A special heat-generating protein in brown fat, called thermogenin or uncoupling protein 1 (UCP1), is a transmembrane protein inside mitochondria that helps brown fat cells produce heat when they break down fats, or triacylglycerols, into free fatty acids. Cells with lots of mitochondria, such as muscle cells and brown fat cells with their heat-generating capabilities, are great at burning extra calories.

Unfortunately, adult humans have very little brown fat, although there has been some association between brown fat, living in cold climates and exercise. For those of us who aren’t athletes living in Alaska, however, there might be good news. White fat cells can take on characteristics of brown fat cells, a process called beiging, with metabolic interventions including exercise in humans and caloric restriction or intermittent fasting in mice. Beige or “brite” fat cells contain more mitochondria and have a different gene expression profile from white fat cells.

The potential for fat browning induced by intermittent fasting hasn’t yet been supported by research in humans, although there are theoretical mechanisms by which it could. Fasting can attenuate inflammatory cytokines, which we will learn below are associated with the dangers of visceral fat.

Read more: White adipose tissue coloring by intermittent fasting, Nature Cell Research

Running Out of Glycogen

“We only store enough glycogen, the storage mechanism for glucose, to keep us going for about 16 hours,” Stephens said. “But most of us can go without calories for two days and be absolutely fine, thanks to lipolysis.”

Fasting triggers lipolysis, or the breakdown of fats into fatty acids for energy use, through adrenergic stimulation, or through chemical messengers such as epinephrine and norepinephrine associated with stress responses in animals and humans. (Interestingly, both fasting and exercise are examples of “good” stress, or activities that can prompt healthy cellular responses to stress.) During lipolysis, triacylglycerol gets released from fat cells and broken down into free fatty acids and into glycerol. Stimulation of adrenergic receptors in fat cells is also known to cause browning of fat tissue, Stephens says.

“Intermittent fasting is not something new — it’s been around for centuries,” Stephens said. “There’s a lot of anecdotal evidence that it works, but recently we’ve seen an increasing number of scientific studies showing that it may be a more manageable alternative, for restricting calories, to traditional dieting.”

Gut Punch

Where your body stores fat is also incredibly important to how metabolically healthy you are, Stephens says. Someone who is obese, but who stores most of their fat subcutaneously, can be metabolically healthy. This includes fat that you can pinch around the gut or hips. The deadly fat is the visceral fat that surrounds your organs and rib cage, especially fat surrounding the liver.

“If you have a fatty liver, chances are likely that you’ll also be diabetic,” Stephens said.

It turns out that subcutaneous fat can be beiged, or prompted to produce more mitochondria with healthy diet and exercise, while visceral fat is difficult to beige. Beige fat tissue is almost always positively correlated with improved metabolic health, while visceral fat is correlated with metabolic inflexibility, Stephens says. Part of this may be due to the inflammatory nature of visceral fat, which contains larger numbers of immune cells that produce cytokines that may in turn inhibit beiging.

“It really depends where your fat is, and what the quality of it is,” Stephens laughed.

“You’d think that fat tissue under the microscope would look like just a bunch of fat cells, but it’s not. Under a microscope, half of the cells are fat cells, but the other half include immune and neuronal cells, and we know that neurons in fat tissue increase their activity with exercise,” Stephens said.

The risk of metabolic dysfunction typically increases with obesity, high blood cholesterol, high fasted triacylglycerol levels, high blood pressure and poor glucose control. Poor glucose control is in turn related to not just overall weight, but where we store our fat and how sensitive our cells are to insulin.

“You can be obese, but if you have good blood pressure and lipid levels because you exercise, you could still be metabolically healthy,” Stephens said. “But if you have several of these risk indicators, especially three or more, the risk of virtually every kind of cardiovascular disease increases by twofold, and risk of death by any disease also increases.”

It’s Good to be Flexible

Metabolic flexibility, or inflexibility, is an indicator of metabolic health or dysfunction. This flexibility involves being able to easily switch from one type of fuel to another, or the ability of an organism or cell to modulate fuel oxidation based on fuel availability.

“Metabolic flexibility is being able to easily switch how you burn fuels,” Stephens said. She points to research produced by Dan Kelly as leading the field in terms of unveiling the mechanisms of metabolic flexibility, or the inflexibility associated with insulin resistance.

“Recent knowledge of insulin receptor signaling indicates that the accumulation of lipid products in muscle can interfere with insulin signaling and produce insulin resistance.” — Kelley & Mandarino, 2000

Metabolic flexibility is often measured and reported in terms of a change in RER, or respiratory exchange ratio, so named because it is measured at an individual’s mouth. At an RER of 0.7, you are burning fat, or in a state of fatty acid oxidation. At an RER of 1.0, you are burning carbohydrates. After eating a mixed meal of fats and carbohydrates, your RER may be around 0.9 to 1.0. On the other hand, your RER is lower, more towards 0.7, in a fasted state.

There are hundreds of genes involved in metabolic flexibility, Stephens says. She just discovered another one in her lab, in mice, that she will soon publish details on. When her lab group knocked the gene out, or rendered it inactive, in adipocytes, they observed huge changes in metabolic flexibility in mice. Many such genes associated with metabolic flexibility, Stephens says, alter the function of cells in fat tissue, skeletal muscle, or liver tissue.

“All of these tissues have key roles not only in insulin action, but also in breaking down carbohydrates and metabolizing lipids,” Stephens said.

The Right Time for Metabolic Flexibility

Insulin resistance, where cells are resistant to insulin signaling and are unable to use it effectively, leading to high blood sugar, is a predictor of type 2 diabetes. But how sensitive or insensitive we are to insulin depends on many factors, including where we store our fat, the level of inflammation in our bodies, and even what time of day it is.

Insulin sensitivity follows a natural up-and-down cycle throughout the day, based on our circadian rhythm. For example, most people are more insulin resistant at night, meaning that when we eat, in addition to how well and where we store the fuels that we eat, can matter to our metabolic health.

Growth hormone is one of the players in the circadian rhythm of our insulin sensitivity. Growth hormone, which increases as we sleep, is great for fat burning and muscle building, but high levels also lead to acute insulin resistance.

Stephens has unpublished results from a mouse study in her lab that highlight the complicated role of growth hormone in weight loss and metabolic health.

“We made some transgenic mice that are deficient in growth hormone signaling within their fat tissue,” Stephens said. “We made the mice really fat, and then injected them with growth hormone. Our wild type mice, which didn’t have any genetic manipulation, lost fat mass, just as you would expect. So did our transgenic mice. But our wild type mice also become diabetic, while our transgenic mice were resistant to getting diabetes.”

Based on how signaling molecules including growth hormone cycle throughout the day, it may not be a good idea to eat late at night or very early in the morning immediately after waking, especially if eating a high carb or sugary meal. However, exercise and prolonged overnight fasting might blunt the negative effects of such a meal, promoting more efficient glucose uptake into muscle, liver and fat cells.

Damage Control: Adapting Fuel Use to Fuel Availability

Tim Allerton, a postdoctoral researcher in Jackie Stephens’ lab, studies the role of exercise in modulating metabolic flexibility, especially in terms of how our bodies adjust fuel sources after we eat.

“If you are metabolically flexible, after you eat, we should see a rapid rise in carbohydrate oxidation, or burning of sugars, and at the same time a suppression of fatty acid release from your fat cells,” Allerton said.

Allerton is an exercise physiologist by training with experience in the clinical aspects of exercise as an intervention for people with obesity, diabetes and other metabolic diseases. As a Ph.D. student, he studied how exercise can change metabolic flexibility in humans. He found that exercise or interval training can potentially reduce the damage that a mixed post-exercise meal high in carbohydrates or fats can do, in terms of creating overly elevated levels of insulin.

Exercise is an example of hormesis, or “good stress” that can prompt an antioxidant adaptive response.

“Immediately after a strenuous bout of exercise, there is a degree of muscle glycogen depletion,” Allerton said. “That glycogen is highly valuable to our muscles, so the moment it is depleted, our bodies want to replenish it quickly. When you eat after exercise, your muscle cells will be very sensitive insulin, the result being that your body drives the glucose from your meal into your muscles for storage. This take the edge off of the sugar you just consumed.”

But it isn’t just our muscle cells that play a role in increased insulin sensitivity following exercise or overnight fasting. Fat cells also play a role. To get glucose where it needs to go after you eat, your body needs to remove the competition of other fuel sources that tissues such as your muscles could use for energy instead, including fatty acids floating around that have come from the adipose tissue during lipolysis. Lipolysis is trigged by fasting, or rigorous exercise. For our bodies to be optimally metabolically flexible, we need our fat cells to shut off lipolysis temporarily once we’ve eaten a meal, as quickly as possible.

Fasting for 12–16 hours or longer also depletes glycogen stores in our liver cells, but not our muscle cells. These cells will hungrily soak up glucose, and ideally be moresensitive to insulin signaling — as long as our fat cells function properly — when we break the fast.

Allerton is now looking at the mechanisms that might help fat cells better shut down lipolysis when you eat following exercise. He suspects that it might be related to oxidative stress and healthy responses to that stress. Oxidative stress, or reactive oxygen species that can damage cellular components including DNA, can impair the ability of tissues including fat to efficiently switch from burning fats to burning sugars and back again. It turns out that meals high in carbohydrates and fats promote oxidative stress.

Oxidative stress is a serious problem in metabolic disorders including diabetes, producing inflammation, tissue damage and reduced metabolic flexibility of muscle, liver and fat tissues. Of interest to Allerton, exercise, which prompts the body to produce antioxidants via a “good stress” response, or perhaps even antioxidant botanical extracts, might impart protection to the high levels of oxidative stress associated with high calorie meals and metabolic disorders. There’s some good evidence for this too. In at least one study, people who took Vitamin E, an antioxidant, before exercise, had reduced metabolic adaptation following exercise, because the antioxidant had blocked the adaptive response to the “good stress” of physical activity. However, the results for the impact of Vitamins C and E on adaptations to exercise are mixed in general.