Human brown fat is on fire
Barbara Cannon
The Wenner-Gren Institute,
Stockholm University
Results in collaboration with
(among others)
Wenner-Gren Institute
Stockholm University
Gustavo Abreu de Vieira
Tore Bengtsson
Helena Feldmann
Valeria Golozoubova
Anders Jacobsson
Elaina Maldonado
Natasa Petrovic
Tomas Waldén
and
Jan Nedergaard
RVC London
Valentina Gburcik
James A. Timmons
University of Copenhagen
Naja Zenius Jespersen
Camilla Scheele
Bente Klarlund Pedersen
Therese Juhlin
University of Ancona
Marie Cristina Zingaretti
Saverio Cinti
A new organ in adult humans:
brown adipose tissue
Before 2007:
”in man, brown adipose tissue
is only found in newborns”
An unexpected
development
from radiology
Tense muscle?
Barrington & Maisey 1996
”In all patients, the soft tissue uptake
was clearly localised within the fatty tissue
of the shoulders
as demonstrated by PET/CT co-registration.”
Hany//von Schulthess 2002
Eur J Nucl Med Mol Imaging
2007:
After 2007:
” in man, brown adipose tissue
is found in newborns and in (certain?) adults”
Classically: keeping human newborns warm
Classically: keeping small mammals warm
Classically: awakening from hibernation
Brown
adipose
tissue
UCP1 is essential
for norepinephrine-induced thermogenesis
in brown adipocytes
UCP1 is the sole mediator
of classical nonshivering thermogenesis
Enerbäck//Kozak 1997
Wild-type mice
UCP1(-/-) mice
UCP1 is the sole mediator
of classical nonshivering thermogenesis
Enerbäck//Kozak 1997
Wild-type mice
UCP1(-/-) mice
Wild-type mice
UCP1(-/-) mice
Wild-type mice
UCP1(-/-) mice
No cold-induced
nonshivering
thermogenesis
without UCP1
How with humans?
Do we have
classical
nonshivering
thermogenesis
www.med.harvard.edu/
JPNM/chetan/normals
UCP1 presence
confirmed
Two independent – but congruent – studies:
Yoneshiro//Saito 2011
Two independent – but congruent – studies:
Yoneshiro//Saito 2011
Two independent – but congruent – studies:
Yoneshiro//Saito 2011
200-400 kcal/day
10-20 % increase
Muzik//Granneman 2012
BAT+
BAT-
We clearly possess nonshivering thermogenesis!
Yoneshiro//Saito 2011
200-400 kcal/day
10-20 % increase
Muzik//Granneman 2012
BAT+
BAT-
We clearly possess nonshivering thermogenesis!
Can we adapt to cold?
Human brown fat can be recruited, just as in mice.
Induced by cold (?) exposure.
Saito//Tsujisaki 2009
burning away food
Food
”work”
Heat
we can abstain - but what if we eat?
Food
”work”
Heat
Food
”work”
Heat
fat
Food
Food
Heat
”work”
”special mechanism
for extra energy
dissipation”
Heat
”work”
fat
Food
Food
Heat
”work”
”special mechanism
for extra energy
dissipation”
Heat
”work”
fat
Food
Heat
”work”
fat
Food
”special mechanism
for extra energy
dissipation”
Heat
”work”
fat
brown fat
Food
”work”
Heat
fat
- such a special mechanism exists
(diet-induced thermogenesis)
- and that it is entirely located to brown adipose tissue
What are the consequences
of lack of
brown fat thermogenesis?
brown fat with UCP1
Food
”work”
Heat
fat
brown fat without UCP1
Food
”work”
Heat
fat
Thus, animals/humans without UCP1
should become obese
WT
WT
WT
WT
Effect of
high fat diet
WT
WT
WT
WT
Without
brown fat
mice
become
fatter
WT
Without
brown fat
mice
become
fatter
at thermoneutrality!
WT
brown fat without UCP1
Food
”work”
Heat
fat
Thus, animals without UCP1
become obese!
i.e. brown fat protects against obesity
brown fat without UCP1
Food
”work”
Heat
fat
Thus, animals without UCP1
become obese!
After some hours of activation
After some hours of activation
Chylomicrons
Lipoproteins
After
Aftersome
somehours
hoursofofactivation
activation
Chylomicrons
Lipoproteins
Lipoprotein
lipase
Bartelt//Heeren 2011
i.e. brown adipose tissue protects against hypertriglyceridemia
Bartelt//Heeren 2011
apoa5–/–
Bartelt//Heeren 2011
apoa5–/–
cold
Bartelt//Heeren 2011
Brown adipose tissue
as a possible ameliorator
of the metabolic syndrome
obesity
hypertriglyceridemia
hyperglycemia
Implications from mice
Brown adipose tissue
and glucose disposal….
Brown-fat cells:
Thermogenesis
log[NE]
Glucose uptake
log[NE]
Marette & Bukowiecki 1991
Cooney et al. 1985
Cooney et al. 1985
Cooney et al. 1985
Brown adipocyte
Blood vessel
Blood vessel
+ norepinephrine
Brown adipocyte
Blood vessel
Blood vessel
LIPID
CARBOHYDRATE
When UCP1
is activated
both lipids
and carbohydrates
are oxidised
Brown fat mitochondria
Bartelt//Heeren 2011
Bartelt//Heeren 2011
Is brown fat of importance for glucose homeostasis?
Glucose tolerance test
Glucose tolerance test
Fasting glucose
Fasting glucose
Fasting glucose
Brown fat is of significance
for glucose control
in mice
i.e. brown adipose tissue
is antidiabetic
Thus, brown adipose tissue protects against
- obesity
- hypertriglyceridemia
- hyperglycemia
So, OK, brown fat is “anti-metabolic syndrome” in mice
(good for them…)
but we are humans…
Does it matter
whether we have brown fat or not?
(i.e. does lack of brown fat
really make us obese?)
Correlative evidence
Zingaretti et al., 2009
Correlative evidence
Present in the younger and slimmer (!)
Zingaretti et al., 2009
Present in the younger and slimmer (!)
Zingaretti et al., 2009
Present in the younger and slimmer (!)
Zingaretti et al., 2009
Only correlation
- obese because they lack brown adipose tissue
- lack brown adipose tissue because they are obese?
- or perhaps both correct?
Before
Vijgen//van Marken Lichtenbelt 2012
Before
After gastric bypass
Vijgen//van Marken Lichtenbelt 2012
Before
After gastric bypass
(Re)activation: physical or “chemical”
Vijgen//van Marken Lichtenbelt 2012
The only “functional” evidence
for possible significance of brown fat in humans
is genetic
The -3826
polymorphism
G/G
A/A + A/G
Nagai et al. 2003
And as time goes
These substitutions
accelerate age-related decrease in BAT activity,
and thereby may associate with
visceral fat accumulation with age.
Yoneshiro//Saito, 2013)
Evidence from man
Correlation of UCP1 genotype with obesity
slimmer
obese
Thus,
the A’s can both eat more than the G’s
– and stay slim…
In our opinion,
extrapolation from
mouse data
to humans
(now allowed)
implies that even in humans
the absence of brown fat
causes obesity
- but why do we lose it
with age?
In our opinion,
extrapolation from
mouse data
to humans
(now allowed)
implies that even in humans
successive diminishment
or absence of brown fat
causes obesity,
worsens triglyceridemia
and disposes to diabetes
In our opinion,
extrapolation from
mouse data
to humans
(now allowed)
implies that even in humans
successive diminishment
or absence of brown fat
causes obesity,
worsens triglyceridemia
and disposes to diabetes
so keep your brown fat active!