Quality over Quantity, in Life and… Fat

Are you metabolically healthy?

In this micrograph, adipocytes are found in clumps (on the right — unstained) throughout loose connective tissue (on the left — collagen in green) supporting a stratified epithelium (red). Credit: Franck Genten, Flickr.com.

The LifeOmic LIFE Intermittent Fasting app and our future LIFE Extend app will help you and others take control of your health and healthspan, partly through positive lifestyle changes. One of these is intermittent fasting, a practice that can improve your metabolic health and help delay or prevent diseases of aging. But what is metabolic health, anyway, and what does fasting have to do with it?

To answer these questions, we’ve turned to several adipose tissue researchers who have a message for you: Metabolic health isn’t about what you look like, at least on the outside. It’s about how you feel. No spring break beach bod tips here. Have you ever heard the phrases, “It’s not the years in your life that count; It’s the life in your years,” or “Friends: It’s not the quantity, but the quality that matters”? Well, we could say the same about fat.

Mice who exercise are metabolically healthier, even if overweight. Credit: Eyesplash, Flickr.com.

Fat gets a bad rap.

Fat cells play critical roles in metabolism in both animals and humans, says Jackie Stephens, Claude B. Pennington, Jr. Endowed Chair in Biomedical Research and a professor at the Pennington Biomedical Research Center in Baton Rouge, Louisiana. Metabolic health doesn’t necessarily mean having less fat tissue, it means having healthier fat cells.

“Animals need fat tissue for hibernation. When you are fasting, your adipose tissue is providing all of your energy. If you don’t have enough fat, you can’t reproduce,” Stephens said.

Of course, too much fat tissue can also cause problems in humans, especially when it is visceral, or around the organs and in the abdominal area, and when combined with poor diet and fitness level.

“Your fat is unhealthy when you have a poor diet, or when you consume a lot of simple carbohydrates and saturated fatty acids,” Stephens said. Poor diet and fitness levels can change gene expression in fat cells that result in reduced metabolic health.

Illustration of adipose cells. Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010.

From Mice to Men

At Pennington and LSU, Stephens studies metabolic dysfunction, specifically related to fat tissue in mice. Her studies are revealing a lot about the role of specific genes expressed in adipocytes (fat cells) in metabolic health and obesity. For example, she recently discovered a new role for a pro-inflammatory protein and cytokine expressed in some people’s fat tissue, called oncostatin, in creating insulin resistance, which is a strong predictor of type 2 diabetes. Oncostatin is also a biomarker for inflammatory diseases like rheumatoid arthritis, liver disease and several types of cancers. To better understand the role of oncostatin in adipose tissue inflammation, Stephens and her research team used mouse models to examine the effects of the protein in obese mice. They found that in obese mice fed a high-fat diet over six months, the population of immune cells in the mice’s adipose tissue increased due to an increase in oncostatin, rendering the mice insulin resistant.

A comparison of a mouse unable to produce leptin, resulting in obesity, constant hunger, and lethargy (left), and an active normal weight mouse (right). Source: Human Genome wall for SC99.

In humans, it is still very difficult to research or manipulate the activity of particular genes in fat tissue, for example. But Stephens’ lab can easily do this in mice. Her group can create transgenic mice that are deficient in a single gene or even in activity of a gene in a single tissue, to study the impact of these specific changes on metabolism, weight gain and overall health.

“It is possible in humans, for example, to run exercise interventions and then take biopsies of liver or fat tissue to study genetic changes,” Stephens said. “But in animal studies, we can establish cause and effect relationships between particular genes or sets of genes, and effects on metabolism and health.”

Stephens recently conducted a series of experiments with mice in her lab to study the impacts of exercise on fat tissue, with implications for metabolic health. She is finding that exercise can improve metabolic flexibility and gene expression in fat cells, which in turn can have systemic effects on liver and muscle function, because fat cells secrete hormones such as adiponectin that impact these other tissues.

“Mice and people who exercise tend to have higher levels of adiponectin, which is a hormone that can be an insulin sensitizer in the liver and muscle and can improve glucose and fat metabolism,” Stephens said.

One of Jackie’s next research steps will be to look at the impact of exercise on senescent cells and senescent cell biomarkers. These “zombie” cells can also cause inflammation and reduced metabolic function in various tissues.

Go Brown

Other factors can impact fat tissue health. Diseases such as cancer and autoimmune disorders can change lipid metabolism and fat cell gene expression in a negative way, Stephens says. There are also different types of fat cells, including white fat cells and brown fat cells, so called because they appear dark under a microscope due to the presence of a large number of mitochondria, the energy producers of cell. Higher levels of brown adipose tissue are associated with improved insulin sensitivity and reduced risk for type 2 diabetes.

Brown fat is hard to find in humans, but hibernating animals in cold climates, like the arctic ground squirrel, have plenty of brown fat reserves. We can study these animals to understand brown fat gene expression. Credit: kuhnmi, Flickr.com.

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.

Main pathways in endocrine regulation of growth. Häggström, Mikael (2014). “Medical gallery of Mikael Häggström 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008.

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.

It might be a good idea to eat antioxidant-rich foods after exercise, to reinforce the body’s antioxidant response. Credit: Scott Bauer, USDA ARS.

Caloric restriction or intermittent fasting, which helps turn over fuel sources and remodel the liver, could also plausibly blunt metabolic inflexibility by activating the AMPK signaling pathway and preventing or reducing senescence, inflammation and further oxidative stress — an exciting possibility for users of our LIFE intermittent fasting app!

Take It Home

“Most of what we are learning about the interventions that lead to greater metabolic health fit common sense,” Stephens said. “You should eat healthy, or eat a balanced diet, and you should exercise. There’s no magic pill that can replace the benefits of exercise, which include reduced psychological stress and symptoms of depression, remodeled skeletal muscle, increased energy expenditure, fuel turnover in your body and heart health.”

“After looking at all of this science, it’s really very simple in the end: healthy eating and exercise. That’s it,” Stephens said.

Allerton recommends that people just move. A sedentary lifestyle is a strong risk factor for metabolic inflexibility. Even breaking up each hour you spend sitting at your work desk with a 5–10 minute walk can substantially improve your health, Allerton says. This “exercise snacking,” when combined with more intense periods of exercise several times per week, won’t turn French fries into health food, can help blunt the negative impacts of unhealthy eating. Periods of fasting can also help, by turning over fuel sources in your body.

“These are three approaches that don’t have to be dramatic changes to your lifestyle, but can substantially improve your metabolic flexibility,” Allerton said. He himself skips lunch daily, partly to reduce calories, and to get more work done in the lab!


Sign up for our LIFE Intermittent Fasting app now, at lifefastingtracker.com, and stay tuned for our LIFE Extend app, which will help you use and track healthy practices such as exercise and nutrition for metabolic and genetic health.