkner. Donate online at http://victors.us/faulknerfund Master’s Education Fund in Physiology The MS in Physiology is designed for students who plan to pursue employment in a research laboratory, or to continue their education as PhD, medical, dental or other health professional schools. Your gift will provide financial assistant to master students. Donate online at http://victors.us/mipmaster Physiology Annual Fund Your gift enables the Department of Molecular & Integrative Physiology to direct resources where they are most needed or where opportunities are greatest, from upgrading or replacing a critical piece of lab equipment to providing resources to our trainees, researchers and faculty. Donate online at http://victors.us/mipfund

Physiology Summer Research Fellows Fund Your gift will support undergraduate students that are interested in research in physiology and/or biomedical sciences. This fund provides financial support to summer research fellows, their research and the summer program activities. Donate online at http://victors.us/mipsummer SEEK Fund The Science Engagement and Education for Kids (SEEK) is an outreach effort driven by the physiology students and department members to promote science in the community. This fund supports the development of outreach educational program and outreach activities. Donate online at http://victors.us/mipseek If you would like to discuss making a major donation to any of the above funds, leaving a gift for us in your will, or offering a pledge or gift of appreciated stock, please contact Joseph M. Piffaretti, our development officer, at 734-763-1318, or piffaret@umich.edu.

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Physiology Matters