Time-restricted eating and the effect of late night eating | Satchin Panda
Findings from recent studies indicate that melatonin – the hormone commonly associated with sleep – influences critical aspects of metabolism, especially those that regulate insulin sensitivity. Melatonin release increases in the evening in response to low light and circadian rhythms to promote sleepiness. But it also binds to receptors in the gut that signal the pancreas to reduce insulin production. Eating late at night when insulin levels are naturally low can have negative effects on human health. Time-restricted eating, however, limits the daytime window during which a person eats to take advantage of the time when metabolism is optimized, improving health and even promoting weight loss. In this clip, Dr. Satchin Panda describes recent research that links melatonin to metabolism and explains how time-restricted eating can capitalize on this link.
Rhonda: I guess, also, what I was wondering is if you think about it, like, so the minute you start your metabolism clocks in your liver, for example...
Rhonda: ...the minute you start those metabolism clocks by your first sip of coffee and breakfast, the clock's ticking and you're insulin-sensitive. You're gonna be able to, you know, take glucose up into various cells after you eat. And then once you get past that time, so you're now 12 hours out, you're not gonna be as insulin-sensitive.
So, let's take someone that is doing intermittent fasting, and they wake up at 6:00 or 7 a.m. They have coffee and breakfast, a big breakfast, and they're done. So then they fast for 12 hours, so now it's 7 p.m., maybe 13 hours, 7:30, 8 p.m. They've been fasting all day, so they're getting a lot of the activation of some of these...
Rhonda: ...you know, stress-response pathways like AMP kinase and, you know, they're making some ketone bodies, Kreb, all these similar pathways are being activated.
Rhonda: ...that, you know, time-restricting feeding also activates. But then, they take a big meal at 7:30 or 8 p.m., so 12 or 13 hours after they've already set their clock.
Rhonda: So now in theory, then, they're…well, I don't know if this is true or not, maybe the intermittent fasting changes some of this, but, you know, their liver wouldn't be, you know, it wouldn't be working as well at that point. Or do you think that just because they were fasting all day that may change some of that and allow them to then eat this meal and it wouldn't have such a negative effect?
Satchin: Yes, so that's a very interesting question that we get many times and we are thinking of addressing that. It's very hard to do that in experimental animal models because if you fast them, if you give them two meals, they reduce their caloric intake, but it's possible to do. But here is something that came out only in last three to four weeks. You mentioned early in our conversation that insulin sensitivity is not the same at the end of the day, and the question is, if you fast enough during the day, is your insulin sensitivity as good enough as in the morning?
[Stachin]: Then everything you can equalize is at least insulin, which is a big thing in metabolism [inaudible 00:55:42].
So recently, what we are finding is actually the smoking gun came almost 10 years ago when people who are doing GWAS studies to find whether there are mutations in given genes that make us more diabetic or obese, surprisingly, people thought that, "Okay, so we'll find some genes that regulate metabolism." Right? So that is the common sense. But then the big surprise was they found melatonin receptor as one of their top hits.
Satchin: And some of the clock genes, like cryptochromes, in the top five or ten genes. That is not only in one study. In multiple studies, they found it. So they are the smoking gun. What is melatonin doing with this obesity and diabetes? And recently, what is interesting is people are finding that melatonin receptor is present in pancreatic islet cells, beta cells, and melatonin receptors, when it's engaged with melatonin, it signals and it inhibits insulin secretion.
Rhonda: What? Really?
Satchin: Yeah. So it just came out, like, four, five weeks...
Rhonda: Wait, so you know that I've always wondered, because, like, most of the melatonin in the body is actually made in the gut, right? So tryptophan from dietary protein gets converted into serotonin...
Rhonda: ...and that's converted in melatonin. This is happening in the gut and...
Satchin: No, serotonin goes to pineal and then gets into...
Rhonda: So there's, so this, so the, it happens in the gut and it also happens in the brain?
Rhonda: There's two separate genes that do this.
Rhonda: And what's really interesting is I don't know what melatonin...why are we making it in our gut? So I'm wondering if it's somehow signaling to the pancreas.
Satchin: Yeah, so this is completely new. So that's why now it brings up...now, it helps us to connect this dot that people have. I mean, for the last 35 years clinicians know that the insulin sensitivity is very different between day and night. And then the GWAS, the human genetics people came and said, "Yes, there is some smoking gun with melatonin." And now, finally we are finally saying, "Yes, melatonin receptor can actually inhibit insulin secretion." So in that way, having an evening meal, maybe with candle light dinner, is not a good idea because you have less light, so you have more melatonin, and that can inhibit... [laughs]
Rhonda: That's fascinating. I have to get that study. It's very, very interesting.
Satchin: So that's one case where we might think that late night, even if you control food calorie, the same calorie taken in late in the night versus early in the evening might have different effect. In fact, there was one study that came out from Spain, two or three years ago now, showing that in a weight loss trial they actually found...although everybody got the same diet, they were controlled for activity, clearly there were two groups of people. One group lost weight significantly, a lot of weight loss, and the other group lost moderate amount of weight. And when they did post-hoc analysis to see what is the difference, the only difference they found was the group that lost weight, they actually had their lunch…in Spain, people eat lunch at 3:00. So they ate lunch earlier whereas the group that did not lose weight, two months, they ate their lunch later. So that is another piece in the puzzle saying that late-night eating might actually prevent weight loss.
Rhonda: Right. And you've now translated some of these findings into some human trials using this smartphone app that you've developed. So that's kind of neat as well.
Satchin: Yeah. So one thing was we wanted to see when people actually eat. And in typical nutrition studies, people are asked, "When do you eat lunch, breakfast, and dinner?" But that doesn't capture, really, all snacking and everything. So that's why we thought how to capture when people eat in a very evidence-based manner. And we thought if we asked people to take a picture of their food, then the picture will speak a volume. It will have every single component. They would not have time to describe everything on their plate, but we'll capture that. It will also have the timestamp. So the whole idea was to see when do actually people eat. Are there a lot of people who eat like mice do that nibble throughout the day and night? And if they actually eat until, say for more than 12 hours or 13 hours, then they are the ones who may benefit from time-restricted feeding.
So when we did this experiment, when we started this project, we thought that…everybody we asked, they would say, "Yeah, I wake up, I have my first sip of coffee and usually I eat all of my food within 12 hours." So we were very discouraged to hear that. But then we carefully selected people who don't do a shift work so they will not have to work in the nighttime, that's when they're changing their eating time, and they're also not on any medication that will change their hunger or satiety. So we took really healthy people from San Diego area because we live here, and they just had to take a picture of their food. And that way, it was also less stressful for them to enter what they ate, and portion size, etc.
Rhonda: Way better compliance, I'm sure.
Satchin: Yeah. There's only three clicks, because if you think about it, open the app, take a picture, and then press the save button. And the option was they could actually describe what they ate. But we found very few people actually describe what they eat. So that means just typing that on your left hand when you're eating is not a very pleasant experience.
What we found is out of these 156 people, nearly 50% people eat during 15 hours. So that means between their first bite, non-water bite, to the last non-water bite or sip in a given day is around 15 hours, which some people think, "Oh, that's normal because if they start their first sip of coffee at 6:00 in the morning, and then after dinner they're watching their favorite show, and then had another glass of wine or chips, that can go up to 9 p.m." But then we asked...well, in mice, we can actually take away food and enforce time-restricted feeding. We can't do that with humans. They have to be self-motivated.
So we asked whether it's feasible for some people to at least restrict the time. So we asked eight of them to see…they were eating for 14 hours or longer and they were a little bit overweight, so we asked if they can eat within 10 to 11 hours. And we said, "We are not going to ask you to change what and how much you eat. The only thing you have to do is select your own time, depending on what time you go to work or what time you come back, select your own time until we'll have 10 to 11 hours and try to stick to it every day, even on the weekend."
And surprisingly, all of these eight people, they self-selected their 10 hours, 10 to 11 hours, and they stuck to it for 16 weeks, and at the end of 16 weeks they came back. We saw that they had lost around 4%, 3.8% body weight within the 16 weeks. They didn't have to do too many, they didn't have to read labels, they didn't have to type portion size. But then when we asked them, "Why did you do it," what is surprising is they said they slept better and they felt more energetic in the morning, and that's why they did it. And since they didn't have to count calories, it was also good.
But what is surprising is in mice, if you do the same experiment, mice will chow down. They will eat the same number of calories as when they have free access to food. But in humans, these people in our study, they actually ate 20% less calories. Even though we asked them to reduce their time, they ultimately reduced their calorie. But if you think about it, this is a much better way to control, manage their diet than to count calories. So in some way this study is inconclusive to say whether time restriction alone was beneficial for weight loss. But what it showed is the feasibility that some people can time-restrict and that can be an indirect way to reduce your calorie.
And since we're collecting picture of every single food, we can also ask another very simple question. "What is the time of the day when people are more likely to eat certain type of food?" As you can imagine, we found people drink most of their coffees, 70% of their coffee, within four to five hours interval in the morning. And people ate 70% of their alcohol in the evening, four to five hours. So now imagine if somebody's time restricting to the daytime, then he or she is more likely to lose on alcohol. So in that way, that also improves the quality of diet. So since we humans eat different type of food at different time of the day, depending on which interval we choose may indirectly result in change in nutrition quality, and to some extent, quantity.
Rhonda: And what about the cutting out, like, the ice cream and desserts?
Satchin: Yeah, so most of the reduction in calorie was due to reduction in late night snacks.
Satchin: And after dinner, ice cream, dessert, and alcohol.
AMP Kinase (AMPK)
An enzyme that plays multiple roles in cellular energy homeostasis. AMP kinase activation stimulates hepatic fatty acid oxidation, ketogenesis, skeletal muscle fatty acid oxidation, and glucose uptake; inhibits cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, and lipogenesis; and modulates insulin secretion by pancreatic beta-cells.
A gene encoding a transcription factor (CLOCK) that affects both the persistence and period of circadian rhythms. CLOCK functions as an essential activator of downstream elements in the pathway critical to the generation of circadian rhythms. In humans, polymorphisms in the CLOCK gene have been associated with increased insomnia, weight loss difficulty, and recurrence of major depressive episodes in patients with bipolar disorder.
GWAS (Genome Wide Association Study)
A type of observational study that searches the genome for small variations, called single nucleotide polymorphisms, or SNPs, that occur more frequently in the DNA of people with a particular disease than in people without the disease. GWAS studies help researchers identify genes that may contribute to a person’s risk of developing a certain disease.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
A broad term that describes periods of voluntary abstention from food and (non-water) drinks, lasting several hours to days. Depending on the length of the fasting period and a variety of other factors, intermittent fasting may promote certain beneficial metabolic processes, such as the increased production of ketones due to the use of stored fat as an energy source. The phrase “intermittent fasting” may refer to any of the following:
- Time-restricted eating
- Alternate-day fasting
- Periodic fasting (multi-day)
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
A hormone that regulates the sleep-wake cycle in mammals. Melatonin is produced in the pineal gland of the brain and is involved in the expression of more than 500 genes. The greatest influence on melatonin secretion is light: Generally, melatonin levels are low during the day and high during the night. Interestingly, melatonin levels are elevated in blind people, potentially contributing to their decreased cancer risk.
 Feychting, Maria, Bill Österlund, and Anders Ahlbom. "Reduced cancer incidence among the blind."_ Epidemiology_ (1998): 490-494.
Pancreatic Islet Cells
A type of cell found in the pancreas that make up 65-80% of the cells in its islets. The primary function of a beta cell is to store and release insulin. These are the cells which are believed to be the cause of type 1 diabetes under circumstances in which the cells themselves are under attack as part of an autoimmune response. In contrast, type 2 diabetics still have functional beta cells, but their body has, instead, become less responsive to the insulin produced.
A small molecule that functions as both a neurotransmitter and a hormone. Serotonin is produced in the brain and gut and facilitates the bidirectional communication between the two. It regulates many physiological functions, including sleep, appetite, mood, thermoregulation, and others. Many antidepressants are selective serotonin reuptake inhibitors (SSRIs), which work by preventing the reabsorption of serotonin, thereby increasing extracellular levels of the hormone.
An essential amino acid. Tryptophan plays key roles in the biosynthesis of proteins and is a precursor to several molecules with physiological significance, including melatonin, niacin, and the neurotransmitter serotonin. Inflammation causes tryptophan to be reallocated from serotonin synthesis to that of kynurenine, which then converts to the neurotoxin quinolinic acid, leading to depression. Dietary sources of tryptophan include most protein-based foods, such as meat, beans, or nuts.
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