Understanding how fasting and feeding influence health and exercise metabolism is a hot topic for those interested in optimizing health and performance. So, let’s explore what happens when we eat, don’t eat, and what happens when we layer in exercise.

Overview of Energy Metabolism

The body primarily relies on fats and carbohydrates for energy. Fuel selection is influenced by two major factors:

1. Nutritional state: Whether you are fasted or fed.
2. Energy demands: Rest versus exercise.

What happens when we eat?

When we eat, nutrients enter the blood stream and are used to fuel immediate energy demands, replenish glycogen in the liver and muscle, and if provided in excess of these two fates, stored as fat. Carbohydrates elevate blood glucose levels, triggering insulin release. Insulin promotes glucose uptake into cells for energy and storage. This shifts whole-body metabolism towards oxidizing carbohydrates, and elevated insulin levels suppress fat oxidation. Any fats that we have consumed alongside a carbohydrate-containing meal are mostly taken up by and stored in adipose tissue, but some are taken up by muscle to be used as fuel or stored as intramuscular triglycerides. In the absence of carbohydrates, we don’t get this increase in carbohydrate oxidation post-meal, but will increase fat oxidation in proportion to what we’ve eaten (i.e., the higher the fat content of the meal, the greater the proportion is used as fuel).

What happens when we stop eating?

During fasting, the body shifts to preserve blood glucose levels (~4.5 mmol/L) through:

• Glycogenolysis: Breaking down stored glycogen.
• Gluconeogenesis: Producing glucose from non-carbohydrate sources.

These changes are the result of low insulin levels and an elevation in the hormone glucagon. Glucagon’s role is to tell the liver to start churning out glucose into the bloodstream to protect against hypoglycemia. Lower insulin levels also result in reduced glucose uptake and thus lower whole-body carbohydrate oxidation. In contrast, now that insulin is no longer inhibiting the release of fats from adipose tissue (and the uptake of fatty acids into skeletal muscle), fat oxidation increases. If we fast long enough, roughly anywhere between 16-24-hours, we start producing ketones and this is when we begin entering the metabolic state of ketosis. If you are in ketosis, this means you have effectively lowered liver glycogen to the point where glycogen and gluconeogenesis (the creation of glucose from non-glucose sources like amino acids, lactate and glycerol) can no longer meet the body’s glucose demands and needs an alternative fuel source – ketones (because unlike fats, ketones can be used as fuel for the brain).

Now, there may be benefits to exposing your brain and body to ketones, but this article isn’t about the benefits of ketosis. Rather, is there a benefit to fasting? 

This question opens a can of worms because the word “benefit” could mean a lot of different things! So, I’m going to approach this question through the lens of muscle. After all, muscle is one of the major determinants of our metabolic health, so improving metabolic health requires us to improve muscle metabolism.

First, let’s address within day fasting protocols, meaning the “fast” is taking place within a 24-hour timeframe – otherwise known as time-restricted eating (TRE). TRE can be a great tool for reducing calorie intake without the cognitive burden of focusing on reducing calorie intake – which is great for those looking to lose weight. If you are carrying excess body fat, weight loss, well, fat loss specifically, is a key mediator for improving metabolic health. However, compared to other forms of calorie restriction, TRE does not appear superior for weight loss and improving markers of metabolic health.

A note on muscle – Skeletal muscle, like I mentioned, is critical for regulating whole-body glucose and fat metabolism. It is essential for mobility, strength, power, and our functional capacity, especially with age. Skeletal muscle is a key determinant of our resting metabolic rate and therefore greatly influences body weight management. Thus, unsurprisingly, skeletal muscle mass and quality is strongly associated with chronic disease and mortality risk factors. Thus, anyone embarking on a weight loss journey or simply interested in improving their metabolic health should be concerned with preserving and/or building muscle alongside whatever else you are doing to get you to your goals – including any form of fasting.

Fasting and Muscle Mass

This goes without saying, but not eating is not going to be a great strategy for building muscle.

Since insulin serves to keep proteins tucked away in muscle tissue (i.e., anti-catabolic), going long periods without nutritional intake means the gates are now open for amino acids to exit muscle. These amino acids are either converted to glucose via gluconeogenesis to support energy metabolism or recycled for protein synthesis – likely in other organs and tissues such as the skin, brain, heart, and liver. Unlike muscle, these other tissues have a relatively constant rate of protein turnover between the fasted and fed states. Whereas in muscle, protein breakdown exceeds protein synthesis in the fasted state. Muscle is the body’s largest reservoir for protein “storage”, and in the absence of dietary protein intake (i.e., fasted state), become the primary source of circulating amino acids (beginning once we’ve exited the postprandially state, which is probably somewhere beyond 6-hours after eating). In the overnight fasted state (~10-12-hours after eating) muscle is in a state of net protein breakdown.

TRE, however, does not inevitably mean we are going to lose muscle. It just means that we should take muscle-centric actions within waking and feeding hours, stimulating muscle protein synthesis through weight-bearing exercise and protein intake, respectively.

Resistance training and amino acids are the two most potent anabolic stimuli for muscle – resistance training primes the body for muscle protein synthesis, and amino acids provide the building blocks.

Longer term TRE trials that incorporate resistance training show you can preserve and even build muscle mass so long as you are consuming at least 1.6g/kg (0.73g/lb) body weight of protein per day. Based on what is known about the acute anabolic response to protein, with each meal within the eating window, truncated or not, we want to maximally stimulate muscle protein synthesis, which requires somewhere around 20-40g of protein intake. Without pairing TRE with resistance training and conscious protein intake, you do run the risk of losing precious muscle tissue.

The takeaway here is that within day fasting, TRE, can be a really great strategy for body weight management but should be paired with resistance exercise and adequate protein intake to preserve and/or grow muscle mass due to the importance of muscle mass for metabolic health and healthy aging. This is true for any dietary regimen, but particularly important for those engaging in any form of fasting due to the catabolic nature of fasting.

Fasting and Muscle Metabolism

The way muscle uses and stores carbohydrates and fats have a massive influence on our overall metabolism, metabolic health, and thus, risk of chronic disease. At the epicenter of our muscle metabolism is mitochondria – where we turn food energy – glucose and fats – into cellular energy.

Low mitochondrial content and poor “function” (I’m using quotations here because function is a bit of a hand wavy term) are associated with insulin resistance – an underlying hallmark of metabolic disease. But mitochondria are highly plastic organelles, and they adapt to energetic stress by growing, multiplying, and improving their capacity for energy production. These adaptations, thus result in improved utilization and appropriate use of carbohydrates and fats – the underlying determinants of “metabolic flexibility”.

Fasting removes energy from the system, so it must be an energetic stress? And energetic stress triggers mitochondrial adaptations, and mitochondrial adaptations improve metabolic health, so fasting must improve metabolic health!! Or so the story goes, and what I thought was just common knowledge and an obvious use case for fasting.

However, after scouring the available literature on fasting and the activation of pathways that regulate mitochondrial adaptations, I was faced with the rude awakening that fasting is not an energetic stress in muscle tissue (up to 72 hours). Meaning, we wouldn’t expect it to increase mitochondrial content nor improve mitochondrial “function”.

Failure to show that fasting is a way to upregulate energetic stress pathways in human muscle contrasts with evidence in rodents, for which fasting is metabolically stressful and does activate those key pathways that are linked to improved health outcomes. In addition, short-term daily fasting improves metabolic health in mice, independent of calories. This is also not true of humans. Lastly, and in support of the acute findings in humans, fasting every other day for eight weeks with or without caloric restriction fails to increase any markers of improved fat oxidation.

Although fasting is a unique metabolic state, it seems that fasting is just a way to increase fat oxidation (acutely, as a response, not an adaptation). We have lots of fat available for our muscles to burn and mitochondrial capacity to meet the energy demands of fasting, without having to “stress” the system. In physiology, if we don’t “stress” the system, we don’t require adaptations because we are already well-equipped to handle whatever it is we are throwing at it. Mitochondria adapt when we exceed their capacity to keep up with energy demands, and this is when we activate glycolysis. This is what happens when we exercise and is why I believe exercise is the only real scenario that benefits skeletal muscle mitochondria.

This doesn’t mean fasting practices are useless. I am just more convinced that the metabolic health benefits of fasting are mostly related to caloric restriction and not related to improved mitochondrial “function”, “metabolic flexibility”, or ability to burn fat.

In Part 2, we will discuss what happens to metabolism and adaptations when we superimpose fasting with exercise.