Why Late-Night Eating is Linked to Weight Gain and Diabetes with Joseph Bass, MD, PhD
Disrupting our internal clocks can lead to diseases such as obesity and diabetes. Scientists at Northwestern have uncovered the mechanism behind why late-night eating is linked to weight gain and diabetes. Joseph Bass, MD, PhD, led the study published in the journal Science. He shares the results and details the two decades of work leading to this latest discovery. Bass is chief of the Division of Endocrinology, Metabolism and Molecular Medicine in the Department of Medicine.
“Simply placing an animal in a high fat diet environment will lead to disruption of the clock system. And this has important implications because it suggests that clocks, although they are intrinsic and cause us to awake each day at a certain time, are also sensitive to our dietary environment." — Joseph Bass, MD, PhD
- Director, Center for Diabetes and Metabolism
- Chief of Endocrinology in the Department of Medicine
- Charles F. Kettering Professor of Medicine
- Professor of Medicine in the Division of Endocrinology
- Member of Northwestern University Clinical and Translational Sciences Institute
- Member of the Robert H. Lurie Comprehensive Cancer Center
Scientists at Northwestern Medicine were the first to understand at the gene level why disrupting our internal clocks can be linked to weight gain and diabetes and how energy release may be the mechanism through which our internal clocks control energy balance.
- Bass says our contemporary understanding of circadian rhythms originated via an observation in plants by Jean-Jacques d'Ortous de Mairan, a French biologist in the 18th century, placed a mimosa plant in a dark box and showed that the leaf opening and closing of the plant continued even in constant darkness. This was the first evidence for an internal intrinsic process that enables all photosensitive organisms to anticipate the daily rising and setting of the sun.
- He arrived at Northwestern University Feinberg School of Medicine during a time when investigators there were exploring a breakthrough understanding between genes that program the regulation of sleep-wake cycles as well as circadian cycles, and processes that regulate endocrine systems. This became a launching pad for the next 20 years of Bass’ work.
- The questions that Bass and his colleagues wanted to address emerged within early studies showing that animals whose sleep-wake cycles are aligned with the rotation of the earth are prone to develop obesity as well as a broad range of other additional metabolic problems when the circadian clock is broken. This led to insights into the purpose of the clock beyond its role as a regulator of behavior.
- Bass and his colleagues also discovered that circadian clocks, although they are intrinsic and cause us to awake each day, are sensitive to our dietary environment, and furthermore, that the time an animal eats can influence its body weight. This was a problem Bass set out to address many years ago: this feedback loop between diet and clock.
- In their research on why eating late at night is linked to weight gain and diabetes, Bass and his team used a set of genetic tools to ask whether the energy burning capacity in the body of animals exhibits a circadian pattern, or in other words, whether the capacity to store or burn food varies according to the light-dark cycle.
- These findings have broad implications for public health. For example, patients who are fed with feeding tubes almost always develop very severe insulin resistance and abnormalities of metabolism, possibly due to a violation of the environmental day-night cycle which may give rise to a range of pathologies or disease.
- Bass describes this bidirectional relationship between timing and both light and nutrients as fundamental, and deepening this research could lead to a profound understanding of how genes are regulated in a rhythmic fashion, both within neurons in the brain to control behavior, and in tissues in peripheral organs to regulate functions such as energy dissipation.
- Ultimately, Bass hopes that this work will stimulate people from a wide range of fields to incorporate these insights into the context of other diseases.
- Browse all of Bass’ publications
- Read the Northwestern University press release about the Science study
- Find out more about the 2017 Nobel Prize in Physiology or Medicine, awarded jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their discoveries of molecular mechanisms controlling the circadian rhythm
Recorded February 1, 2023.
[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Northwestern Medicine scientists have uncovered the mechanism behind why late night eating is linked to weight gain and diabetes. These findings are built on more than 20 years of research at Northwestern that could have broad implications on our health and wellbeing, from dieting to sleep loss, to the way we feed patients who require long-term nutritional assistance. Here with details is Dr. Joseph Bass, chief of Endocrinology, metabolism and molecular medicine in the Department of Medicine and Director of the Center for Diabetes and Metabolism here at Feinberg. He led this study published in the journal Science and joins me today. Welcome Dr. Bass.
[00:01:03] Joseph Bass, PhD: Thank you.
[00:01:04] Erin Spain, MS: Knowledge of the circadian clock has been around since the 18th century and the 2017 Nobel Prize was awarded to scientists for their discoveries of molecular mechanisms controlling the circadian rhythm. Tell me about this field today and how your team at Northwestern is helping to push it forward.
[00:01:23] Joseph Bass, PhD: I think a little bit of background is helpful to understand the launching pad, so to speak, for the work that we've done, and as you mentioned or alluded to, the origins of the field really stem from the observation in plants, believe it or not, by de Mairan, a, a French biologist who in the 18th century placed the mimosa plant in a dark box and showed that the leaf opening and closing of the plant continued even in constant darkness. So that was the first evidence for an internal intrinsic process that enables organisms, all photosensitive organisms, to anticipate the daily rising and setting of the sun. So all organisms have this internal clock system, and it was really a breakthrough in genetics and molecular biology that occurred more than a century later in the period, the explosion of molecular understanding of biology, initially by mutagenizing flies, Seymour Benzer and Ron Konopka showed that genes control circadian behavior and in essence processes that also regulate the timing of sleep. And ultimately, those genes were cloned, and that was the award of the prize. However, the fly results provided us with the first entry point into understanding the molecules. But it was really work at Northwestern that was critical in, first of all, identifying a missing arm of the clock and secondly, providing evidence and a pathway to manipulate that arm in mammals, in animals, and this was done in mice using mouse genetics. And that was work initiated by both Fred Turek and then ultimately the molecular cloning was performed by Joe Takahashi, who then moved on to UT Southwestern. So I arrived at Northwestern in the setting of this breakthrough set of discoveries, and around the same time, a parallel transformation had occurred in our understanding of the signals and molecular pathways that regulate endocrine systems. And so we had the notion or that there may be an intersection between these genes, that program behavior regarding sleep and the regulation of sleep-wake cycles and circadian cycles and those processes that regulate endocrine systems and, and that was really what happened 20 years ago when I arrived here. We had the opportunity to bring these two fields together and, and that was the essentially launching pad for this work.
[00:04:06] Erin Spain, MS: Yeah, tell me a little bit about the environment right now at Northwestern. Who all is working on these projects with you?
[00:04:12] Joseph Bass, PhD: There are many people, too many to mention, and the environment has evolved over time as the development of molecular sciences and biomedical research has really exponentially increased on the Chicago campus at Northwestern. I would say over about the past decade and a couple of the key factors there were the expansion of capabilities for genetic studies in animals, which is critical for understanding molecular processes and extending insight from what was discovered in fruit flies. And what we discussed a moment ago, and transferring that information into mammals, and in this case we use mice. And so that infrastructure really developed at Northwestern and much of the biochemical and molecular aspects of the work also evolved. I mean, I would say initially with the introduction of next generation sequencing, for instance, and bio-energetic and behavioral studies at each one of these developments on the ground at Northwestern has provided the platform to remain at the leading edge of these intersectional fields.
[00:05:31] Erin Spain, MS: Mice were used in this study that we're gonna be discussing today that was recently published in Science. And before we dive into the results and what happened in this study, tell me a little bit about these mice that you use and about the diet that you fed them in this study.
[00:05:46] Joseph Bass, PhD: Because mice share over 95 percent of the genome with humans, and because we can manipulate the genome of the mouse, it represents really the best opportunity to delve into the fundamental pathways that regulate physiology. So in this case, the questions that we wanted to address really emerged with our very early studies nearly 20 years ago, showing that first of all animals in which the circadian clock, the timing that maintains the sleep wake cycle in alignment with the rotation of the earth or the light-dark environment. These animals, when this clock is broken, are prone to develop obesity, and they also develop a range of broad range of other additional metabolic problems, such as the failure of the pancreas to produce insulin. So that set of discoveries which occurred over many years led to insights into the purpose of the clock, beyond its role as a regulator of the behavior. And at the same time, one of the ways in which we found and and confirmed the interrelationship between the clock system and body weight or energy balance was that in simply observing the effects of a Western over-nutrition diet, so to speak. In other words, when animals are provided with more food than they would normally encounter in the wild, they overeat just as humans do. But what was interesting in our early observations was that we found that even animals that have normal genes programming the clock, begin to exhibit abnormalities that mirror the effects of a broken clock. In other words, simply placing an animal in a high-fat environment, high-fat diet environment will lead to disruption of the clock system. And this has important implications because it suggests that clocks, although they are intrinsic and cause us to awake each day at a certain time are also sensitive to our dietary environment. This observation led to the concept that the time that an animal eats influences its body weight, and it does so through a mechanism that must involve the intrinsic timing system, and that was a problem that we set out to address many years ago. This feedback from the diet to the clock, how does this happen and what are the regulators of this connectivity between clocks and diet?
[00:08:41] Erin Spain, MS: You recently published some results about these questions in the journal Science where your team uncovered the mechanism behind why eating late at night is linked to weight gain and diabetes. Tell me about this study and the results.
[00:08:56] Joseph Bass, PhD: We knew from our original work in the mutant animals, which was published in 2005 originally, and then subsequently work that was in Cell Metabolism in 2007. We knew that when an animal eats the equivalent amount of fat during the time when it should be asleep, it will begin to gain more weight than it should. In fact, almost all of the excess calories that animals consume as they become obese can be accounted for by the increase in their eating at the wrong time of day. So this observation suggested to us that there is something about providing equivalent or what we would call isocaloric diets at different times in the day and night cycle, in the light dark cycle that influences energy balance. And energy balance is a thermodynamic concept, which is essentially the difference between energy intake or food consumed and energy dissipated and animals dissipate energy as heat, burning energy in order to maintain body temperature and to dissipate energy as heat as well. And this process, we conjectured, must be somehow influenced by the clock. The efficiency with which an animal either stores the food it consumes or burns it as heat. And what we began to do was to use a set of genetic tools to ask whether the energy burning capacity in the body of the animal exhibits a circadian pattern that is whether the capacity to store or burn food varies according to the light-dark cycle, but also varies in a way that is dependent upon the pathways in energy dissipating tissues that have been discovered over the past decade.
[00:10:58] Erin Spain, MS: So this is basic science, the work that you're doing, but there is a connection for potential breakthroughs for patients, for people, especially patients who are in need of chronic care, such as being fed with feeding tubes. Why is that?
[00:11:12] Joseph Bass, PhD: The framework for understanding problems in medicine often returns us to the laboratory in order to provide a framework for our understanding of the problems. And as an example, beyond energy balance per se, meaning beyond body weight, we know that parallel processes also regulate metabolic health. So while in animals we may observe differences in body weight that are dependent upon the time when an animal eats, we know that these also travel together with differences in health and in this, I mean in particular, for instance, glucose metabolism, which is relevant in diabetes and lipid metabolism in inflammation, just to name a few. So these processes are tethered together, and if we observe differences in weight gain, this is a clue to us that the pathways that also regulate other metabolic functions may also exhibit day-night variation under the molecular control of the clock. Now, one scenario, there are number of scenarios where we observe differences across the day in metabolism. Most commonly, we know that, for instance, reproductive hormones exhibit very strong variation from morning to night. We also know that glucocorticoids exhibit a strong variation. Conversely, in the setting of intensive care or in the hospital where individuals who are unable to eat, for instance, are provided with enteral nutrition, meaning feeding through a tube. Almost all of these individuals develop very severe insulin resistance and abnormalities in metabolism. So one hypothesis that's related to the work that we've done is that some of the deleterious effects of the continuous feeding that occurs in the setting of critical illness and other interventions that are used to support life, but done so in a way that violates this environmental day-night cycle may give rise to a range of pathologies or disease. So one important and emerging idea is that the time when individuals are provided nutrition in the hospital should be considered very carefully from the context of when the intrinsic clock cycle may optimally handle that nutrition.
[00:13:46] Erin Spain, MS: I'm curious, Dr. Bass, what is it about this work that you find so fascinating and that keeps you working on these new discoveries and bringing new scientists into the field?
[00:13:57] Joseph Bass, PhD: Well, I think there are many ways of answering that. One is learning something new every day. There are many areas in science that afford that opportunity. I think biomedical research offers an immediate opportunity in so far as in when we learn about physiology and how systems work, we also begin to learn how much we don't know about those systems. And so we can break down the problem and and go into the laboratory and when I was training really in the 90s, the introduction of molecular tools into physiology was really exploding. And the ability to integrate an understanding of how systems work, meaning beyond an individual organ how do different tissues function to maintain health? And how are these pathways integrated with brain and behavior? So endocrine sciences are uniquely designed in, to enable studies of both the brain and behavior and of body organ systems in a sort of succession so that we can consider the network effects of molecular processes beyond an individual cell. So that is really exciting to me that we may be able to yield insights into processes such as the biology of eating and metabolism at the level of brain and peripheral organs together.
[00:15:28] Erin Spain, MS: And the question of the next generation. You really are training a lot of folks in your lab who were major contributors to this work that we're discussing today. Can you tell me about the folks who worked with you on this project?
[00:15:41] Joseph Bass, PhD: Well, I want to give a special shout to Chelsea Hepler, who is the postdoc whose talent was essential in advancing these ideas. Chelsea trained with Rana Gupta, a close collaborator of ours who at the time was at UT Southwestern and is now, in Dallas, and is now at Duke. And Rana discovered some of the core molecules that control energy dissipation in animals, and Chelsea understood the availability of these models and, and their application in the context of obesity. And it was her skill in unifying or merging these tools and ideas from different angles that enabled the work. And I also want to point out that it was critical and the support of our current dean, Dean Nielsen and Doug Vaughn our chair in the recruitment of both Grant Barrish who came here from the Salk and also Lisa Beutler, who came more recently from UCSF to create the environment that fosters training and exchange of ideas and bring different skills to the table that enable this work. It's really a collaborative group effort and I would also add that Nav Chandel, who is a bio energetics expert, has been a close collaborator, as has been Milan Mrksich, who's now the VP for research at Northwestern. So many different colleagues and scientists in the university have been key in advancing important contributing aspects of the work.
[00:17:14] Erin Spain, MS: So how does this latest study impact the arc of the work that you've been doing at Northwestern?
[00:17:20] Joseph Bass, PhD: Well, I think we, we come back to some core problems such as how do we understand fundamentally the problems that arise when either the sleep-wake cycle is misaligned with the environmental cycle or the environment causes a change in the alignment of these cycles. So, the arc of our work really is that this bidirectional relationship between timing and both light and nutrient are fundamental and insofar as the pathway is programmed by a set of what we call transcription factors. Our understanding of this interrelationship can build from the very fundamental level of how genes are regulated in a rhythmic fashion within both neurons in the brain to control behavior and tissues in peripheral organs to regulate functions such as energy dissipation. We continue to work on these cycles and to examine abnormalities that occur when we turn on or off switches using genetic tricks to manipulate in a cell type specific way, how these gears operate to regulate physiology and ultimately this will, we believe, stimulate people from a wide range of fields to incorporate the insights into the context of other diseases. As an example in the context of inflammation or growth in proliferation or regeneration of tissues.
[00:18:59] Erin Spain, MS: Well, thank you so much, Dr. Joseph Bass for coming on the show today and talking about this study.
[00:19:04] Joseph Bass, PhD: Thank you.
[00:19:15] Erin Spain, MS: Thanks for listening, and be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts. And rate and review us. Also for medical professionals this episode of Breakthroughs is available for CME credit. Go to our website, Feinberg.northwestern.edu.
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Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.
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At the conclusion of this activity, participants will be able to:
- Identify the research interests and initiatives of Feinberg faculty.
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The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Credit Designation Statement
The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Joseph Bass, MD, PhD, has received honoraria from NovoNordisk but the relationship has ended. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. Feinberg School of Medicine's CME Leadership and Staff have nothing to disclose: Clara J. Schroedl, MD, Medical Director of CME, Sheryl Corey, Manager of CME, Allison McCollum, Senior Program Coordinator, Katie Daley, Senior Program Coordinator, Michael John Rooney, Senior RSS Coordinator, and Rhea Alexis Banks, Administrative Assistant 2. All the relevant financial relationships for these individuals have been mitigated.