Written by Daniel Gwartney, M.D.
06 October 2011

By Daniel Gwartney, M.D.

           Just as scientists and the public were inaccurate in regarding all dietary fat as “fat,” so, too have they been in regarding the different forms of body fat as “fat.” When scientists, dietitians and clinicians looked past their entrenched bias, they discovered that some forms of dietary fat are more readily burned versus being stored, specific fatty acids act as hormone precursors and still others offer health benefits that remain to be fully understood.1,2
            In the recent score of years (a score is 20, as used in the famous opening of Abraham Lincoln’s Gettysburg Address, “Four score and seven years ago…”), scientists have discovered that various depots (anatomical locations) of fat have different functions; also, they have different effects on a person’s metabolism and health. The layperson (everyday people; non-scientists) generally focuses on subcutaneous fat, the fat depot that lies just under the skin and can be grabbed by the “Special K pinch.” Subcutaneous fat is actually composed of two layers, deep and superficial.3 Superficial subcutaneous fat (the fat that is just below the skin) is typical of what people and scientists long considered fat to be; a storage “warehouse” for fat to be used as energy if food availability is limited. People who eat too much add to the superficial layer of fat quickly, while those who are calorie deficient lose from this fat compartment. This explains the quick change in appearance with weight loss over bony areas. Lean people, or those who have recently lost a considerable amount of weight, show the ridges of bone or muscle definition in athletes due to a rapid loss of superficial fat. However, superficial fat also serves a cosmetic function, as it smoothes the contours, particularly in the traditional feminine body. Plastic surgeons are careful not to intrude severely into the superficial layer as it leads to ripples, trenches and noticeable defects.
            If there is a long-term imbalance in diet and activity leading to fat gain, fat also deposits in other fat depots, including the deep subcutaneous fat layer. The deep subcutaneous fat layer is not just a “warehouse” that shuttles calories (as fat, or more correctly fatty acids) into and out of the bloodstream. Deep fat appears to serve several functions. Deep and superficial fat provide a protective buffer against changes in the environment, easing the impact of minor collisions against doorframes and countertops. Deep fat is also vital in maintaining body temperature, acting as an insulating “blanket” against heat loss and warming/cooling blood that returns from the skin’s surface that may be significantly colder/hotter than the internal body temperature. However, deep subcutaneous fat also behaves like an organ, releasing hormone-like molecules called lipokines that affect the level of whole-body inflammation, insulin resistance, etc. The relationship between deep subcutaneous fat and insulin resistance (and other disorders) is significant in men, less so in women.4
            Within the abdomen, there is another, often ignored, fat depot called visceral fat. Visceral fat has been the recent focus of medical research, as it has been shown to be a particularly strong predictor of type 2 diabetes, insulin resistance, cardiovascular disease, Metabolic Syndrome and other health problems.5 As previously described in deep subcutaneous fat, visceral fat releases potent lipokines that directly affect the liver, as well as influencing whole-body inflammation.
            These fat depots play a considerable role in regulating energy balance, weight maintenance and health. Clinicians and researchers are feverishly trying to uncover drug treatments that target these separate depots and positively influence health and weight status. Given the plight of America due to the obesity/overweight epidemic and society’s obsession with image, the terms visceral and subcutaneous fat have become household words.
            Yet, there is another fat that has not been mentioned (yet) on the evening news or “pimped” on late-night infomercials. This fat is wildly different from the other fat types mentioned, and for good reason. This bizarrely mysterious fat is called “brown fat.”
            The term “brown fat” differentiates this form from the more familiar “white fat” that comprises subcutaneous and visceral fat. Brown fat was long considered to be a non-issue in human physiology, as it is only present in significant amounts in newborns.6 Brown fat holds more relevance in the animal world, as it is a vital, life-sustaining tissue in hibernating mammals. The term mammal is a categorical designation describing life forms that share several characteristics, including: body hair, live birth, milk-producing glands to feed young and maintaining a constant body temperature. A mammal’s body temperature is primarily generated through the action of muscle, which is typically the most active tissue in the body. When the environment cools considerably, mammals will increase muscle contraction, either voluntarily or by shivering.7 Muscle contraction is fairly inefficient metabolically, with approximately half (50 percent) of energy lost as heat, rather than being used as mechanical energy (i.e., contracting the muscle; lifting a weight).8 Maintaining, or raising, body temperature is a demanding task. This is one of the reasons people lose weight during a febrile (feverish) illness. The constant shivering necessary to raise the body temperature (fever) increases metabolic demand, and thus calorie burning, considerably.
            Nature provides several examples of conditions in which a mammal may need to generate heat when the muscles are not active. The most relevant is the state of hibernation. Hibernating animals, such as bats and several types of rodents, enter a type of “deep sleep” that lasts for months. Bears are not considered “true hibernators” as they maintain a near-normal body temperature and are quick to arouse, much to the chagrin of researchers who were sneaking up on the sleeping grizzlies. In an immobile, comatose-like state, there is very little muscle activity and body temperature drops; in some cases to near-freezing. However, the animals, particularly bears, who only experience a drop of 12ºF or so, do keep body temperature above the frigid ambient conditions through the actions of a specialized tissue called “brown fat.”
            Brown fat looks like fat in that it is a tissue filled with globules of stored fat in the fed state, but the resemblance ends there. As the name suggests, brown fat is darker due to a high degree of vascularity (blood vessels) and being packed with mitochondria. Mitochondria are the organelles (specialized parts) of the cell that generate most of the energy (ATP) for cell function. However, brown fat is programmed to direct its mitochondria to generate heat rather than produce ATP, through a process called “uncoupling.”9 Uncoupling is a process that is similar to holding the clutch down in a manual transmission car. When the clutch is pressed (disengaged), the transmission is “uncoupled” from the engine, and the power is not transferred to the wheels. Hence, when the clutch is pressed, the engine turns and does not create movement. If the engine runs, the energy produced is lost as heat. If the gas pedal is pressed, the engine turns faster but no movement occurs as long as the clutch is disengaged; instead the rate of energy (gasoline) consumed is increased and additional heat is lost.
            The mitochondria in brown fat are like engines with the clutch disengaged. Normally, the body temperature is maintained through activity and the brown fat is metabolically quiet. However, during hibernation, brown fat plays a much greater role in maintaining body temperature, so the mitochondria become more active, much like an engine running at a high rpm with the clutch disengaged. They burn more energy (not gas but calories), which is lost as heat. This heat is transferred to the rest of the body through the bloodstream (remember, brown fat is highly vascular).
            This review in mammalian physiology would seem to be of little value in humans, as there is very little brown fat in adults, the primary audience suffering from dysfunctional weight management. This is not to say that there is not any, it is just very limited. In adults, what brown fat exists lies in fairly small and specific areas, including: cervical, supraclavicular, paravertebral, mediastinal, para-aortic and suprarenal regions. These regions lie along the path of major blood vessels, which is logical as the adult-remnant of brown fat likely exists to maintain core body temperature in the event of prolonged immobility or cold environmental exposure. As healthy adults are capable of generating a considerable amount of muscular activity, there is little need for an energy-demanding tissue whose primary (maybe only?) purpose is to generate heat; particularly in the age of climate-controlled housing.

Surprising Origins Of Brown Fat
            Recently, the origin and lineage of brown fat was determined, delivering surprising revelations to the scientific community. When first described in 1551 by the Swiss naturalist Konrad Gessner, brown fat was referred to as being “neither fat nor flesh,” meaning it did not appear to be fat or muscle.10 Under the microscope, brown fat contains globules of fat, but is also densely packed with mitochondria. It does not contract and does not appear to secrete any identifiable hormone(s). It was reasonable to pigeon-hole brown fat as a type of adipose (fat cell), as it did not appear to have a function in humans.
            However, with the advances in gene mapping, cell biology and markers of differentiation (cells maturing from stem cells to fully functional cells), it became possible to trace brown fat back to its early precursors. The discovery was shocking. Dr. Patrick Seale of Harvard Medical School and a team of colleagues reported in the journal Nature that brown fat is derived from a precursor cell in the skeletal muscle line.11 In other words, brown fat is a close relative to muscle, and only distantly related to white fat.
            The specifics of this study truly are amazing. Unfortunately, to fully appreciate the methods used and the results that lead to this newsworthy conclusion requires a familiarity with cell differentiation markers. However, a brief description, relying upon the popularity of the television series “CSI,” should offer some idea of why researchers are excited.
            Every human begins from a single cell, a sperm-fertilized ovum (egg cell) that combines traits from the biologic father and mother. As the fetus grows, the cells begin to “specialize” into specific tissue in order to form the “parts” that make a human. Cells become different in order to become blood cells, liver tissue, brain matter, muscle, heart, kidneys, etc. Even in adults, a “pool” of early, undifferentiated cells remains to replace cells lost to age or injury.
            These early cells are the cave men in the evolution of cells. The earliest forms are called stem cells, and represent embryo-like cells that can become a number of different types of cells. As the stem cells evolve, they become more developed and commit to becoming one specific type of cell. At an early point, white fat cells and skeletal muscle share a common precursor cell. In the presence of androgens and other factors, these common precursor cells commit to becoming either white fat or muscle.12 Think of this common precursor as a cellular “missing link.” In muscle, this “missing link” cellular cave man evolves (differentiates) into a Neanderthal-like myoblast (early muscle cell) that then evolves into the mature muscle cell (modern man).
            What Seale and his colleagues discovered was that brown fat expressed proteins that were found only in the muscle cell line, not the white fat line.11 It was the cellular equivalent to realizing that gorillas were showing up to Thanksgiving dinner because they were no longer distant cousins to mankind, but first cousins to us all. Tracing brown fat backward, Seale showed the point where brown fat and muscle diverge. Certain signals that determine whether this common brown fat-skeletal muscle precursor commits to brown fat or muscle were also define.11,13
            Aside from the academic interest these findings inspired, the therapeutic promise of increasing brown fat levels in humans has not gone unnoticed. Remember, adult humans have little brown fat, as heat-generating needs are met by skeletal muscle, the “first cousin” to brown fat. All a person needs to do to generate heat (and waste calories) is move around, exercise or even shiver.
            Unfortunately, being able to be active does not mean people necessarily are, particularly if their occupation is not labor-based. In the pursuit of effortless solutions to the American obesity crisis, researchers are looking at brown fat as a possible target for weight management.
            On the face of things, this seems reasonable. After all, if a signal could be generated by a pill that would induce a 10 percent to 20 percent increase in daily energy expenditure, it could be the metabolic equivalent of “exercise in a pill.” Yet, there are problems with this approach. First, there is little brown fat in adults, the primary population suffering from overweight and obesity-related consequences. So directly stimulating brown fat as it exists is fairly futile due to the limited effect.6 The “promise” of brown fat lies in increasing the total amount of brown fat to a significant amount of the total body mass and then stimulating it to increase daily energy expenditure (the number of calories burned during the day). However, there are three serious drawbacks to this proposal that have not been fully considered.

The Skinny On Brown Fat
         Brown fat arises from the same precursors as skeletal muscle. In order to increase brown fat, the signals for cellular differentiation have to be switched from pro-muscle to pro-brown fat. By favoring the commitment to brown fat, the precursor pool for skeletal muscle is depleted and the body is impaired relative to responding to exercise or muscle injury. In a society where frailty and inactivity have contributed to the obesity problem, this is a drawback that needs to be strongly considered. There are potential ways of doing this, prompting the precursor cells to become brown fat, including an identified transcriptional regulator called PRDM16, as well as PPAR-gamma activators, olive oil and garlic.14-16
       The “waste” product for brown fat when it is burning calories is heat. The body can only tolerate a limited range of body temperature before catabolism, fatigue and tissue damage occurs. In extreme cases, the brain can “cook” and a person can die from hyperthermia (excessively high body temperature). People, particularly infants, can suffer from high fevers reaching over 105ºF. If this temperature persists, brain damage and death can occur in hours to days. Even a persistent lesser fever can cause problems with cognition (thinking) and organ function, including dehydration from pronounced sweating. Certain people are particularly sensitive to certain anaesthetics and enter into a state known as malignant hyperthermia when being put under for surgery.17 This is a medical emergency and is treated very aggressively when it happens. The uncoupling drug DNP (2,4 dinitrophenol), used by many weight trainers to reduce body fat, has been implicated in at least two deaths.18
       Even if brown fat could be “metered” to produce only a set amount of heat, it is stimulated by beta-adrenergic stimulants— drugs like adrenalin. This class of drug was used for decades, as skeletal muscles respond to the same drugs by increasing heat production and cellular activity, the so-called “thermogenic” weight loss drugs and supplements. Unless beta-adrenergic drugs specific to brown fat are developed, the potential for adverse cardiovascular effects or mood disturbances are just as relevant as they were with ephedrine-products and clenbuterol.19
       It is amazing that brown fat acts much like muscle, despite being a cell that stores fat (temporarily). It makes sense in terms of evolution/development and survival that a heat-producing tissue would be needed during periods of prolonged immobility or hibernation. When one thinks about the shared functions of skeletal muscle and brown fat in regards to maintaining a steady temperature, the revelation that they are closely related tissues becomes logically apparent. For centuries, brown fat was considered a fat, proving once again appearances can be deceiving.
         One possible use for brown fat generation/stimulation therapy could be in treating comatose patients or those who have suffered a stroke with resulting paralysis. Yet, for the athlete, even the healthy non-athlete, manipulating brown fat and the shared brown fat/muscle precursors to boost calorie burning and reduce body fat may have unintended negative consequences. For now, chalk this discovery to the (very) interesting, but likely of little practical value for active adults category. In fact, the same benefit could likely be achieved by reclining in a cool bath until the water gets cold enough to induce shivering.20 I used the technique to drop body fat in preparation for competition but the practice holds risk for those with heart conditions, so it should not be attempted without checking with one’s personal physician.

References:
1.     Leaf A. Historical overview of n-3 fatty acids and coronary heart disease. Am J Clin Nutr, 2008 Jun;87(6):1978S-80S.

2.     Kien CL, Bunn JY, et al. Increasing dietary palmitic acid decreases fat oxidation and daily energy expenditure. Am J Clin Nutr, 2005 Aug;82(2):320-6.

3.     Walker GE, Verti B, et al. Deep subcutaneous adipose tissue: a distinct abdominal adipose depot. Obesity, (Silver Spring) 2007 Aug;15(8):1933-43.

4.     Miyazaki Y, Glass L, et al. Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab, 2002 Dec;283(6):E1135-43.

5.     Fox CS, Massaro JM, et al. Circulation, 2007 Jul 3;116(1):39-48.

6.     Asakura H. Fetal and neonatal thermoregulation. J Nippon Med Sch, 2004 Dec;71(6):360-70.

7.     Rintamaki H. Human responses to cold. Alaska Med, 2007;49(2 Suppl):29-31.

8.     Henchoz Y, Malatesta D, et al. Effects of the transition time between muscle-tendon stretch and shortening on mechanical efficiency. Eur J Appl Physiol, 2006 Apr;96(6):665-71.

9.     Watanabe M, Yamamoto T, et al. Cold-induced changes in gene expression in brown adipose tissue: implications for the activation of thermogenesis. Biol Pharm Bull, 2008 May;31(5):775-84.

10.  Cannon B, Nedergaard J. Neither fat nor flesh. Nature, 2008 Aug 21;454:947-8.

11.  Seale P, Bjork B, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature, 2008 Aug 21;454(7207):961-7.

12.  Singh R, Artaza JN, et al. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology, 2003 Nov;144(11):5081-8.

13.  Seale P, Kajimura S, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab, 2007 Jul;6(1):38-54.

14.  Centers for Disease Control and Prevention. Heat-related deaths--United States, 1999-2003. MMWR Morb Mortal Wkly Rep 2006 Jul 28;55(29):796-8.

15.  Oi-Kano Y, Kawada T, et al. Extra virgin olive oil increases uncoupling protein 1 content in brown adipose tissue and enhances noradrenaline and adrenaline secretion in rats. J Nutr Biochem, 2007 Oct;18(10):685-92.

16.  Oi Y, Kawada T, et al. Allyl-containing sulfides in garlic increase uncoupling protein content in brown adipose tissue and noradrenaline and adrenaline secretion in rats. J Nutr, 1999 Feb;129(2):336-42.

17.  Rosenberg H, Davis M, et al. Malignant hyperthermia. Orphanet J Rare Dis, 2007 Apr 24;2:21.

18.  Miranda EJ, McIntyre IM, et al. Two deaths attributed to the use of 2,4-dinitrophenol. J Anal Toxicol, 2006 Apr;30(3):219-22.

19.  Chan TY. Food-borne clenbuterol may have potential for cardiovascular effects with chronic exposure (commentary). J Toxicol Clin Toxicol, 2001;39(4):345-8.

20.  Pretorius T, Cahill F, et al. Shivering heat production and core cooling during head-in and head-out immersion in 17 degrees C water. Aviat Space Environ Med, 2008 May;79(5):495-9.