Evidence Review: Intermittent Fasting, Meal Frequency

21 min read

Intermittent fasting and meal frequency are two topics that are intertwined as far as eating goes. Intermittent fasting has gained a notorious reputation for having many health effects in the recent years. On the other hand, the model of eating six meals per day and not one less remains deeply engraved in the mindset of most people. I review the available evidence for both concepts.

Post guide

I will be talking about intermittent fasting (IF), caloric restriction (CR), and meal frequency. With that said, let us cut the introduction and go straight to the information. First, I will revise the evidence that speaks for IF and CR as ways of improving various health markers, and why you should think about adding it to your eating patterns as well. Then I revise the evidence for meal frequency.


Introduction to intermittent fasting and caloric restriction

I will kick off with a video, a nice short introduction to the practical application of intermittent fasting and how you can incorporate it in your eating patterns with different IF protocols presented.

Please don’t be put off by his outer appearance. He gives a very clear and concise presentation about intermittent fasting and some other important metabolic aspects of leading a healthy life by optimizing what we eat and how we live. If you are wondering what intermittent fasting actually is, it is what the name says – you fast, intermittently; now and then. There are a few conceptual ideas on how to do this. It works under a framework of three oopses (the oopses will serve as a cute analogy for the conventional intermittent fasting protocols commonly used and recommended). The purpose is to (un)intentionally skip your breakfast (oops), lunch (double oops) and dinner (triple oops).

You can either:

(1) Skip one meal – I am sure many of us do this now and then because of different circumstances in which we find ourselves in. This represents one lonely oops. By skipping one meal you can either make your eating time frame more condense (the usual recommendation is a 4 to 8 hour period) or you can divide your eating window to two time frames in one day. That means you would eat breakfast and dinner and skip lunch or vice versa. This is left to personal preference.

(2) Skip two meals (double oops). With this you are opting for a 24 hour fast. For example, you have a lunch at 2pm and do not eat until the next day at around the same time.

(3) Skip three meals (triple oops). This is also called alternate day fasting (ADF), you do not eat for one day, eat the other, and continue doing this for a certain amount of time.

By doing any of the three you are calorically restricting your body. This is somewhat obvious given the fact that you are skipping one or more meals in one day. By doing so you are consuming less calories. And while caloric restriction and intermittent fasting have some overlapping mechanisms because of which the noted effects happen, intermittent fasting also has some independent outcomes that cannot be explained by caloric restriction alone.

This online calculator can help you do intermittent fasting with better precision. You put in your weight, height, and other variables, and then you can play around with your preferred macronutrient composition. It is a really good way to optimize your food intake to stay on track if you are trying to maintain muscle, bulk up, or lose weight.

By now you’ve probably asked yourself “Well ok, why should I even try intermittent fasting? It really sounds like a fad”

Here is why:


Research on people

Studies that were interested in the effects of caloric restriction and intermittent fasting have been done on animals since 1935. So this is not something really new, to be honest. One of the pioneering studies with mice from 1945 noted this: both male (69 days) and female (91 days) mice lived longer on average if they underwent an IF protocol. The numbers in the brackets represent their lifetime extension. In any case, this was just a short history lesson.

The first study I will be talking about was an intervention trial with two obese groups of women. Both did an intermittent fasting protocol. One was eating normal food with weekly consultations by a dietitian and the other consumed a liquid diet. At this point, it is worth mentioning that the study was sponsored by a company which sells liquid meal replacements.

After seven weeks, both groups had a big reduction in heart disease risk (reduced LDL cholesterol, triglycerides and increases in LDL particle size – good). This was partly due to improvements in messenger proteins that are excreted by fat (adipokines).

The liquid diet intermittent fasting group had better results. Their triglycerides decreased by 20%. However, this is most likely due to the fact that this group had lost more weight as they consumed less calories in total. The average amount of weight lost during this period was 4 kg in the liquid replacement group, and around 3 kg in the normal food group.

The group with the liquid meals noted the following decreases:

(1) Leptin (26%): Leptin is an adipokine and is a really important hormone in our body. It is an appetite inhibitor if it works correctly, and it is really sensitive to food fluctuations. If we do not eat – it lowers, if we eat – it goes up. It is especially sensitive when we do not eat as it lowers faster. Worth noting is that an absence of leptin usually will lead to uncontrolled eating. So why would a reduction in leptin be a good thing you ask? Because there is also a thing called leptin resistance. Obese people usually have a high amount of available leptin. They seem to be more desensitized to leptin. Because of this their brain does not receive the signal that they should stop eating when their body doesn’t need food anymore.

(2) IL-6 (19%): this ugly duckling is an interleukin that has been implicated in a variety of diseases.

(3) TNF-alpha (25%): is another adipokine involved in inflammation. An odd production of this gentleman has been implicated in Alzheimer’s, different types of cancer, major depressive disorder, and inflammatory bowel disease. It promotes the inflammatory response – this causes problems that can be observed in different autoimmune disorders. Because of this they are sometimes treated with an inhibitor of TNF.

(4) IGF-1 (10%): it is the only protein among this lot. But does it have role in our bodies – Reduced IGF-1 signaling is what is supposed to have the anti-aging effect of intermittent fasting/caloric restriction. Not only that, increased levels of IGF signaling lead to increased growth of cancer cells already present in our bodies.

Another randomized clinical trial found an average decrease of around 5 kg over a course of 12 weeks in the non-obese and obese groups. Their triglyceride levels dropped by 20%, while LDL particle size was increased – similarly as in the previous study. However, the issue I have with this study is the sample size. There were only 16 people present. But astonishingly it was enough for the effects to pronounce themselves quite consistently.

Another study noted an improvement in the body’s ability at using insulin (insulin sensitivity) following intermittent fasting. However, this was observed only in men. Intermittent fasting seems to have affected women differently as they even had a negative reaction towards glucose tolerance which may lead to type two diabetes. These are the findings of one study though – replicated results are always welcome.

Furthermore, one study noted an increase in HDL cholesterol only for women, and triglyceride level decreases only for men. There were no differences in blood pressure. However, this was only after three weeks which may have been too early to note such effects.

Further research in this field is needed to see if these sex specific results would be found consistently.

A post on Paleo For Women covers the topic of intermittent fasting for women more specifically. It is true that it mostly focuses on animal studies, as the majority have been done with animals, but it offers a thorough read about the differences that can occur with intermittent fasting.

Very recent findings suggest significant decreases in tension, anger, confusion, total mood disturbance, and improvements in vigor. This was observed in men who followed an intermittent fasting protocol for three months. This is great since it can lead to an enhancement in overall well-being in men. The observed changes were probably a consequence of an increase in available serotonin, endogenous opioids and endocannabioids. These molecules have been often found to have mood-enhancing effects.

Other authors observed increased efficiency when it came to glucose use and losing fat through intermittent fasting of their participants. This is yet another piece of evidence to support the notion that cycling between eating and not eating can improve metabolic functioning. These findings could also hint that intermittent fasting and training in the gym probably increase insulin action through different mechanisms, considering the energy stores didn’t change during fasting. Another interesting thing was that they didn’t see higher levels of fat in the muscles (intramuscular fat) after the fasting period. This is something the authors were expecting from earlier studies. And lastly. Intermittent fasting also improved blood vessel flow and with that reduced oxidative stress and inflammation.

 I would like to stop here for a second and explain why this duo is a naughty little pair.

Oxidative stress is classified as an imbalance between the chemically reactive molecules in our body that contain oxygen and the ability of our body to detoxify these reactive molecules, or at least repair the resulting damage. This imbalance in itself has a variety of negative effects on our body. It can cause the formation of free radicals or cause disruption in cellular signaling. Oxidative stress is probably involved in the development of cancer cells, heart failure, Alzheimer’s, Parkinson’s, stroke, and others.

Inflammation, however, is a body’s natural response, it’s a protective attempt to remove dangerous stimuli and to enable the body to start recuperating again. This short response is called acute inflammation. The problem arises when your body becomes exposed to chronic (long-term) inflammation. Chronic exposure can lead to a number of issues inside our bodies. These include atherosclerosis, rheumatoid arthritis, different types of cancer, periodontitis, and others.

Now we can see why reduced oxidative stress and chronic inflammation is something we would want in our lives, don’t we?


Research on animals

As I’ve mentioned at the start of my post, studies done with CR and IF on rats and observing their life-span have been done since 1935. But they are not the only species. Life extension has been consistently observed in mice, fruit flies, nematodes, water fleas, spiders, fish, and rhesus monkeys. What is interesting is that the amount by which life-span is extended has been shown to increase more as caloric intake is reduced – to the point of starvation, obviously.

There have also been observed positive effects on various cancer risk factors in animals.

Mice that underwent a calorie restriction or intermittent fasting protocol had a noticeable reduction of damage to hippocampal neurons. These neurons are connected to the preservation of memory and learning. This could have implications for disorders that have impaired memory as their symptoms, such as Alzheimer’s, Huntington’s, and Parkinson’s. In some studies, intermittent fasting protocols even improved their ability to learn and memorize.

For further reading on animal studies, I recommend this review from the John Hopkins University if you have access. It offers a detailed review of animals studies.

There have been no human studies that were well-controlled and scientific when it comes to observing possible life extension or long-term effects of caloric restriction or intermittent fasting. However, there have been some studies with our relatives – rhesus monkeys. When they underwent this regime, the restriction seemed to have life- and health-extending properties for them as well.


Concluding remarks about IF

I have written about the cool effects it has on people but here is another important thing. Fasting in such a way turns on this process in our bodies called autophagy. Basically, it is a mechanism/process through which the cells in your body recycle your own waste material and repair themselves, this is really just another proof how cool our bodies are. And while autophagy is a good thing as it is important for homeostasis through maintaining muscle mass, reducing negative effects of aging, and having neuroprotective effects, not everything is so fine and dandy.

The possible, but not necessary, negative effects that autophagy can have on us, can be read about on Caveman Doctor.

To give you the short version, there is a possibility that autophagy can decrease our immune system, help cancer cells stay alive in a particular way, could damage the liver if it is defunct in people undergoing an IF or CR protocol, and it can decrease/slow down the healing of wounds.

As with all things – overdoing this and putting our body under too much long-term stress is not healthy. While putting our body under smaller amounts of short-term stress now and then can have the mentioned beneficial effects.

For further reading on this topic in general I recommend the page of Brad Pilon.

References used: [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]


Meal frequency

There is a prevalent dogma which states that we need to consume five to six meal per day in order for our body to become a “blasting furnace”.

But let us take a little look at the evidence.

An intervention study in men and women that lasted 6 months and was examining differences between eating once per day and three times per day noticed:

  • No changes in bodyweight; all stayed within a 2 kg window from the start until the end
  • Heart rate, body temperature, various blood chemicals were unaffected
  • People who ate one meal per day had a significant reduction of fat mass and significant increases in HDL and LDL cholesterol, as well as worse morning glucose tolerance together with higher levels of fasting plasma glucose

The higher levels of fasting plasma glucose can be explained with them eating a bigger amount of food for dinner since blood glucose was measured in the morning. These higher plasma glucose levels were very quickly restored when returning to a three meal based eating pattern. This means it had no long-lasting effects on glucose metabolism.

There were also no changes in:

  • Leptin
  • Glucagon. It has an effect that is opposite to that of insulin, it raises blood glucose levels and causes the liver to convert stored glycogen to glucose. This glucose gets then released into the bloodstream.
  • Fasting insulin levels
  • Ghrelin. Mr. ghrelin is leptin’s counterpart. Its levels go up before we eat and go down after we eat, it’s also important as it allows our brain to change due to environment and helps in the process of learning.
  • Adiponectin. This little piggy is involved in the regulation of glucose levels and the oxidation of fats. Levels of this hormone are thus inversely connected to the body fat percentage has.
  • Resistin. Another hormone whose role seems not to be so clear as of yet. There have been a lot of studies for and against the support of his role in obesity and type two diabetes.
  • BDNF. The brain-derived neurotrophic factor is a protein in our bodies. It helps the neurons in our brain to survive. Not only that, it also encourages new neurons and synapses to grow and differentiate.

There was, however, a change in terms of a decreased insulin sensitivity in those who ate once per day.

The researchers in this study noted another interesting (albeit very common sense) thing. People were prone to consuming less calories if they had to eat only once per day – this is rather self-explanatory. Not everyone can munch down a meal that is around 2000 calories heavy. Which is why they had to ask them to consume the same amounts for better between group comparisons.

I think that I have written enough about the beneficial effects of intermittent fasting and caloric restriction that would have probably happened if people were left unchecked and followed a one meal eating pattern per day. Combined meal skipping with intermittent fasting would most probably result in health benefits that would include improved glucose regulation, if there was that overall decrease in how much food they ate during a day.

Another randomized clinical trial that is of interest was observing the satiety levels of people; how well did those who ate once per day feel. As we can imagine, getting used to eating once per day is hard. This was reflected in the study as well. People did not get accustomed to the feeling of being hungry during their fasting days, nor did they report lower levels of hunger during that time. This information was collected via subjective comments made by the people who participated.

Those who ate once per day saw a small increase in blood pressure at the end of the study. However, this increase was still within normal levels (116/70). To contradict these findings, another study with caloric restriction in the sense of eating once per day saw improved blood pressure and heart rate after exercise. These people also lost weight and body fat in particular under this condition. While this could be attributed to a lower calorie consumption, here is something interesting. The average weight at the start was 66.5 kg with an average 16.2 kg of fat mass. When the study was finished, people who ate once per day had lost 0,6 kg, on average. The ones who ate three times per day had gained 0,8 kg, on average.

Now the really interesting stuff. The average fat mass dropped by 2 kg in the group who ate once per day. The other group saw an increase of 0,1 kg.

This was probably due to gluconeogenesis which usually begins 4 to 6 hours after the last meal. It really starts to kick in once your liver glycogen gets totally depleted. It is also often connected to ketosis, basically, it’s a metabolic pathway which makes sure we have enough glucose in our bodies from sources that are not carbohydrates.


Worth mentioning

In a study done with people who have type 2 diabetes, they noted that reduced meal frequency (three meals per day) did not have any adverse effects on fasting lipid, insulin, or glucose levels. Neither did it have any effect on glucose, insulin, or triglyceride responses to a glucose load. This was observed when they were compared to another group who ate nine meals per day.

This may support the idea that an increased meal frequency for people with type two diabetes when considering practical implications (who eats 9 times a day?), is of little value. The increased meal frequency was also connected to the possibility of eating more calories during the day which is not what we would want, is it? A limitation of this study was a smaller sample though – it included only 13 men and women.

Another study done with people who had type 2 diabetes noted smaller blood glucose and insulin fluctuations after frequent smaller meals. However, there were no detectable changes in blood glucose after 8 hours. Higher fluctuations in the group with reduced meal frequency were most probably a normal response to an increased meal size which enhanced the secretion of insulin in their bodies as an answer. A limitation of this study was its smaller sample size. It was consisted out of 12 men and women.

One particular epidemiological study, that I would like to focus on, found a connection between an increased meal frequency and a reduced BMI. This goes hand in hand with breakfast skipping as a factor that needs more attention when it comes to eating.


  • It did not concern itself with the quality of food eaten in the two groups which is not cool. The food choices and total amounts of food eaten throughout the day are obviously more important than the number of times one eats.
  • The adolescents that were overweight also reported less physical activity.
  • The real connections between meal frequency and BMI were hilariously low, no serious scientist would regard them as practically important (an overlap of 1-3%).

And let me add another small thing. There is such a thing called reverse causality. For some reason, these two words don’t seem to be mentioned that much, at least, not as often as I would like them to. What if in all the epidemiological studies where people with reduced meal frequency have been noted to be overweight, had that reduced meal frequency because it was their way of losing weight? Mindblown?


What about my gains?

When it comes to people who do sports and movement, there have been very few studies that directly addressed this issue. The few good studies show:

(1) Those who ate six times per day had a significantly smaller loss of muscle mass and creatine in their bodies after two weeks – when compared to others who ate three times per day. However, this was only observed in a diet which made them lose weight.

(2) Noticeable increases in lean body mass (1,2 kg), which is not the same as muscle mass, and observed fat loss (1%). This happened after two weeks of three meals and three snacks as opposed to only three meals. Those who consumed six meals also had an increase in anaerobic power when they did the Wingate test.

Further reading about this topic can be obtained on Robb Wolf’s page, on Body Recomposition, and the biggest bodybuilding forum (the last one deals with the muscles aspect, for people that are concerned about gains).

References used: [19, 20, 21, 22, 23, 24, 25, 26 ]


The thermic effects

About the thermic effect. An older study about this found a whopping difference of 16 kcal (!) when people ate a 750 kcal meal in one sitting or in 6 different sittings at 30 minute intervals. That difference entitles you to eat three more mushrooms during the day ( the equivalent of that caloric intake).

But let us stop for a second. That is one meal of 750 kcal. You need almost/around 2 times that amount of calories each day to satisfy your needs. That would mean you could burn around 50kcal by consuming three large meals instead of 18 smaller ones! Ohh I can definitely see that beach body coming by doing that.

Ok, I had to be a bit sarcastic. When we talk about the thermic effect of food we are talking about the energy that is required for food that we put into our bodies to get fully processed inside. Different macronutrients have a different percentage when it comes to the thermic effect of food:

  • Proteins use around 20 to 30% of their own energy
  • Carbohydrates use around  5 to 10%
  • Fats use around 0 to 3%

The joint thermic effect usually provides for around 3 to 10% of our daily energy expenditure. The basal metabolic rate providing from 50 to 70%, and the active metabolic rate providing 30 to 40%. Moreover, different studies have shown that proteins are the most satiating macronutrient. This is the reason you should feel less hungry if your eating patterns involve higher amounts of protein.

Another important lesson would be that combining the macronutrient composition of our meals strategically could add up to a certain amount of calories that would be used just to process the foods we are eating. A study showed that combining chili and MCT oil can increase the thermic effect of food by around 50%. This can add up quite substantially.

Worth mentioning is that a limitation of this study was the number of people that were participating. It was conducted on 7 people. Therefore, I would be somewhat skeptical about the generalizability of these results. However, future studies will no doubt shed more light, as this topic has shown a lot of mixed results when it comes to certain food items that supposedly enhance the thermic effect of food.

References used: [27, 28]



If we wrap up most of these and others studies, we can end by saying that an increased meal frequency does not seem to have any important effect on the thermic effect of food, weight loss, or weight gain.

It does, however, cut the feelings of hunger and increases feelings of satiety. It also does not have a harmful effect on blood markers as reduced meal frequency raises LDL cholesterol and insulin levels.

In some cases it did raise LDL cholesterol levels but this was a transition from smaller to bigger, more effective, LDL particles which is a good thing.

You do not need to eat six time per day to “stoke your metabolism”.

Eating multiple times becomes important if you are leading a very physically demanding life in the sense of being an athlete.

Fasting and calorically restricting your body every once in a while will improve certain health markers connected to longevity and a reduced risk for common diseases of the Western world.

If you are a woman, be careful when doing fasting and calorically restricting your body for extended periods of time, read the link.

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