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Can Skinny Fat Beat Obesity?

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DOI: 10.1511/2014.109.1

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 FEATURE ARTICLE

Can Skinny Fat Beat Obesity?

Newly discovered in adult mammals, beige fat cells can switch between
accumulating fat and burning it, depending on metabolic needs.

Philip A. Rea, Peter Yin, and Ryan Zahalka

W
hen we hear the word bling brown fat were recognized in crucial to human survival. Without the
fat, most of us think of the medical images of adults as well. calorie reserves stored in white fat, our
ice cream, French fries, However, the discoveries related to fat ability to minimize heat loss and to
or the greasy white stuff did not end there. The complex biolo­ subsist between meals would be se­
in a rasher of streaky bacon. We associ­ gy of adipose tissue continues to yield verely limited; hibernation, for those
ate becoming fat with an increased risk surprises, including the insight that a species that eke out their stored fat
of cardiovascular disease, metabolic newly characterized type of body fat to survive the winter months, would
syndrome, and type 2 diabetes. These could ultimately play a major role in simply not be an option. To take a very
risks are real enough, but they pertain fighting obesity. loose analogy, if we think of the mam­
to only one of the several types of fat malian body as a dwelling, white fat
that are found in the human body. Why Must We Have Fat? is something like a combination of the
White adipose tissue (or, in non­ Both white and brown adipose tis­ home’s fuel reserve and insulation.
technical terms, fat), the main culprit sue are fat depots—that is, they hold By extension of this analogy, brown
in weight gain, tends to accumulate the body’s fat reserves—but they dif­ fat is the physiological equivalent of
under the skin and as visceral deposits fer radically in their composition and the furnace in a home heating sys­
around internal organs. By contrast, function. A white fat cell is made up tem that is switched on when the
brown adipose tissue usually appears of a single fat droplet surrounded by a temperature of the home falls below
as deposits in the neck area and be­ wafer-thin ring of cytoplasm, which in a set point. Like the thermostat of a
tween the shoulders. Medical research­ turn contains only a scattering of mito­ home heating system, thermorecep­
ers first described brown fat in hiber­ chondria, the powerhouse organelles tors under the skin and in the body
nating mammals and, among our own that burn fats, carbohydrates, and pro­ core transmit an electrical signal—in
species, in newborn babies. tein down to carbon dioxide and wa­ our case, through thermosensory neu­
Until recently, brown fat was ter. A brown fat cell, on the other hand, rons—to a part of the brain known as
thought to exist in humans for only is made up of several smaller fat drop­ the hypothalamus. If it senses a sus­
a short time after birth to serve as a lets embedded in a more extensive tained drop below the physiological
stopgap for the maintenance of body cytoplasm containing a large number set point of about 37 degrees Celsius
temperature, in lieu of the shivering of mitochondria. Whereas white fat (98.6 degrees Fahrenheit), it sends ex­
reflex that develops later in life. It was gets its off-white color from the fat that citatory signals through the sympa­
not until 2002, with the large-scale is its main component, brown fat is thetic nervous system to brown fat
adoption of positron emission tomog­ full of mitochondria rich in iron- and reserves. These reserves then respond
raphy (PET) scans, that areas resem­ heme-containing respiratory enzymes like a furnace switched on by a sig­
that give it a rusty brown coloration; nal from the thermostat: the hormone
Philip A. Rea is professor of biology and Rebec- moreover, brown fat is infiltrated by noradrenalin, released from the ter­
ka and Arie Belldegrun Distinguished Director a much denser network of blood ves­
of the Roy and Diana Vagelos Program in Life sels and capillaries. Brown fat is a heat For all functions of life, from maintaining
Sciences & Management at the University of generator and distributor; white fat is a stable body temperature to growth and
Pennsylvania. He has received the President’s a fuel depot and heat capacitor. movement, animals and plants obtain much
Medal of the Society for Experimental Biol- Although the calorie-dense diet of their energy from the mitochondria con-
© Dennis Kunkel Microscopy, Inc.

ogy and has been elected as a Fellow of the popular in many Western societies, in tained in most cells. The color-coded electron
American Association for the Advancement of micrograph at right shows the double mem-
combination with a sedentary lifestyle,
Science for his fundamental research. Peter Yin brane through which protons must pass in
and Ryan Zahalka are rising seniors in Penn’s
is now leading to an unprecedented order for the mitochondrion to synthesize
College of Arts & Sciences. Yin is majoring in epidemic of obesity, we should not lose energy in the form of adenosine triphosphate
computational biology; Zahalka, in molecular sight of the fact that throughout most (ATP); the inner membrane projects into the
biology. Address: Department of Biology, of our evolutionary history the ability mitochondrion, forming an extensive net-
University of Pennsylvania, Philadelphia, PA to hedge against starvation by laying work of infoldings that greatly increase its
19104. E-mail: parea@sas.upenn.edu down white adipose tissue has been surface area.

272 American Scientist, Volume 102 © 2014 Sigma Xi, The Scientific Research Society. Reproduction
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www.americanscientist.org © 2014 Sigma Xi, The Scientific Research Society. Reproduction 2014 July–August 273
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 protons flow back through the ATP
a progenitor cell
synthase, the electrochemical energy
(the same type of energy stored in an
electrical battery) in the proton gradi­
ent is converted to chemical bond en­
ergy by the combination of ADP with
food food Pi to give ATP. These mitochondria
brown fat cell are said to be coupled, because the
muscle
(contraction)
combustion of carbon compounds is
tightly linked to the production of ATP.
When the mitochondria of brown fat
ATP fat droplets
(energy) cells engage in thermogenesis, the trick
they play is to allow the protons that
UCP1
mitochondria are pumped out during respiration to
move down their inwardly directed
heat gradient through a proton channel dis­
CO2 + H2O CO2 + H2O tinct from the channel in the ATP syn­
thase. Aptly named uncoupling protein
b c 1 (UCP1), this channel conducts pro­
tons from the outside to the inside of
progenitor cell progenitor cell the brown fat cell mitochondrion, thus
bypassing proton movement through
the ATP synthase. In this way UCP1
accelerates fuel consumption, while at
food the same time releasing energy as heat
food UCP1 instead of storing the energy as ATP.
Why do our brown fat cells engage
in such elaborate maneuvers simply in
white fat cell beige fat cell order to generate heat? The true genius
of this system is that it is driven by the
fat droplet fat droplets
products of fat breakdown. If UCP1 is
to ferry protons across the inner mito­
mitochondrion
chondrial membrane, it must first bind
fatty acids—the same fatty acids that
heat
CO2 + H2O are derived from the breakdown of
storage fat, which in turn is triggered
The three kinds of fat in the human body each originate from a different progenitor cell. by the interaction of noradrenalin with
Brown fat (a) derives from the same progenitor cells that give rise to muscle. White fat cells its receptors on the surfaces of brown
(b), each containing a large fat droplet and very little cytoplasm, have their own progenitor fat cells. In other words, the preferred
cells, as do beige fat cells (c), which have a smaller proportion of lipid but many more mito- fuel for thermogenesis and the intra­
chondria. (Adapted from B. Cannon and J. Nedergaard, Nature 488:286-287.) cellular signal that initiates it are one
and the same thing: fatty acids derived
minals of sympathetic nerves, binds rod-shaped structures—serve as the from breakdown of the fat droplets
to receptors on the surface of brown power plants for turning foodstuffs stored in brown fat cells.
fat cells, prompting them to fire up into respiratory energy. In muscle and
thermogenesis and distribute the heat most other healthy cells, the energy Sleeper Cells
generated throughout the body via the released by the burning of fats, car­ What we have described is only one
bloodstream. bohydrates, and proteins is used, in part of the story—the part explaining
If this process sounds unfamiliar, part, for the synthesis of adenosine tri­ the function of brown fat in general,
that’s because it takes place continu­ phosphate (ATP), the universal energy along with the relatively recent real­
ously and without our conscious par­ currency of living things. The energy ization that brown adipose tissue, or
ticipation. The response to cold that released by the oxidation of foodstuffs something resembling it, exists in hu­
we are more likely to notice is shiver­ is used to pump protons across the man adults. Another, newer part of the
ing, but that is actually a much less ef­ innermost membrane of the mitochon­ story, however, has emerged in just the
ficient process caused by the activation drion from the inside to the outside to past couple of years, with the discov­
of antagonistic muscle pairs when the set up a proton gradient. This differ­ ery that the tissue hailed as brown fat
usual system of thermogenesis can­ ence then powers the synthesis of ATP in healthy adult humans does not have
not meet the immediate challenge of a from adenosine diphosphate (ADP) the same composition as the classical
sudden blast of cold. and inorganic phosphate (Pi) when brown fat cells of newborn babies. In
protons come back across the inner fact, this third type appears different
Source of Energy Inside the Cell membrane through a channel in the from the well-known forms of both
Inside the cells of animals and plants, enzyme (ATP synthase) that is respon­ brown and white adipose tissue. Even
mitochondria—double-membraned, sible for catalyzing this reaction. When more intriguing, the number of such

274 American Scientist, Volume 102 © 2014 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact perms@amsci.org.
cells can change in response to an
individual’s metabolic needs. These
cells, resembling brown fat embed­
ded 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

Renee Morris Animal Collection/Alamy

like brown fat cells, and like brown
fat cells they express UCP1. Because
they are embedded within subcutane­
ous white fat, where they contribute a
brown coloration to an otherwise off-
white 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 Piglets are unusual among mammals in that they are born without the benefits that brown fat
to brown fat. We now know, howev­ brings; for this reason, they often shiver and huddle together for warmth. During their long
er, that no such transformation takes evolution and then domestication from wild boars, pigs lost their brown adipose tissue and
place, for two very good reasons. the gene for uncoupling protein 1 (UCP1), the protein required for thermogenesis.
First, the developmental pathway for
brown fat cells is distinct from that conducted the study, considers this Instead they draw on the beige cells
for white fat cells. Astonishing as it “the most shocking result in [his] 30 stored in their white fat reserves. As
may seem, brown fat cells share their years as a principal investigator.” mentioned earlier, the precursors or
origins not with white fat but with The second piece of evidence “sleeper cells” that give rise to beige
muscle cells. In an animal model, against a white-to-brown-fat switch fat have a different lineage from that of
when one of the genes is blocked that has just been published. In 2013 an­ either brown or white fat.
ordinarily shows high levels of ex­ other Harvard team, led by Yu-Hua Beige fat cells demonstrate a versa­
pression in brown fat precursor cells, Tseng of the Joslin Diabetes Center, tility that classical white and brown
these cells do not revert to white fat studied mice that have no brown fat fat cells lack: After being recruited for
cells—instead they convert to muscle cells at all, owing to a mutation in the thermogenic purposes, they can switch
cells. Remarkably, these cells begin to signaling pathway. By rights, these an­ from burning fat to accumulating fat
twitch! Harvard medical researcher imals should have to shiver constantly and back again. In their unstimulated,
Bruce Spiegelman, whose laboratory in order to maintain their body tem­ sleeper state, beige fat cells resemble
at the Dana-Farber Cancer Institute perature, and yet they do not do so. their white neighbors, with minimal

White fat cells, at left, each contain a single large droplet of lipid eral smaller drops of lipid in a greater proportion of cytoplasm, with
(white) surrounded by a thin layer of cytoplasm that contains only many more mitochondria. Beige fat cells, at right, are found embed-
a few energy-providing mitochondria (striped brown ovals). By con- ded among white fat cells and contain both lipid and a considerable
trast, the brown fat cells shown in the middle panel each contain sev- number of mitochondria.

www.americanscientist.org © 2014 Sigma Xi, The Scientific Research Society. Reproduction 2014 July–August 275
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 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 clas­
sical 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
These two positron emission tomography–computed tomography (PET-CT) scans show the change than originally thought.
same individual, first in thermoneutral conditions (left) and then after two hours’ exposure to
mild cold (right). The dark areas around the neck and collarbone in the scan at right indicate
Bright Prospects for Beige Fat
more active glucose metabolism—a sign that beige fat has been recruited and is being burned
to generate heat in response to the cold environment. (All images on this page courtesy of T. Certain take-home lessons for us hu­
Yoneshiro et al., Journal of Clinical Investigation 123:3404–3408. Reproduced with permission mans are already becoming clear. Beige
of American Society for Clinical Investigation.) fat in adults likely represents an evo­
lutionarily conserved mechanism for
expression of the genes associated with the cells found in the supraclavicular adaptive thermogenesis, by means of
thermogenesis, including UCP1. Un­ regions of healthy human adults— the recruitment of this cell type accord­
der the stimulus of a cold environment, where earlier researchers thought they ing to need. In more practical terms,
however, beige fat cells increase their had found classical brown fat—now beige fat satisfies many of the require­
expression of UCP1 to levels character­ turn out to have a gene expression pro­ ments of a therapeutic target that until
istic of brown fat cells. Moreover, and file more like that of beige fat in mice recently was not even known to exist.
this is what gives the discovery of beige than that of classical brown fat cells in If there is a target for the treatment of
fat cells such far-reaching implications, newborn humans. obesity and obesity-associated cardio­
vascular disease and type 2 diabetes
that stands out as particularly manipu­
0 weeks 6 weeks 0 weeks 6 weeks lable and potentially “druggable,” it is
beige fat, rather than white or brown.
White fat deposition, weight gain,
1 2 and obesity develop when energy bal­
ance is out of whack, because energy
intake consistently exceeds expendi­
ture. The discovery of beige fat offers
nothing new here: The first line of at­
3 4 tack in weight control is still diet and
exercise. Two insights, however, are
unprecedented. The first is our appre­
ciation that in adult humans, the abun­
dance and activity of what was for­
merly thought to be classical brown fat
5 6 but is now known to be beige, are in­
versely related to total body fat. Skin­
ny types generally have more beige fat
than others, and although it decreases
with age, those who hold on to their
7 8 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 ef­
fect on the recruitment or activation of
beige fat, or if drugs can be developed
Researchers at Hokkaido University, in Japan, used (PET-CT) scanning to investigate whether
chronic exposure to cold could lead to the recruitment of thermogenic tissue (what is now that have the same effect, it may some­
suspected to be beige fat) in healthy young men. The subjects spent two hours per day in a day become possible to halt unwanted
chilly room; after six weeks, all showed varying degrees of enhanced thermogenesis. Here the weight gain, or even to reverse it.
images are color-coded as green, yellow, or red, depending on whether the response was weak, The second insight to be gained
moderate, or intense. from the discovery of beige fat con­

276 American Scientist, Volume 102 © 2014 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact perms@amsci.org.
cerns two unfortunate aspects of A Deadly Surrogate
adulthood: diet-induced weight gain
and middle-age spread. Specifically,

T
we now have a better understanding o students of dietary history,
of what it is about regular exercise the idea of combatting obesity
that makes it such a potent antidote to by means of uncoupling me­
the downside of aging. tabolism is not altogether new. Long
These results are promising, but it before the discovery of thermogenic
remains to be determined if they will fats, a yellow phenolic by the name
prove as applicable to older people of 2,4-dinitrophenol (2,4-DNP),
or to those whose health is compro­ which in the 19th century had been
mised (for example, because of weight added to commercial baked prod­
problems) as they are to the healthy ucts to make them appear buttery or

Wikimedia Commons
subjects of these studies. Other ques­ “egg-rich,” had been brought to mar­
tions remain, such as how long the ef­ ket as a slimming agent in the 1930s.
fects may last and whether there are 2,4-DNP was used extensively in
harmful repercussions. Patrick Seale the manufacture of explosives, first 2,4-dinitrophenol (2,4-DNP)
(who, with his colleague Spiegelman, in France during World War I and
first demonstrated the common origin then in the late 1920s and early 1930s For irisin and its mimetics, quite the
of brown fat and muscle cells), points in Belgium and the United States. contrary is true, for the simple rea­
out that finding the answers to these The compound was also studied for son that the effects exerted by irisin
questions may not be as simple as it its toxic properties, specifically the el­ are tissue-specific, whereas 2,4-DNP
appears, because increasing the activ­ evation of body temperature associ­ is indiscriminate in its uncoupling
ity of beige or brown fat inevitably ated with its ingestion. The outcome action. The feature of 2,4-DNP that
entails expending more energy and of these inquiries was that 2,4-DNP makes it so dangerous is that it un­
burning more calories in a system that stimulated metabolism (measured as couples electron flow from ATP syn­
normally is all about energy conser­ oxygen consumption) while promot­ thesis indiscriminately in muscle,
vation. In his words, “Our bodies are ing weight loss and elevation of body nerve, epithelial, or any other cell
very smart”: The metabolic system can temperature. type, to abolish ATP synthesis and
find ways to compensate for a rise in Appalling as it may seem in the impose mock thermogenesis. In strict
demand, whether through increased light of what we now know, more contrast, irisin is exquisitely specific,
appetite or reduced physical activity. than 100,000 people in the United with its thermogenic action restricted
States, and many more in Europe, to UCP1-containing beige fat cells.
A Crucial Messenger eventually used these medications.
In the course of millions of years of evo­ It was only after many fatalities as­
lution our ancestors have struggled to sociated with a precipitous elevation
take in enough calories for sustenance, of body temperature, innumerable
so perhaps it is not surprising that to­ cases of cataracts and blindness (as
day, some of us find it very difficult to reported, for example, in this July 9,
lose weight and keep it off. Be that as 1935, item in the New York Times) and
it may, in the light of our new under­ other adverse reactions that the anti-
standing, lifestyle changes of this type obesity medications containing 2,4-
surely warrant further investigation, if DNP were banned.
only as a way of possibly augmenting With the benefit of hindsight, we
more robust regimens to fight obesity. now understand what makes this
The search for ways to control obe­ phenolic so toxic. As an uncoupling
sity has gone on a long time, but in agent, 2,4-DNP is a fat-soluble weak
just the past couple of years it may acid that rapidly—in some cases, too
have reached a major turning point: rapidly—equilibrates protons across
the discovery of the hormone irisin, a the inner mitochondrial membrane
polypeptide secreted by muscle cells. with the release of heat.
First identified in rodents by the Spie­ One might think we have learned
gelman research team, irisin increases from this lesson; yet, to this day, 2,4-
the expression of UCP1 and other ther­ DNP can still be purchased on the
mogenic genes in white fat deposits, Internet as an aid to bodybuilding
while at the same time increasing dis­ and weight loss. Every so often, there
sipative energy expenditure. are news reports of overzealous or
If white adipose tissue can be said uninformed bodybuilders or weight­
© The New York Times

to have a nemesis, it is this hormone, watchers who succumb and die after
which has little or no effect on classical dosing themselves up with it.
brown fat cells but causes a marked This cautionary tale is not meant
increase in the browning of white fat, to imply, however, that uncoupling
and whose circulating level in both agents are inherently hazardous.

www.americanscientist.org © 2014 Sigma Xi, The Scientific Research Society. Reproduction 2014 July–August 277
with permission only. Contact perms@amsci.org.
 irisin digm shift, but close to it—in a mat­
precursor ter of only a few years. First we had
protein 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
muscle cells irisin the scales in favor of thermogenic dis­
enters the sipative fat combustion to melt the
bloodstream white stuff away.
Tantalizing as these recent advances
are, we should be careful not to over­
state the case. The global epidemic of
obesity, diabetes, and cardiovascular
disease is an inordinately complex is­
muscle fibers sue. Not only does it involve the in­
tricate interplay of many biological
factors but it is also rife with gnarly so­
beige fat cells cioeconomic, geopolitical, and psycho­
logical 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 in­
exercise
(energy expenditure)
exorable development of strategies for
heat playing around with the ratio of beige
production fat to white fat by means of drugs,
surgery, or genetic manipulation, we
should be ever mindful of potentially
Muscle cells are stimulated by exercise to produce the hormone irisin by cleaving its precursor
protein. Once in the bloodstream, irisin acts as a signal to beige fat cells, which are embedded
deleterious side effects, either in the
within white fat reserves. The beige fat cells respond to this signal by engaging in thermogen- short term or in the long term. A case
esis (heat production) and further energy expenditure. (Adapted from D. Bownds Mindblog, in point is the study published by an
http://mindblog.dericbownds.net/2012/04/more-on-why-exercise-is-so-good-for-us.html.) international group led by Yihai Cao,
of the Karolinska Institute, indicating
rodents and humans rises in response kinds of thermogenesis: the way we that when chilling is used as a stimu­
to sustained activity. In recognition of warm our bodies by shivering when lus to activate brown fat and expand
its role as a muscle-to-fat go-between, we’re cold and the way we keep warm the beige fat cell population in mice
the researchers have named the sub­ enough most of the time without shiv­ with cardiovascular disease, the cold
stance after Iris, the messenger of the ering. When we undergo a prolonged accelerates the growth of atheroscle­
Olympian gods. Spiegelman and his spell of shivering, the secretion of rotic plaque in their arteries instead
colleagues are currently exploring the irisin may perhaps serve to activate of halting it. That is, in mice with dis­
potential of irisin as a pharmaceutical beige fat thermogenesis to further en­ eased arteries, a cold environment ac­
product for the treatment of type 2 dia­ hance heat production. If this hypoth­ tually raises the risk of heart attack.
betes and obesity through their private esis holds true, the increased energy This isolated report has yet to be
company, Ember Therapeutics (with we expend in maintaining body tem­ independently corroborated, but one
which the authors of this paper have perature would eventually be shifted insight already clear from this work is
no commercial ties). from muscle to fat, the latter of which that knocking out the gene encoding
In evolutionary terms, the secretion is calorically richer in energy reserves UCP1 in mice with preexisting cardio­
of irisin by muscle cells in response to than the former (which draws on vascular disease effectively puts the
sustained physical activity may not carbohydrate, or glycogen, reserves). brakes on cold-induced disease pro­
seem highly adaptive for mammals. If Such a system would explain why the gression. It is as if the loss of UCP1 and
anything, the opposite trait—a capacity benefits of regular endurance exercise the resulting abolition of cold-induced
to extend energy reserves as far as pos­ far outweigh those expected from the thermogenesis collude to bring about a
sible—should be helpful for survival. extra calories consumed when actually cardioprotective state. This discovery,
Why, instead, do we have a regulatory performing the exercise: There would together with the finding that healthy
circuit that apparently increases beige be a sustained after-burn as a result mice do not appear to be susceptible
fat thermogenesis and dissipative en­ of exercise-triggered irisin production to the cold-induced progression of car­
ergy expenditure just when energy ex­ and beige fat recruitment. diovascular disease, indicates that re­
penditure by muscle is at its greatest? Our understanding of the biochem­ searchers should proceed with caution
The question remains open, but the istry, physiology, and developmental when it comes to ramping up beige or
most reasonable explanation offered so biology of body fat has undergone a brown fat–associated thermogenesis
far concerns the balance between two radical revision—perhaps not a para­ in people who already have cardiovas­

278 American Scientist, Volume 102 © 2014 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact perms@amsci.org.
cular disease or are predisposed to it. pus, a part of the brain responsible for Nedergaard, J., T. Bengtsson, and B. Can­
non. 2007. Unexpected evidence for active
Researchers have not yet determined memory and learning. brown adipose tissue in human adults.
whether the mouse model of cardio­ Although it has yet to be deter­ American Journal of Physiology, Endocrinol-
vascular disease is truly equivalent to mined if this effect is accompanied by ogy, and Metabolism 293:E444–E452.
the disease in humans in this context. improved cognitive function, the im­ Rajakumari, S., et al. 2013. EBF2 determines
If the mouse model proves true, how­ plication is obvious. The brain-health and maintains brown adipocyte identity.
ever, its implications will include a bit­ protein in question, brain-derived neu­ Cell Metabolism 17:562–574.
ter irony: Cao’s study will indicate that rotrophic protein, is known to promote Seale, P., et al. 2008. PRDM16 controls a brown
fat/skeletal muscle switch. Nature 454:961–
people with preexisting cardiovascular the formation of new nerves and neu­ 967.
disease, those who stand to gain the ral connections, and there are only two Schultz, T. J., et al. 2013. Brown-fat paucity due
most from getting their weight under areas in the brain known to generate to impaired BMP signaling induces com­
control through beige fat recruitment, new nerve cells in an adult. One of pensatory browning of white fat. Nature
may be poor candidates for an inter­ these areas is the hippocampus, the 495:379–383.
vention of this type, because they are structure in which irisin elicits an in­ Spiegelman, B. M. 2013. Banting Lecture.
Regulation of adipogenesis: Toward new
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and human. Cell 150:366–376.
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Wu, J., P. Cohen, and B. M. Spiegelman. 2013.
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just a muscle-to-fat go-between. There themselves in this position.
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