Highlights of Hope Spring/Summer 23

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RESEARCH Study reveals two major obesity subtypes linked to random chance How does random chance — the same kind that governs a roll of the dice — impact our health? Quite a lot, it turns out. A team led by VAI scientist Dr. J. Andrew Pospisilik has identified two distinct types of obesity with physiological and molecular differences that may have lifelong consequences for health, disease and response to medication. Importantly, it appears that random chance plays a role in an individual’s predisposition to one type of obesity versus the other. The findings, published in the journal Nature Metabolism, offer a more nuanced understanding of obesity than current definitions and reveal new insights into the link between insulin and obesity. “Nearly two billion people worldwide are considered overweight and there are more than 600 million people with obesity, yet we have no framework for stratifying individuals according to their more precise disease etiologies,” Pospisilik said. “Using a purely data-driven approach, we see for the first time that there are at least two different metabolic subtypes of obesity, each with their own physiological and molecular features that influence health. Translating these findings into a clinically usable test could help doctors provide more precise care for patients.” Currently, obesity is diagnosed using body mass index (BMI), an index correlated to body fat that is generated by comparing weight in relation to height. It is an imperfect measure, Pospisilik says, because it doesn’t account for underlying biological differences and can misrepresent an individual’s health status. The findings also reveal the role chance plays in predisposing a person to one of the two obesity subtypes. Only 30%–50% of human trait outcomes can be linked to genetics or environmental influences. That means as much as half of who we are is governed by something else. This phenomenon is called unexplained phenotypic variation (UPV), and it offers both a challenge and untapped potential to scientists like Pospisilik and his collaborators. The study indicates that the roots of UPV likely lie in epigenetics, the processes that govern when and to what extent the instructions in DNA are used. Epigenetic mechanisms are the reason that individuals with the same genetic instruction manual, such as twins, may grow to have different traits, such as eye color and hair color. Epigenetics also offer tantalizing targets for precision treatment. “This unexplained variation is difficult to study, but the payoff of a deeper understanding is immense,” Pospisilik said. “Epigenetics can act like a light switch that flips genes ‘on’ or ‘off,’ which can promote health or, when things go wrong, disease. Accounting for UPV doesn’t exist in precision medicine right now, but it looks like it could be half the puzzle. Our findings underscore the power of recognizing these subtle differences between people to guide more precise ways to treat disease.” Read more at vai.org/obesity-subtypes. Research reported in this publication was supported by Van Andel Institute; Max Planck Gesellschaft; the European Union’s Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie grant agreement no. 675610; the Novo Nordisk Foundation and the European Foundation for the Study of Diabetes; the Danish Council for Independent Research; the National Human Genome Research Institute of the National Institutes of Health under award no. R21HG011964 (Pospisilik); and the NIH Common Fund, through the Office of the NIH Director (OD), and the National Human Genome Research Institute of the National Institutes of Health under award no. R01HG012444 (Pospisilik and Nadeau). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other granting organizations. Approximately 5% ($50,000) of funding for this study is from federal sources; approximately 95% ($950,000) is from non- U.S. governmental sources. DR. J. ANDREW POSPISILIK 12 | VAN ANDEL INSTITUTE HIGHLIGHTS OF HOPE
Cellular waste may supercharge immune cells The immune cells that protect us from infection and cancer seek out a wide array of fuel sources to power their function — including some long thought to be cellular waste products. That’s the surprising takeaway from recent findings published in the journal Cell Metabolism by VAI’s Dr. Russell Jones and collaborators. Their discovery lays the foundation for future personalized dietary recommendations designed to supercharge the immune system and augment therapies for cancer and other diseases. “Every process in the body is powered by metabolism, which in turn is fueled by the nutrients we consume through our diet,” said Jones, chair of VAI’s Department of Metabolism and Nutritional Programming and senior author of the study. “We found that immune cells are much more flexible in selecting the nutrient fuels they consume and, importantly, that they prefer some nutrients that were previously dismissed as waste. This understanding is crucial for optimizing T cell responses and developing new strategies for boosting our ability to fight off disease.” T cells are the soldiers of the immune system and are tasked with combating bacteria, viruses and even cancer cells. They absorb nutrients from the foods we eat to generate the energy required to carry out their jobs. The findings stem from a novel approach that could reshape how metabolism is studied. Historically, T cells are grown in the lab in dishes of nutrient-containing media — a gel-like substance chock full of certain cellular “foods.” However, this doesn’t fully reflect the rich array of nutrients found in the human body. To solve the problem, Jones and his colleagues developed media packed with a more diverse range of nutrients. Lactate is also an important byproduct of cancer cells and facilitates cancer’s ability to invade other tissues and evade attack by the immune system. Some research suggests that too much lactate may be bad for T cells. The work from Jones’ group indicates that, at lower levels, lactate may actually enhance T cell function. The findings also suggest that T cell function and survival are strongly influenced by the nutrients available in their environment. Going forward, Jones and his colleagues aim to delve deeper into the intricate relationships between metabolism and the immune system in search of new insights to further illuminate how these crucial systems collaborate. Read more at vai.org/supercharge-tcells. Research reported in this publication was supported by Van Andel Institute (Jones) and an Allen Distinguished Investigator Award, a Paul G. Allen Frontiers Group advised grant of the Paul G. Allen Family Foundation (Jones). Jones is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. R01AI165722. Support for authors on this project include a postdoctoral fellowship award from Fonds de la Recherche du Québec–Santé (FRQS) (Dahabieh); a VAI Metabolism and Nutrition (MeNu) Program Pathway-to-Independence Award (Longo); National Cancer Institute award no. T32CA251066-01A1) (Watson) and award no. R35CA2202901 (DeBerardinis); and the Howard Hughes Medical Institute Investigator Program (DeBerardinis). The content is solely the responsibility of the authors and does not necessarily represent the official views of granting organizations. “Previously, we were giving immune cells a very basic diet — the equivalent of just eggs and toast,” Jones said. “We found that, when we offer them a full buffet, these cells actually prefer a wider array of ‘fuels’ than previously believed. This has major implications for how we tailor dietary recommendations as ways to promote health and combat disease.” One example is lactate, a cellular waste product responsible for muscle aches after a long workout. When presented with glucose, a common sugar found in the body and in lab media, and lactate, the T cells preferentially used the lactate to power energy production — a decision that enhanced their function. VAN ANDEL INSTITUTE HIGHLIGHTS OF HOPE | 13
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Highlights of Hope Spring/Summer 23

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