Vol 458|16 April 2009
NEWS & VIEWS
OBESITY
Be cool, lose weight
Stephen R. Farmer
To lose weight, would you rather diet, exercise or subject yourself to cool temperatures? The last choice is
not such an odd one, as adult humans have brown fat tissue that burns calories in response to cold.
Fat is mainly stored in two types of adipose
tissue: white and brown. White adipose tissue
stores calories as large lipid droplets within
individual cells. By contrast, brown adipose
tissue (BAT) stores little fat, instead burning
it to produce heat and regulate body temperature. Small mammals and newborn humans
have copious amounts of BAT around their
shoulder blades, which helps them to survive cold temperatures. Adult humans, however, were largely thought to lack BAT, with
only one investigation1 describing adipose
tissue that seemed to function as BAT. Three
independent studies 2–4, just published in
The New England Journal of Medicine, follow
up this observation, and conclusively identify
BAT in adult humans.
BAT’s ability to burn rather than store
calories depends on each brown fat cell having
many mitochondria — organelles that function
as cells’ power plants. Mitochondria are also
abundant in the skeletal and heart muscles, and
in the brain, where they convert metabolized
sugars (glucose) and fats into the highly energized ATP molecule to fuel organismal activities. The mitochondria of brown fat cells are
unique in that they contain UCP1, a protein
that uncouples metabolism from ATP production in order to produce heat5.
To detect BAT in adult humans, all three
studies2–4 used 18FDG-based positron emission tomography/computerized tomography
(PET/CT). This medical imaging technique measures the absorption of consumed
18
F-fluorodeoxyglucose (18FDG) — a harmless radioactive form of glucose — into various tissues, providing information about the
metabolic activity of each tissue. For definitive
identification of BAT, the authors also performed histological and biochemical analysis
of UCP1 in tissue biopsy samples.
In small mammals, exposure to cold
stimulates the sympathetic nervous system to
release the hormone adrenaline, which triggers brown fat cells to consume more fat and
glucose for heat production. Virtanen et al.2
scanned healthy volunteers on two separate
days: on one day at normal room temperature;
and on the other at 17–19 °C while volunteers
immersed one foot in cold (7–9 °C) water
Brown adipose
tissue
Internal
organs
White adipose
tissue
Figure 1 | When fat is good. Adult humans seem to contain brown adipose tissue (BAT) primarily behind
the muscles of the lower neck and collarbone, as well as along the spine of the chest and abdomen2–4.
After food consumption, the absorbed fats and sugars are used to provide energy for daily functions,
with excess calories being stored as fat in the white adipose tissue, which is mainly located under the
skin of the buttocks and legs in women and around the internal organs in men. BAT can be activated in
response to various stimuli, including exposure to cold, to burn fat and sugars. This process seems to be
more prominent in the young and lean than in the old and obese, and in women rather than in men.
for 5 minutes, every other 5 minutes. In all
individuals, exposure to cold led to a 15-fold
increase in 18FDG uptake into the adipose
tissue of the collarbone (supraclavicular)
region. Tissue biopsy of precisely this region in
three of the volunteers, based on morphology
and UCP1 expression, revealed the presence of
BAT. The authors detected 63 grams of supraclavicular BAT in one of the individuals — a
mass they estimate could burn the equivalent
© 2009 Macmillan Publishers Limited. All rights reserved
amount of energy during a year as is stored in
about 4 kilograms of white fat tissue.
Van Marken Lichtenbelt et al.3 examined the
presence, distribution and activity of BAT in
10 lean and 14 overweight/obese men in relation to body composition — percentage fat and
lean-muscle mass — and energy metabolism.
They report BAT activity in 23 of 24 individuals when measured at 16 °C, but not at 22 °C.
The one individual with no BAT activity also
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NEWS & VIEWS
had the highest percentage (42%) of body fat.
In fact, BAT activity within the group showed
a significant negative correlation with percentage body fat and correlated positively with
resting metabolic rate.
Excess storage of fat disrupts metabolic
balance, leading to obesity-related disorders,
such as diabetes and cardiovascular disease,
which are collectively known as metabolic
syndrome6. When fat accumulates in the
intra-abdominal regions around internal
organs — as it does mostly in men — the risk
of developing metabolic syndrome is highest;
women, by contrast, are at a lower risk, because
they often store fat under the skin, around the
thighs and buttocks7 (Fig. 1). Cypess and colleagues4 analysed 3,640 previously recorded
scans of 1,972 patients (both men and women)
who had undergone 18FDG-PET/CT diagnostic screening for various medical reasons.
The authors find scans corresponding to BAT
activity in 7.5% of women and 3.1% of men.
Moreover, women had a greater BAT mass,
which absorbed more 18FDG.
Larger amounts of active BAT also showed
a positive correlation with younger age and
lower outdoor temperature on the day each
patient was scanned4. The authors detected an
inverse relationship between active BAT and
both smoking and patients’ use of beta-blocker
drugs for the treatment of high blood pressure
and cardiovascular disease.
It is likely that the percentage of positive
BAT scans Cypess et al. observed is lower compared with the other two reports2,3 because the
authors4 relied on scans that were performed
only at room temperatures. These studies,
however, reach several similar conclusions:
irrespective of age and gender, adult humans
contain metabolically active BAT in their neck
and upper chest regions; cold temperatures can
activate BAT in adult humans, apparently more
often in women than in men; and the presence
of BAT correlates inversely with body fat,
especially in older people.
Having reached pandemic levels worldwide,
obesity and its related diseases have drastically increased health-care costs. With a role
in adult-human metabolism, could BAT be
exploited as a therapy for obesity?
For individuals with metabolically active
BAT, one way to lose weight might simply
be exposure to cold. As for others, years of
investigation into the formation and function of BAT in mice has provided a wealth of
knowledge that could aid the development of
anti-obesity therapies targeting BAT in adult
humans. For instance, weight loss might be
achieved through drugs that mimic the cold
by activating the sympathetic nervous system.
Enhancing the formation of BAT, rather than
white adipose tissue, might be another useful
strategy. Such an enterprise has recently come
closer to realization with the discovery 8–10 of
the stem-cell origins of the two adipose tissues.
Moreover, the BMP7 protein has been identified11 as the factor that selectively controls the
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NATURE|Vol 458|16 April 2009
growth and development of brown fat cells,
and so drugs that mimic its action might also
be effective anti-obesity agents.
■
Stephen R. Farmer is in the Department of
Biochemistry, Boston University School of
Medicine, Boston, Massachusetts 02118, USA.
e-mail: [email protected]
1. Nedergaard, J., Bengtsson, T. & Cannon, B. Am. J. Physiol.
Endocrinol. Metab. 293, E444–E452 (2007).
2. Virtanen, K. A. et al. N. Eng. J. Med. 360, 1518–1525 (2009).
3. van Marken Lichtenbelt, W. D. et al. N. Eng. J. Med. 360,
1500–1508 (2009).
4. Cypess, A. M. et al. N. Eng. J. Med. 360, 1509–1517 (2009).
5. Cannon, B. & Nedergaard, J. Physiol. Rev. 84, 277–359
(2004).
6. Lean, M. E. J. Proc. Nutr. Soc. 59, 331–336 (2000).
7. Wajchenberg, B. L. Endocr. Rev. 21, 697–738 (2000).
8. Seale, P. et al. Nature 454, 961–967 (2008).
9. Tang, W. et al. Science 322, 583–586 (2008).
10. Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Cell 135,
240–249 (2008).
11. Tseng, Y.-H. et al. Nature 454, 1000–1004 (2008).
BIOCHEMISTRY
Anchors away
Maria Paola Costi and Stefania Ferrari
Nature often adopts several approaches to crack the same problem. The
finding that the mechanism of a crucial enzyme in certain disease-causing
bacteria differs from that in mammals offers scope for drug discovery.
On page 919 of this issue, Koehn et al.1 propose
that, in certain microorganisms, a previously
unknown biochemical mechanism underpins
the function of an enzyme that is essential to
the microorganisms’ survival. In mammals, the
activity of this enzyme — thymidylate synthase
— depends on an ‘anchor’ in its active site that
binds covalently to the enzyme’s substrate.
But the authors find that, in some microbes
(including many that threaten human life),
thymidylate synthase is active in the absence of
such an anchor. The mechanism that explains
this behaviour is a potential target for antibiotic drugs that would be toxic to microbes,
but not to humans.
This difference1 between taxonomic groups
is a clear example of how some cells evolved
to have well-developed enzyme mechanisms
that have high energy costs (as in mammalian
thymidylate synthase), whereas others make
do with less-specialized mechanisms that
have lower energy costs (as in the microbial
enzyme). Thymidylate synthase produces a
deoxythymidine nucleotide (dTMP), which
is necessary for DNA synthesis. Classic biochemical2 and proteomic studies3 have clearly
shown that there are two kinds of thymidylate
synthase, each having distinct evolutionary
origins (based on their different mechanisms
of action and structures). Those found in
humans and other mammals are known as
TS enzymes, whereas the other group, found
in 30% of microbial genomes4, is known as the
FDTS family of enzymes.
The mechanistic differences between the
two groups hinge on the cofactors required
and on the reactions that occur between the
enzymes and their substrate, a deoxyuridine
nucleotide (dUMP). In mammalian TS, synthesis of dTMP begins when a cysteine aminoacid residue in TS forms a covalent bond to a
specific carbon in dUMP (see Fig. 1 here, and
Fig. 1a on page 920). This bond anchors the
© 2009 Macmillan Publishers Limited. All rights reserved
substrate to the enzyme. In the next step, a
carbon atom is transferred from a cofactor
to the carbon adjacent to the anchor. This is
a high-energy process, which occurs only
because the anchor aligns the reacting groups
perfectly for reaction. In the final step, the
newly attached carbon atom is converted
into a methyl group and the anchor breaks,
releasing the resulting dTMP product.
But Koehn et al.1 have found that microbial FDTS enzymes do not covalently anchor
dUMP, reducing the energy cost of their
reactions. To prove this, they performed
conceptually simple experiments on the active
site of FDTS from the microbe Thermotoga
maritima. It had previously been thought that
a serine amino-acid residue in the active site
acts as an anchor for dUMP, in the same way
as a cysteine residue does in TS enzymes. The
authors therefore mutated the serine to alanine,
whose side chain is incapable of reacting with
dUMP to form a covalent anchor. The mutant
FDTS retained its activity, thus showing that
substrate anchoring is not necessary to drive
the enzyme’s reaction.
The authors also made a serine-to-cysteine
mutant, which was expected to be active by
analogy with the TS enzymes. In fact, it was
less active than the non-mutated enzyme. A
crystal structure1 of the mutant revealed that
the cysteine residue does not form a covalent
bond to dUMP, yet Koehn et al. obtained other
evidence suggesting that the cysteine does
form a complex with the substrate. Taken
together, these results suggest that the observed
cysteine–dUMP complex is a dead end that
doesn’t form part of the FDTS catalytic cycle.
These data serve as a reminder that, although
mutagenesis experiments are often very useful,
local changes to protein structures can translate
into mostly unpredictable long-range effects.
Indeed, previous mutagenesis experiments4,5 on
the FDTS of the bacterium Helicobacter pylori