Does early time-restricted feeding improve autonomic nervous system function?

Time-restricted feeding(TRF) is a method of meal scheduling that involves restricting your eating window every day, typically to 12 hours or less.  The data seems to be up and down on whether it’s useful for anything, likely because there are other factors that are at play for most of the things they study it for.

Let’s be frank here.  I feel time-restricted feeding can be extremely useful for optimizing your health.  All life under the Sun, and likely in the sea, have circadian rhythms driven either by the Sun or tides, respectively.  But just like anyone can formulate a crappy diet following vegan, Paleo, keto, or Mediterranean diet principles, so to can people following TRF.

Whereas crappy versions of the former diets are formulated based on food quality and quantity, crappy versions of TRF are formulated via poor timing of food intake in relation to other factors related to circadian rhythms.  This is because circadian rhythms optimize physiology by exposure to factors that our body uses as environmental cues to alter the various systems throughout the body (Endocrine, cardiovascular, nervous, immune, digestive, etc.).  Feeding is just one of those cues.

Circadian exposures integrate the various systems within the body via the autonomic nervous system and the release of hormones, neurotransmitters, and various other molecular messengers.  For example, TRF likely relays the feeding/fasting cycle through changes in insulin, bile output, ghrelin, orexin, and other hunger hormones.  The reward system in the brain also likely plays a role.

Light exposure ties all of these things to the day/night cycle.  Light exposure also plays a role in blood glucose regulation via melatonin, which acts as a brake on insulin secretion at night to prevent hypoglycemia during the fasting window.  That’s great for preventing hypoglycemia when you fast, but not great for preventing hyperinsulinemia and hyperglycemia when you eat late at night.  Note: some people are more sensitive to this effect due to genetic polymorphisms mentioned in the hyperlinked article, and those people have an increased risk for Type 2 diabetes.  Me being one of them.

Evidence also supports the idea that melatonin reduces the sensitivity of the adrenal gland to adrenocorticotropin hormone(ACTH), which reduces cortisol secretion.  Cortisol increases blood glucose levels indirectly via the counter-regulatory hormone to insulin, glucagon, which increases blood glucose by causing the liver to breakdown glycogen and release it as glucose.

Physical activity, sleep, and food quality are other factors that will have an effect on blood glucose regulation and all of the aforementioned hormones.  So we can’t expect to simply look at meal timing alone unless we control for other variables that impact the circadian clock.  A more holistic approach to circadian rhythms is needed.

So if TRF is to be useful and show consistent results in clinical trials, a few factors will need to be controlled:

  • It will likely have to be a within-subjects design to prevent genetic variability and past history among participants from impacting results
  • Food quality and quantity need to be matched
  • Other factors that affect circadian rhythms have to be controlled and/or measured (Light exposure, physical activity, social interaction, sleep)

Fortunately, a study was recently published that was successful in meeting most of that criteria, and the results were pretty impressive.

Early time-restricted feeding(eTRF) without weight loss for improving blood glucose

The purpose of this study was to look at changes in cardiometabolic factors in pre-diabetic men who consumed 3 meals in either a 6- or 12-hour window.  The diets were identical in both scenarios and each person followed each plan for 5 weeks with a 7 week washout period in between.  This was a counter-balanced design meaning some received eTRF first while others had the control diet first.  During the 6-hour eating window, participants consumed their last meal prior to 3 pm.

Large image of Figure 1.

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The diet was designed to promote weight maintenance, not weight loss, because they wanted to determine whether there are beneficial effects of eating timed within the appropriate circadian window.  Weight loss is known to have many benefits that would confound the results.

Given the short time period for the trials, the results were impressive.  While the participants saw no change in their blood glucose levels when they were performing eTRF, they saw large drops in peak insulin, mean insulin levels, and increased insulin sensitivity and beta cell responsiveness in their 3-hour oral glucose tolerance test(OGTT).

They also saw decreased hunger in the evening as well as a greater than 10 point drop in both their systolic and diastolic blood pressure, a drop consistent with that seen with the use of ACE inhibitors.  Based off questionnaires, eTRF was considered easy to stick to, probably due to the changes in hunger.  There were also a couple of odd findings that give us a little perspective.

First, while inflammatory markers didn’t change at all, oxidative stress levels increased substantially in the control arm of the study.  This led to a 14% lower level of oxidative stress in the eTRF group.  I chalk this up to the poor quality diet, which is, ironically, similar in composition to what is generally recommended for people with Type 2 diabetes.  Although those recommendations also promote weight loss over maintenance, processed food doesn’t appear to be well-tolerated in people with Type 2 diabetes.

Second, for those people who experienced eTRF first, the improvements in insulin sensitivity lasted through the 7 week washout period and in to the baseline testing for the 12-hour eating arm of the study.  This definitely confounded the results a bit, as did the slightly longer fasting window at the end of the eTRF arm.  Interestingly, these factors likely led to an underestimation of the beneficial effects of eTRF on insulin sensitivity.

Next, fasting triglycerides increased significantly during eTRF by 57mg/dL.  This isn’t the least bit surprising as they would have fasted for a much longer period of time than they are used to, and I imagine triglyceride metabolism wouldn’t improve in a 5 week window without increasing physical activity or exercise.  This is an adaptation that would take a longer period of time or a properly prescribed aerobic exercise program to improve.  Still, I would want confirmation that this is what was truly happening.

Finally, one person actually saw an increase in insulin levels during the eTRF portion of the study.  It’s worth it to mention that this individual had a long history of working night shift prior to the trial.  It’s not the least bit surprising that someone with a history of working night shift might respond poorly to eTRF given that their habitual patterns outside of their feeding/fasting window probably affect other circadian factors such as melatonin and cortisol output.

Now that we’ve gone over the results, let’s take a look at how we could provide more clarity on these results.

Additional measurements that would be useful

While this study is probably the best controlled study on TRF to date, it could be improved.  All of the dependent variables (OGTT, blood pressure, etc) were only measured in the morning.

Since we’re dealing with things regulated via circadian rhythms, a better approach would be to measure things continuously throughout the day.  Especially blood glucose as the circadian regulation of blood glucose in people with type 2 diabetes seems to have the biggest impact on morning blood glucose levels.  The authors brought this up in the discussion.  In addition to continuous blood glucose monitoring, continuous measures of heart rate, body temperature, and heart rate variability would also be nice.

Also, an increase in fasting triglycerides is concerning if taken out of context.  It makes sense that this would happen due to what I mentioned earlier.  However, you could measure daily physical activity and VO2max to confirm that the increase is due to poor triglyceride metabolism.  VO2max measures the maximum amount of oxygen you can use which is a surrogate measure of mitochondrial function.  Since triglycerides are metabolized in the mitochondria where oxygen is consumed, this would likely confirm this notion.

With all that being said, this is a fantastic study that gives us some true insight in to how we can improve our health simply by changing the times when we eat.  But how and why does this happen?  Let’s take a systems approach to looking at the potential mechanism behind these results.

Image result for autonomic nervous system

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eTRF, circadian rhythms, and the autonomic nervous system

This brings us to how the processes involved in the study results are regulated.  Since we’re dealing largely with things beyond our conscious control, taking a look at the autonomic nervous system and how circadian exposures regulate it can provide insight in to how things are improving with eTRF.

In simple terms, the autonomic nervous system has 2 arms:  The sympathetic nervous system and the parasympathetic nervous system.  Greater activation of the sympathetic nervous system puts our body in fight or flight mode, diverting resources to the muscles and mobilizing energy via the stress response.  The parasympathetic nervous system, on the other hand, puts the body in rest and digest mode, diverting resources to the organs of digestion and the immune system.

Theses systems work together to help you successfully navigate your environment.  You need to be able to freely move between the 2 arms of the autonomic nervous system for your organ systems to function properly with one another.  With decreased parasympathetic activity, the organ systems that are enhanced by the parasympathetic nervous system enter dysfunction.

A recent study found that inducing mild hyperlgycemia and doubling insulin output in healthy men led to a change in how the autonomic nervous system regulates cardiac output.  The circadian drop in heart rate and blood pressure that comes at night were eliminated within 2 days.  Heart rate variability, a measure of autonomic nervous system balance also decreased.  This would affect a slew of physiological activities including sleep and digestion.  The drop was due to a decrease in vagus nerve activity, which controls the parasympathetic arm of the autonomic nervous system and functions as the communication hub in the gut-brain axis.

Since this change was induced in a couple of days, it indicates that the change in autonomic function was completely unrelated to weight gain and was due to improper glucose and insulin signaling.  This is something that eTRF can improve by eliminating swings in blood glucose at night and likely explains the improvement in blood pressure seen with eTRF in the recent study.

Sympathetic nervous system dominance is a hallmark of Type 2 diabetes with the earliest changes happening in the first 5-10 years of the disease.  This helps explain their chronically elevated levels of inflammation as well as their increased risk for gut disorders and cardiovascular disease.

It appears that eTRF may be a useful way to begin addressing autonomic dysfunction, at least in the cardiovascular system of prediabetics.  Addressing other issues such as light exposure, physical activity, and improving sleep hygiene will likely have added benefits but require further study.

Conclusion

Time-restricted feeding, particularly when it falls within the proper circadian window, can be a useful way to improve health in people with prediabetes.  But it’s important to point out that TRF only manipulates 1 of many circadian time cues.

While eTRF places food intake at the proper time of day, our circadian architecture isn’t set by the time on the clock, it’s set by light exposure.  Therefore, it’s important to address and measure light and sleep for optimal effect.  This may help explain why some people respond well to eTRF while others don’t.

Ideally, other factors such as physical activity and VO2 max should be measured to provide clarity on seemingly detrimental measures such as increased fasting triglycerides.  In the context of someone performing eTRF, increased fasting triglycerides may be a beneficial effect showing improved ability to access body fat during your fasting period.  It can also be easily improved with exercise which is where confirmation of the mechanism can come in handy.

Optimizing circadian rhythms is an important aspect of health that’s only recently being given the attention it deserves.  By improving autonomic function, it has the potential to lower chronic disease burden and enhance healthspan without weight loss.  Based on the data in this study, it appears eTRF is something people can stick to once they start.  But for true health optimization, addressing other lifestyle exposures that help regulate the circadian is also necessary.

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