Can Skinny Fat Beat Obesity?

Philip A Rea, Peter Yin, Ryan Zahalka. American Scientist. Volume 102, Issue 4. Jul/Aug 2014.

When we hear the word fat, most of us think of ice cream, French fries, or the greasy white stuff in a rasher of streaky bacon. We associate becoming fat with an increased risk of cardiovascular disease, metabolic syndrome, and type 2 diabetes. These risks are real enough, but they pertain to only one of the several types of fat that are found in the human body.

White adipose tissue (or, in nontechnical terms, fat), the main culprit in weight gain, tends to accumulate under the skin and as visceral deposits around internal organs. By contrast, brown adipose tissue usually appears as deposits in the neck area and between the shoulders. Medical researchers first described brown fat in hibernating mammals and, among our own species, in newborn babies.

Until recently, brown fat was thought to exist in humans for only a short time after birth to serve as a stopgap for the maintenance of body temperature, in lieu of the shivering reflex that develops later in life. It was not until 2002, with the large-scale adoption of positron emission tomography (PET) scans, that areas resembling brown fat were recognized in the medical images of adults as well. However, the discoveries related to fat did not end there. The complex biology of adipose tissue continues to yield surprises, including the insight that a newly characterized type of body fat could ultimately play a major role in fighting obesity.

Why Must We Have Fat?

Both white and brown adipose tissue are fat depots-that is, they hold the body’s fat reserves-but they differ radically in their composition and function. A white fat cell is made up of a single fat droplet surrounded by a wafer-thin ring of cytoplasm, which in turn contains only a scattering of mitochondria, the powerhouse organelles that bum fats, carbohydrates, and protein down to carbon dioxide and water. A brown fat cell, on the other hand, is made up of several smaller fat droplets embedded in a more extensive cytoplasm containing a large number of mitochondria. Whereas white fat gets its off-white color from the fat that is its main component, brown fat is full of mitochondria rich in iron and heme-containing respiratory enzymes that give it a rusty brown coloration; moreover, brown fat is infiltrated by a much denser network of blood vessels and capillaries. Brown fat is a heat generator and distributor; white fat is a fuel depot and heat capacitor.

Although the calorie-dense diet popular in many Western societies, in combination with a sedentary lifestyle, is now leading to an unprecedented epidemic of obesity, we should not lose sight of the fact that throughout most of our evolutionary history the ability to hedge against starvation by laying down white adipose tissue has been crucial to human survival. Without the calorie reserves stored in white fat, our ability to minimize heat loss and to subsist between meals would be severely limited; hibernation, for those species that eke out their stored fat to survive the winter months, would simply not be an option. To take a very loose analogy, if we think of the mammalian body as a dwelling, white fat is something like a combination of the home’s fuel reserve and insulation.

By extension of this analogy, brown fat is the physiological equivalent of the furnace in a home heating system that is switched on when the temperature of the home falls below a set point. Like the thermostat of a home heating system, thermoreceptors under the skin and in the body core transmit an electrical signal-in our case, through thermosensory neurons-to a part of the brain known as the hypothalamus. If it senses a sustained drop below the physiological set point of about 37 degrees Celsius (98.6 degrees Fahrenheit), it sends excitatory signals through the sympathetic nervous system to brown fat reserves. These reserves then respond like a furnace switched on by a signal from the thermostat: the hormone noradrenalin, released from the terminais of sympathetic nerves, binds to receptors on the surface of brown fat cells, prompting them to fire up thermogenesis and distribute the heat generated throughout the body via the bloodstream.

If this process sounds unfamiliar, that’s because it takes place continuously and without our conscious participation. The response to cold that we are more likely to notice is shivering, but that is actually a much less efficient process caused by the activation of antagonistic muscle pairs when the usual system of thermogenesis cannot meet the immediate challenge of a sudden blast of cold.

Source of Energy Inside the Cell

Inside the cells of animals and plants, mitochondria-double-membraned, rod-shaped structures-serve as the power plants for turning foodstuffs into respiratory energy. In muscle and most other healthy cells, the energy released by the burning of fats, carbohydrates, and proteins is used, in part, for the synthesis of adenosine triphosphate (ATP), the universal energy currency of living things. The energy released by the oxidation of foodstuffs is used to pump protons across the innermost membrane of the mitochondrion from the inside to the outside to set up a proton gradient. This difference then powers the synthesis of ATP from adenosine diphosphate (ADP) and inorganic phosphate (Pi) when protons come back across the inner membrane through a channel in the enzyme (ATP synthase) that is responsible for catalyzing this reaction. When protons flow back through the ATP synthase, the electrochemical energy (the same type of energy stored in an electrical battery) in the proton gradient is converted to chemical bond energy by the combination of ADP with Pi to give ATP. These mitochondria are said to be coupled, because the combustion of carbon compounds is tightly linked to the production of ATP.

When the mitochondria of brown fat cells engage in thermogenesis, the trick they play is to allow the protons that are pumped out during respiration to move down their inwardly directed gradient through a proton channel distinct from the channel in the ATP synthase. Aptly named uncoupling protein 1 (UCP1), this channel conducts protons from the outside to the inside of the brown fat cell mitochondrion, thus bypassing proton movement through the ATP synthase. In this way UCP1 accelerates fuel consumption, while at the same time releasing energy as heat instead of storing the energy as ATP.

Why do our brown fat cells engage in such elaborate maneuvers simply in order to generate heat? The true genius of this system is that it is driven by the products of fat breakdown. If UCP1 is to ferry protons across the inner mitochondrial membrane, it must first bind fatty acids-the same fatty acids that are derived from the breakdown of storage fat, which in turn is triggered by the interaction of noradrenalin with its receptors on the surfaces of brown fat cells. In other words, the preferred fuel for thermogenesis and the intracellular signal that initiates it are one and the same thing: fatty acids derived from breakdown of the fat droplets stored in brown fat cells.

Sleeper Cells

What we have described is only one part of the story-the part explaining the function of brown fat in general, along with the relatively recent realization that brown adipose tissue, or something resembling it, exists in human adults. Another, newer part of the story, however, has emerged in just the past couple of years, with the discovery that the tissue hailed as brown fat in healthy adult humans does not have the same composition as the classical brown fat cells of newborn babies. In fact, this third type appears different from the well-known forms of both brown and white adipose tissue. Even more intriguing, the number of such cells can change in response to an individual’s metabolic needs. These cells, resembling brown fat embedded in white fat reserves, were first observed in the 1980s, but it was not until 2012 that researchers came to understand their unique nature. The cells look for all intents and purposes like brown fat cells, and like brown fat cells they express UCP1. Because they are embedded within subcutaneous white fat, where they contribute a brown coloration to an otherwise offwhite matrix, these have been dubbed “beige” or “brite” (as in brown in white) cells.

For some time, scientists attempted to identify the developmental switch responsible for transforming white fat to brown fat. We now know, however, that no such transformation takes place, for two very good reasons. First, the developmental pathway for brown fat cells is distinct from that for white fat cells. Astonishing as it may seem, brown fat cells share their origins not with white fat but with muscle cells. In an animal model, when one of the genes is blocked that ordinarily shows high levels of expression in brown fat precursor cells; these cells do not revert to white fat cells-instead they convert to muscle cells. Remarkably, these cells begin to twitch! Harvard medical researcher Bruce Spiegelman, whose laboratory at the Dana-Farber Cancer Institute conducted the study, considers this “the most shocking result in [his] 30 years as a principal investigator.”

The second piece of evidence against a white-to-brown-fat switch has just been published. In 2013 another Harvard team, led by Yu-Hua Tseng of the Joslin Diabetes Center, studied mice that have no brown fat cells at all, owing to a mutation in the signaling pathway. By rights, these animals should have to shiver constantly in order to maintain their body temperature, and yet they do not do so. Instead they draw on the beige cells stored in their white fat reserves. As mentioned earlier, the precursors or “sleeper cells” that give rise to beige fat have a different lineage from that of either brown or white fat.

Beige fat cells demonstrate a versatility that classical white and brown fat cells lack: After being recruited for thermogenic purposes, they can switch from burning fat to accumulating fat and back again. In their unstimulated, sleeper state, beige fat cells resemble their white neighbors, with minimal expression of the genes associated with thermogenesis, including UCP1. Under the stimulus of a cold environment, however, beige fat cells increase their expression of UCP1 to levels characteristic of brown fat cells. Moreover, and this is what gives the discovery of beige fat cells such far-reaching implications, the cells found in the supraclavicular regions of healthy human adultswhere earlier researchers thought they had found classical brown fat-now turn out to have a gene expression profile more like that of beige fat in mice than that of classical brown fat cells in newborn humans.

Because it has been established that the gene expression profiles of these cells in human adults clearly differ from those found in the corresponding regions of human newborns, we must consider the possibility that many if not most studies thought to have been conducted on human adult brown fat were actually not carried out on classical brown adipose tissue at all, but instead were done on thermogenically active, UCP1 -positive, beige fat cells. The bottom line is that the presence of thermogenically active fat cells in adults, once thought to be decided by an all-or-none roll of the genetic dice, may turn out to be more amenable to change than originally thought.

Bright Prospects for Beige Fat

Certain take-home lessons for us humans are already becoming clear. Beige fat in adults likely represents an evolutionarily conserved mechanism for adaptive thermogenesis, by means of the recruitment of this cell type according to need. In more practical terms, beige fat satisfies many of the requirements of a therapeutic target that until recently was not even known to exist. If there is a target for the treatment of obesity and obesity-associated cardiovascular disease and type 2 diabetes that stands out as particularly manipulable and potentially “draggable,” it is beige fat, rather than white or brown.

White fat deposition, weight gain, and obesity develop when energy balance is out of whack, because energy intake consistently exceeds expenditure. The discovery of beige fat offers nothing new here: The first line of attack in weight control is still diet and exercise. Two insights, however, are unprecedented. The first is our appreciation that in adult humans, the abundance and activity of what was formerly thought to be classical brown fat but is now known to be beige, are inversely related to total body fat. Skinny types generally have more beige fat than others, and although it decreases with age, those who hold on to their beige fat longer are less likely to put on weight later in life. In short, if changes in lifestyle can be found to have an effect on the recruitment or activation of beige fat, or if drags can be developed that have the same effect, it may someday become possible to halt unwanted weight gain, or even to reverse it.

The second insight to be gained from the discovery of beige fat con- cerns two unfortunate aspects of adulthood: diet-induced weight gain and middle-age spread. Specifically, we now have a better understanding of what it is about regular exercise that makes it such a potent antidote to the downside of aging.

These results are promising, but it remains to be determined if they will prove as applicable to older people or to those whose health is compromised (for example, because of weight problems) as they are to the healthy subjects of these studies. Other questions remain, such as how long the effects may last and whether there are harmful repercussions. Patrick Seale (who, with his colleague Spiegelman, first demonstrated the common origin of brown fat and muscle cells), points out that finding the answers to these questions may not be as simple as it appears, because increasing the activity of beige or brown fat inevitably entails expending more, energy and burning more calories in a system that normally is all about energy conservation. In his words, “Our bodies are very smart”: The metabolic system can find ways to compensate for a rise in demand, whether through increased appetite or reduced physical activity.

A Crucial Messenger 1

In the course of millions of years of evolution our ancestors have struggled to take in enough calories for sustenance, so perhaps it is not surprising that today, some of us find it very difficult to lose weight and keep it off. Be that as it may, in the light of our new understanding, lifestyle changes of this type surely warrant further investigation, if only as a way of possibly augmenting more robust regimens to fight obesity.

The search for ways to control obesity has gone on a long time, but in just the past couple of years it may have reached a major turning point: the discovery of the hormone irisin, a polypeptide secreted by muscle cells. First identified in rodents by the Spiegelman research team, irisin increases the expression of UCP1 and other thermogenic genes in white fat deposits, while at the same time increasing dissipative energy expenditure.

If white adipose tissue can be said to have a nemesis, it is this hormone, which has little or no effect on classical brown fat cells but causes a marked increase in the browning of white fat, and whose circulating level in both rodents and humans rises in response to sustained activity. In recognition of its role as a muscle-to-fat go-between, the researchers have named the substance after Iris, the messenger of the Olympian gods. Spiegelman and his colleagues are currently exploring the potential of irisin as a pharmaceutical product for the treatment of type 2 diabetes and obesity through their private company, Ember Therapeutics (with which the authors of this paper have no commercial ties).

In evolutionary terms, the secretion of irisin by muscle cells in response to sustained physical activity may not seem highly adaptive for mammals. If anything, the opposite trait-a capacity to extend energy reserves as far as possible-should be helpful for survival. Why, instead, do we have a regulatory circuit that apparently increases beige fat thermogenesis and dissipative energy expenditure just when energy expenditure by muscle is at its greatest?

The question remains open, but the most reasonable explanation offered so far concerns the balance between two kinds of thermogenesis: the way we warm our bodies by shivering when we’re cold and the way we keep warm enough most of the time without shivering. When we undergo a prolonged spell of shivering, the secretion of irisin may perhaps serve to activate beige fat thermogenesis to further enhance heat production. If this hypothesis holds true, the increased energy we expend in maintaining body temperature would eventually be shifted from muscle to fat, the latter of which is calorically richer in energy reserves than the former (which draws on carbohydrate, or glycogen, reserves). Such a system would explain why the benefits of regular endurance exercise far outweigh those expected from the extra calories consumed when actually performing the exercise: There would be a sustained after-burn as a result of exercise-triggered irisin production and beige fat recruitment.

Our understanding of the biochemistry, physiology, and developmental biology of body fat has undergone a radical revision-perhaps not a paradigm shift, but close to it-in a matter of only a few years. First we had brown fat, which we found out was only for babies; then we had beige fat, which is probably what our brown fat is; and now we have muscle-derived factors that can drive the browning/ beiging of white fat to potentially tip the scales in favor of thermogenic dissipative fat combustion to melt the white stuff away.

Tantalizing as these recent advances are, we should be careful not to overstate the case. The global epidemic of obesity, diabetes, and cardiovascular disease is an inordinately complex issue. Not only does it involve the intricate interplay of many biological factors but it is also rife with gnarly socioeconomic, geopolitical, and psychological ones. Stated plainly, it would be folly to think in terms of diet pills that drive beige fat expansion or activation as a simple fix or cure-all.

In a similar vein, with the all but inexorable development of strategies for playing around with the ratio of beige fat to white fat by means of drugs, surgery, or genetic manipulation, we should be ever mindful of potentially deleterious side effects, either in the short term or in the long term. A case in point is the study published by an international group led by Yihai Cao, of the Karolinska Institute, indicating that when chilling is used as a stimulus to activate brown fat and expand the beige fat cell population in mice with cardiovascular disease, the cold accelerates the growth of atherosclerotic plaque in their arteries instead of halting it. That is, in mice with diseased arteries, a cold environment actually raises the risk of heart attack.

This isolated report has yet to be independently corroborated, but one insight already clear from this work is that knocking out the gene encoding UCP1 in mice with preexisting cardiovascular disease effectively puts the brakes on cold-induced disease progression. It is as if the loss of UCP1 and the resulting abolition of cold-induced thermogenesis collude to bring about a cardioprotective state. This discovery, together with the finding that healthy mice do not appear to be susceptible to the cold-induced progression of cardiovascular disease, indicates that researchers should proceed with caution when it comes to ramping up beige or brown fat-associated thermogenesis in people who already have cardiovascular disease or are predisposed to it. Researchers have not yet determined whether the mouse model of cardiovascular disease is truly equivalent to the disease in humans in this context. If the mouse model proves true, however, its implications will include a bitter irony: Cao’s study will indicate that people with preexisting cardiovascular disease, those who stand to gain the most from getting their weight under control through beige fat recruitment, may be poor candidates for an intervention of this type, because they are the ones most at risk of suffering serious side effects.

Clearly, despite these potential concerns, we should make the most of every advantage gained, no matter how small. Irisin is one such advantage, in that it not only has the potential to confer the fat-burning benefits of exercise but also, as shown in just the last few months in mice, appears to stimulate the production of neuroprotective factors in the brain.

Irisin may turn out to be more than just a muscle-to-fat go-between. There is still a lot of work to be done in this area, but the results of some preliminary studies have been intriguing. In the bloodstream of mice that have undergone endurance exercise on a running wheel over the course of 30 days, a rise in irisin levels is associated with an increase in the expression of a brain-health protein in the hippocampus, a part of the brain responsible for memory and learning.

Although it has yet to be determined if this effect is accompanied by improved cognitive function, the implication is obvious. The brain-health protein in question, brain-derived neurotrophic protein, is known to promote the formation of new nerves and neural connections, and there are only two areas in the brain known to generate new nerve cells in an adult. One of these areas is the hippocampus, the structure in which irisin elicits an increase of this neurotrophic factor.

Irisin or its mimetics therefore offer the promise of a surrogate for the weight control and cognitive benefits of regular exercise to the morbidly obese and those who are wheelchairbound or have advanced cardiovascular disease, for whom exercise is not an option. If safe drugs that specifically target beige fat can be found-something that was not even a remote possibility two or three years ago-they could give hope to those who find themselves in this position.