barbara cannon the wenner-gren institute , stockholm university
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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 - PowerPoint PPT PresentationTRANSCRIPT
Barbara CannonThe Wenner-Gren Institute,
Stockholm University
Human brown fat is on fire
Results in collaboration with(among others)
Wenner-Gren InstituteStockholm UniversityGustavo Abreu de VieiraTore BengtssonHelena FeldmannValeria GolozoubovaAnders JacobssonElaina MaldonadoNatasa PetrovicTomas WaldénandJan Nedergaard
RVC London University of CopenhagenUniversity of AnconaValentina Gburcik Naja Zenius Jespersen Marie Cristina ZingarettiJames A. Timmons Camilla ScheeleSaverio Cinti
Bente Klarlund PedersenTherese Juhlin
A new organ in adult humans:
brown adipose tissue
”in man, brown adipose tissue is only found in newborns”
Before 2007:
An unexpected developmentfrom radiology
Barrington & Maisey 1996
Tense muscle?
”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:
” in man, brown adipose tissue is found in newborns and in (certain?) adults”
After 2007:
Classically: keeping human newborns warm
Classically: keeping small mammals warm
Classically: awakening from hibernation
Brownadipose tissue
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UCP1 is essential for norepinephrine-induced thermogenesisin brown adipocytes
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Enerbäck//Kozak 1997
UCP1 is the sole mediatorof classical nonshivering thermogenesis
Wild-type mice
UCP1(-/-) mice
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Enerbäck//Kozak 1997
UCP1 is the sole mediatorof classical nonshivering thermogenesis
Wild-type mice
UCP1(-/-) mice
Wild-type mice
UCP1(-/-) mice
Wild-type mice
UCP1(-/-) mice
No cold-inducednonshiveringthermogenesiswithout UCP1
www.med.harvard.edu/JPNM/chetan/normals
How with humans?Do we have classical nonshivering thermogenesis
UCP1 presenceconfirmed
Two independent – but congruent – studies:
Yoneshiro//Saito 2011
Two independent – but congruent – studies:
Yoneshiro//Saito 2011
Two independent – but congruent – studies:
Yoneshiro//Saito 2011
BAT+ BAT-
Muzik//Granneman 2012
200-400 kcal/day10-20 % increase
We clearly possess nonshivering thermogenesis!
Yoneshiro//Saito 2011
BAT+ BAT-
Muzik//Granneman 2012
200-400 kcal/day10-20 % increase
We clearly possess nonshivering thermogenesis!
Can we adapt to cold?
Saito//Tsujisaki 2009
Human brown fat can be recruited, just as in mice.
Induced by cold (?) exposure.
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burning away food
”work”Food Heat
we can abstain - but what if we eat?
”work”Food Heat
”work”Food Heat
fat
”work”Food Heat
”work”Food Heat
fat
”special mechanismfor extra energy dissipation”
”work”Food Heat
”work”Food Heat
fat
”special mechanismfor extra energy dissipation”
”work”Food Heat
fat
”work”Food Heat
fat
”special mechanismfor extra energy dissipation”
”work”Food Heat
fat
brown 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?
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”work”Food Heat
fat
brown fat with UCP1
”work”Food Heat
fat
brown fat without UCP1
Thus, animals/humans without UCP1 should become obese
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Effect ofhigh fat diet
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WT
Withoutbrown fatmice becomefatter
WT
WT
Withoutbrown fatmice becomefatter
at thermoneutrality!
”work”Food Heat
fat
brown fat without UCP1
Thus, animals without UCP1 become obese!
”work”Food Heat
fat
brown fat without UCP1
Thus, animals without UCP1 become obese!
i.e. brown fat protects against obesity
After some hours of activation
ChylomicronsLipoproteins
After some hours of activation
ChylomicronsLipoproteins
After some hours of activationAfter some hours of activation
Lipo-proteinlipase
Bartelt//Heeren 2011
Bartelt//Heeren 2011
i.e. brown adipose tissue protects against hypertriglyceridemia
Bartelt//Heeren 2011
apoa5–/–
Bartelt//Heeren 2011
apoa5–/–cold
Brown adipose tissueas a possible ameliorator of the metabolic syndrome
obesityhypertriglyceridemiahyperglycemia
Implications from mice
Brown adipose tissue and glucose disposal….
Thermogenesis
Glucose uptake
log[NE]
log[NE] Marette & Bukowiecki 1991
Brown-fat cells:
Cooney et al. 1985
Cooney et al. 1985
Cooney et al. 1985
Brown adipocyte
Blood vessel Blood vessel
+ nor-epinephrine
Brown adipocyte
Blood vessel Blood vessel
When UCP1is activatedboth lipidsand carbohydratesare oxidised
LIPID CARBOHYDRATE
Brown fat mitochondria
Bartelt//Heeren 2011
Bartelt//Heeren 2011
Is brown fat of importance for glucose homeostasis?
Glucose tolerance test
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Glucose tolerance test
Fasting glucose
Fasting glucose
Fasting glucose
Brown fat is of significance for glucose controlin mice
i.e. brown adipose tissueis 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 fatreally make us obese?)
Zingaretti et al., 2009
Correlative evidence
Present in the younger and slimmer (!)
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
- obese because they lack brown adipose tissue - lack brown adipose tissue because they are obese?
- or perhaps both correct?
Only correlation
Vijgen//van Marken Lichtenbelt 2012
Before
Vijgen//van Marken Lichtenbelt 2012
Before After gastric bypass
Vijgen//van Marken Lichtenbelt 2012
Before After gastric bypass
(Re)activation: physical or “chemical”
The only “functional” evidencefor possible significance of brown fat in humans is genetic
The -3826polymorphism
Nagai et al. 2003
G/G
A/A + A/G
And as time goes
These substitutionsaccelerate age-related decrease in BAT activity, and thereby may associate with visceral fat accumulation with age.
Yoneshiro//Saito, 2013)
Correlation of UCP1 genotype with obesity
Evidence from man
obeseslimmer
Thus, the A’s can both eat more than the G’s– and stay slim…
In our opinion,extrapolation from mouse datato humans(now allowed)implies that even in humansthe absence of brown fat causes obesity
- but why do we lose itwith age?
Stress
Stress
In our opinion,extrapolation from mouse datato humans(now allowed)implies that even in humanssuccessive diminishment or absence of brown fat causes obesity,worsens triglyceridemiaand disposes to diabetes
In our opinion,extrapolation from mouse datato humans(now allowed)implies that even in humanssuccessive diminishment or absence of brown fat causes obesity,worsens triglyceridemiaand disposes to diabetes
so keep your brown fat active!
