Transcription:
Research: Energy State to Transcription during Time-Restricted Feeding

Melanie Cole (Host): This is Better Edge, a Northwestern medicine podcast for physicians. I'm Melanie Cole and I invite you to listen as we explore the research on energy state to transcription during time restricted feeding. Joining me is Dr. Joseph Bass. He's the Chief in the Division of Endocrinology and the Director of the Center for Diabetes and Metabolism at Northwestern Medicine. Dr. Bass, it's a pleasure to have you join us today for this very interesting topic. Tell us a little bit about the focus of your research on circadian rhythms and metabolic homeostasis.

Joseph Bass, M.D., Ph.D. (Guest): Thank you Melanie. It's a pleasure to share with you some of the progress in the research environment at Northwestern University, that's in the umbrella of the medical center. This is really work that emerged in two campuses of Northwestern on both the Evanston Campus in Chemistry and the group of Milan Mirkovich who's Vice President for Research at Northwestern and our group on the Streeterville Campus. Our interest is in understanding the genetic and environmental links between the circadian system, which is the intrinsic system that governs sleep, wake cycles and all other internal 24 hour cycles and metabolic health.

So this story really began almost 20 years ago, the line of research when I moved to Northwestern and began to investigate the reasons why animals that had mutations in the core mechanism that regulates circadian rhythms, develop metabolic disease. What had happened was in the search for the genes that regulate the sleep wake cycle or the core clock, which is an endeavor that was awarded the Nobel prize in 2017, there was an effort at Northwestern and University of Wisconsin Madison, in fact, to apply genetic approaches in the mouse to identify the genes that regulate circadian rhythm, and actually the first genes in the animal kingdom to be identified in mammals that is, that govern rhythm were found in the 1990s by Joe Takahashi's group. And earlier work with Fred Turik had also developed an infrastructure to analyze these animals for their sleep-wake behavior. And when I landed at Northwestern, we identified effects of these mutations on energy balance and found that these animals eat at the wrong time of day when they should be asleep and develop obesity. So really leap forward many years.

And we come to this newest story where we identify one of the underlying mechanisms that bridges the process that regulates the sleep wake cycle with metabolic health. And the field really intersects with studies of calorie restriction and aging and lifespan, because it turns out that the mechanism that intersects between clocks and metabolism involves some of the same molecules that had been identified as important in what we call health span or lifespan regulating pathways in all sorts of organisms across all kingdoms of life. So, here we have sort of fundamental rules that govern the sleep wake cycle and metabolic health intersecting. And this is what we have continued to pursue.

Host: That's fascinating. And as you're telling us about the relationship between homeostasis and metabolism, tell us about some of the conclusions that you've drawn from your recent study published in Nature Metabolism.

Dr. Bass: Well, what we observe is that as cells undergo puric cycles, as animals and cells in the animals undergo the cycles of food storage and energy expenditure, that is the sort of daily cycle between eating and fasting that corresponds with when you're awake and when you're asleep. All of the cells in the body also have a clock that is ticking and telling the cell when to store energy and when to liberate it.

And we call that a redox cycle and it turns out that there are special molecules that report on the redox state in the cell and communicate with the ticking of the clock. And so what our newest studies do is to sort of peel back the layers of the onion here and look at how the redox cycle is actually detected at the level of the hands of the clock to either speed up or slow down metabolism, according to both the time of day and how much the animal has eaten during its period of wakefulness.

Host: So, then what's the significance of finding NADH inhibition of SIRT1 links, energy state to transcription during that time restricted feeding? How do you see this translating to patient care? And certainly with the issues that we see with metabolism and metabolic disease state today.

Dr. Bass: Well, we can view translation from many different angles and it's speculative. That's the caveat. This is very basic work and there are implications that we can project based on what we know about the chemistry of the molecules that we study and Milan's group, has special techniques to understand what's called a transcriptional regulator called SIRT1. And the sirtuins are a set of enzymes that detect redox and detect a molecule that's actually provided in vitamins, which is NAD, one of the B vitamins. And there's a great amount of interest in whether or not NAD exerts effects on health.

So, this nexus between this detection of NAD and the activity of this enzyme that regulates transcription SIRT1 is the core instructive set of ingredients that tells the clock whether to speed up or slow down each day. So, it's the levels of NAD and the way that NAD is consumed by these enzymes that regulate the clock that determines the rate of our metabolic cycle.

And these enzymes that the levels of NAD and the levels of the gene regulating enzyme, the sirtuins and the family of these enzymes are important across a wide variety of scenarios. They're important in inflammatory cells in regulating the response to infection, they're important in controlling and coordinating growth cycles with cycles of DNA replication in growing cells. So, they have implications in cancer biology, and they have activities in the cells in the brain that regulate our sleep wake cycle. So, there are broad implications for the basic chemical insight that came from our studies in a controlled experimental setting that ramify across our understanding of processes such as inflammation and cancer and cell growth. And even neurological functions such as sleep.

Host: So many, as you say, implications for this type of research. So, how are you incorporating these findings into your work at Northwestern Medicine? And how do you feel that this research will be beneficial in those treatment options for patients in the future? I mean, as you've just said, there are so many avenues that this could take.

Dr. Bass: So, our approach is to continue to build a deeper understanding of the basic chemical principles that govern the system. And in pursuing this, we take advantage of a range of technologies that are in place at Northwestern that have grown, and some of these have been spearheaded by another colleague important in this work, Nav Chandelle who's in the pulmonary division, in the department of medicine and Nav has implemented what's called metabolomic studies. So, what we would like to do is not only understand the effects of such cycles on transcriptional states, in the conditions of cancer and inflammation, for instance, but also on how metabolites shuttle around in cells. And how cells detect energy availability. And we're using approaches from metabolomics and from genomics to get at some of these basic questions. Ultimately there are implications for understanding sleep, but these are in the future. And, we continue to build through a focus on chemistry and genetics.

Host: I'll be so interested, as an exercise physiologist to see how some of this turns out. And I hope you'll join us again, Dr. Bass and fill us in as this research updates. Can you leave us with one parting piece of information for providers listening, what would you like the key takeaway to be?

Dr. Bass: I would say that one key takeaway is that the control of metabolic rate or energy expenditure is tightly linked to how much and when an animal eats. And I think that as we get a more granular understanding of this relationship between the time an animal eats and the nutrient content of the diet, we'll be able to apply these findings across a wide variety of disease states, and also to enhance the health of individuals, for instance, during aging, when the structure of the timing and relationship between sleep, wake cycles and the timing of the fasting feeding cycle may break down. So, we would like to develop a clear understanding of the principles of the system so that we can apply it and test the application of such understanding in the context of variety of diseases, which we are interested in and are actively under study at Northwestern.

Host: Thank you so much, Dr. Bass for joining us today and sharing this incredible research with us. To refer your patient or for more information you can visit nm.org to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. Please always remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. And for updates on the latest medical advancements and breakthroughs, please follow us on your social channels. I'm Melanie Cole.