The ticking clock of metabolic disease

Mitchell Lazar planned on becoming a chemist. But when his chemistry studies landed him in a lecture on the brain, he became fascinated by how neurotransmitters and drugs could influence sophisticated brain functions. “As somebody interested in chemistry and also with some family history of mental illness, I thought this would be a great way to understand the biochemical basis of behavior,” Lazar said. He pivoted to pursue an MD-PhD to study neurochemistry and went on to train as an endocrinologist, conduct research on thyroid hormone receptors, and eventually become a leading expert on the molecular mechanisms underlying metabolic disease. 

In many ways, his career path parallels the metabolic mechanisms he studies, where unforeseen external influences trigger cascades with far reaching and unexpected ripple effects. Now the director of the Institute for Diabetes, Obesity, and Metabolism at the University of Pennsylvania, Lazar investigates the transcriptional regulation of metabolism and how environmental factors such as circadian disruption can throw it out of balance, leading to obesity and diabetes. By examining the effects of genetic and environmental changes on metabolic physiology, he maps the complex interactions between circadian rhythms, transcription factors, and metabolism. His research provides insights that help identify new drug targets, drug time courses, and biomarkers to treat metabolic disease. 

How would you characterize the roles of genetic and environmental factors in driving metabolic disease?

Our destinies are a combination of our genes and our environments. Studies of identical twins show that obesity and diabetes are highly genetic in origin. On the other hand, metabolic diseases and their consequences, including heart disease, kidney disease, and to some extent, cancer, are advancing at a rate that cannot be explained by changes in our genomes. Evolution doesn't happen within the 50- to 100-year period in which we’ve seen this drastic increase in these diseases. There has to be something about the environment, and for most people, that’s access to high calorie, tasty, and relatively inexpensive foods at all times of day. The question is what to do about it from a public health point of view. The obvious almost glib answer is to eat less and exercise more, but that’s a lot harder than one might think. The vast majority of people who lose weight while on a diet gain it back. That begs the questions: Is there something else in addition to watching what one eats and exercising that would be effective? What are the pathways that could work together to fight the obesity and diabetes crisis?

What is the relationship between circadian disruption and metabolic disease?

There are clear epidemiological associations. People working night shifts show much higher rates of diabetes and obesity than the general population or people on the day shift, and researchers have proposed a range of explanations. The basic notion is that our metabolism is affected by a mismatch between when we eat and when we have evolved to eat. For example, during a meal, insulin drives glucose into the muscle for fuel. When we sleep, we're not eating anything, but the body still needs glucose for our brains while we dream. To sustain glucose levels during sleep, the body turns off insulin production. Essentially, people working the night shift eat at times when their body is programmed to sleep. 

Another potential factor, although the epidemiology is less clear, is the recent bombardment of light at night. We have lights everywhere: incandescent lights, fluorescent lights, and cell phones and tablets we use while lying in bed. That’s a real change, and there's a theoretical reason to think that it could affect our circadian rhythms because light is one of the major drivers of our internal clocks. Just as our hormonal system evolved to deal with not eating when we're sleeping, our internal clocks evolved to deal with the normal daylight pattern instead of all this artificial light.

What have you discovered about how circadian rhythms influence transcription and how that regulates metabolism?

There are certain transcription factors where expression changes over time in a circadian manner, leading the genes they regulate to also be activated or repressed in a circadian fashion. Early in my career, I serendipitously discovered a transcription factor termed Rev-erb (1). Later on, a key paper demonstrated that Rev-erb had a distinct circadian pattern of expression in both cultured cells and mice (2). In mice, it showed almost complete knockout at night when they are active, and high levels in many tissues, including the liver and brain, during the day when they are inactive. As we studied how that relates to metabolism, my team and the whole circadian rhythm field came to recognize that there is a clear circadian regulation of metabolism that can go awry. 

There is a clear circadian regulation of metabolism that can go awry. 
- Mitchell Lazar, University of Pennsylvania 

There are many feedback mechanisms and intersecting loops that make it challenging to define the relationships between transcription factors such as Rev-erb, metabolic genes, and the internal clock, but we're doing our best. We recently investigated the role of Rev-erb in the master clock, which resides in the part of the brain known as the suprachiasmatic nucleus (3). By receiving light signals from the retina and sending them to the rest of the body, the master clock synchronizes peripheral clocks that exist in almost every cell of the body but don't have a direct input from light.

We used genetic tricks to knock out Rev-erb in the suprachiasmatic nucleus in mice and exposed them to a 24-hour cycle of light and darkness. Interestingly, the mice displayed a rhythm of activity and rest that recurred every 21 hours, meaning that their master clocks were running fast. These mice also showed weight gain, elevated blood sugar, and fat accumulation in the liver. When we changed the cycle of light and darkness to simulate a 21-hour day to match their internal clocks, the mice did not gain as much weight, their blood sugar went down, and the amount of fat in their livers decreased. We're still trying to understand how Rev-erb maintains this circadian period in the master clock, but this result is exciting because it provides longitudinal evidence that circadian metabolic disruption results from a mismatch between the environment and the internal clock. 

What does your research reveal about drug targets and other therapeutic interventions for metabolic disease?

We have shown that the heme molecule that carries oxygen in hemoglobin can also bind a ligand pocket in Rev-erb and regulate its activity (4). We don’t yet understand the physiological implications of that interaction, and heme’s role in hemoglobin has a much larger effect on the body than whatever it's doing to Rev-erb. But Rev-erb is potentially druggable, and we can knock it out genetically or add more of it to the whole body or to specific tissues to evaluate the effects of loss or gain of Rev-erb in different cell types. But when we take it out, we're taking it out all the time, and when we put it in, we're putting it in all the time, so it's very difficult to mimic its circadian functions in those experiments.

Rev-erb and other clock factors drive so many phenomena all over the body in a circadian manner. And yet, when we give drugs, we typically imagine that the target of the drug is present 24/7. But if we know that the target is not there half of the day, we might want to design a drug that’s only there when the target is there in order to reduce side effects. We’ve demonstrated this chronopharmacology approach in model organisms, and while it would be challenging to apply to humans, it could show great promise even in taking existing drugs and improving their therapeutic indexes (5,6).

The idea of mismatch between the internal clock and the environment could be used to guide behavioral interventions for night shift workers. The right time to eat is when the body's clock thinks it's light because that’s when we’ve been programmed to eat. If we could identify biomarkers that tell us where a person’s internal clock is relative to the right time, we could possibly develop a quick test to tell someone where he or she is in the clock and when would be the best time to eat.

This interview has been condensed and edited for clarity.

References

1. Lazar, M.A., Hodin, R.A., Darling, D.S., & Chin, W.W. A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit. Mol Cell Biol  9, 1128-1136 (1989). 
2. Balsalobre, A., Damiola, F., & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell  93, 929-937 (1998). 
3. Adlanmerini, M. et al. Rev-erb nuclear receptors in the suprachiasmatic nucleus control circadian period and restrict diet-induced obesity. Sci Adv  7, eabh2007 (2021). 
4. Yin, L. et al. Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways. Science  318, 1786-1789 (2007). 
5. Guan, D. et al. Diet-induced circadian enhancer remodeling synchronizes opposing hepatic lipid metabolic processes. Cell  174, 831-842 (2018). 
6. Everett, L.J. & Lazar, M.A. Nuclear receptor Rev-erbα: up, down, and all around. Trends Endocrinol Metab  25, 586-592 (2014).