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
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Barbara CannonThe Wenner-Gren Institute,
Stockholm University
Human brown fat is on fire
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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
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A new organ in adult humans:
brown adipose tissue
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”in man, brown adipose tissue is only found in newborns”
Before 2007:
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An unexpected developmentfrom radiology
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Barrington & Maisey 1996
Tense muscle?
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”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
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2007:
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” in man, brown adipose tissue is found in newborns and in (certain?) adults”
After 2007:
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Classically: keeping human newborns warm
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Classically: keeping small mammals warm
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Classically: awakening from hibernation
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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
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Wild-type mice
UCP1(-/-) mice
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Enerbäck//Kozak 1997
UCP1 is the sole mediatorof classical nonshivering thermogenesis
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Wild-type mice
UCP1(-/-) mice
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Wild-type mice
UCP1(-/-) mice
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Wild-type mice
UCP1(-/-) mice
No cold-inducednonshiveringthermogenesiswithout UCP1
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www.med.harvard.edu/JPNM/chetan/normals
How with humans?Do we have classical nonshivering thermogenesis
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UCP1 presenceconfirmed
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Two independent – but congruent – studies:
Yoneshiro//Saito 2011
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Two independent – but congruent – studies:
Yoneshiro//Saito 2011
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Two independent – but congruent – studies:
Yoneshiro//Saito 2011
BAT+ BAT-
Muzik//Granneman 2012
200-400 kcal/day10-20 % increase
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We clearly possess nonshivering thermogenesis!
Yoneshiro//Saito 2011
BAT+ BAT-
Muzik//Granneman 2012
200-400 kcal/day10-20 % increase
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We clearly possess nonshivering thermogenesis!
Can we adapt to cold?
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Saito//Tsujisaki 2009
Human brown fat can be recruited, just as in mice.
Induced by cold (?) exposure.
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burning away food
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”work”Food Heat
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we can abstain - but what if we eat?
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”work”Food Heat
”work”Food Heat
fat
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”work”Food Heat
”work”Food Heat
fat
”special mechanismfor extra energy dissipation”
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”work”Food Heat
”work”Food Heat
fat
”special mechanismfor extra energy dissipation”
”work”Food Heat
fat
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”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
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What are the consequences
of lack of
brown fat thermogenesis?
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”work”Food Heat
fat
brown fat with UCP1
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”work”Food Heat
fat
brown fat without UCP1
Thus, animals/humans without UCP1 should become obese
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WT
WT
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WT
WT
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Effect ofhigh fat diet
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WT
WT
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WT
WT
Withoutbrown fatmice becomefatter
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WT
WT
Withoutbrown fatmice becomefatter
at thermoneutrality!
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”work”Food Heat
fat
brown fat without UCP1
Thus, animals without UCP1 become obese!
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”work”Food Heat
fat
brown fat without UCP1
Thus, animals without UCP1 become obese!
i.e. brown fat protects against obesity
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After some hours of activation
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ChylomicronsLipoproteins
After some hours of activation
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ChylomicronsLipoproteins
After some hours of activationAfter some hours of activation
Lipo-proteinlipase
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Bartelt//Heeren 2011
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Bartelt//Heeren 2011
i.e. brown adipose tissue protects against hypertriglyceridemia
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Bartelt//Heeren 2011
apoa5–/–
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Bartelt//Heeren 2011
apoa5–/–cold
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Brown adipose tissueas a possible ameliorator of the metabolic syndrome
obesityhypertriglyceridemiahyperglycemia
Implications from mice
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Brown adipose tissue and glucose disposal….
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Thermogenesis
Glucose uptake
log[NE]
log[NE] Marette & Bukowiecki 1991
Brown-fat cells:
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Cooney et al. 1985
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Cooney et al. 1985
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Cooney et al. 1985
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Brown adipocyte
Blood vessel Blood vessel
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+ nor-epinephrine
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Brown adipocyte
Blood vessel Blood vessel
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When UCP1is activatedboth lipidsand carbohydratesare oxidised
LIPID CARBOHYDRATE
Brown fat mitochondria
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Bartelt//Heeren 2011
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Bartelt//Heeren 2011
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Is brown fat of importance for glucose homeostasis?
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Glucose tolerance test
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Glucose tolerance test
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Fasting glucose
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Fasting glucose
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Fasting glucose
Brown fat is of significance for glucose controlin mice
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i.e. brown adipose tissueis antidiabetic
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Thus, brown adipose tissue protects against
- obesity- hypertriglyceridemia- hyperglycemia
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So, OK, brown fat is “anti-metabolic syndrome” in mice(good for them…)
but we are humans…
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Does it matter whether we have brown fat or not?
(i.e. does lack of brown fatreally make us obese?)
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Zingaretti et al., 2009
Correlative evidence
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Present in the younger and slimmer (!)
Zingaretti et al., 2009
Correlative evidence
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Present in the younger and slimmer (!)
Zingaretti et al., 2009
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Present in the younger and slimmer (!)
Zingaretti et al., 2009
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- obese because they lack brown adipose tissue - lack brown adipose tissue because they are obese?
- or perhaps both correct?
Only correlation
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Vijgen//van Marken Lichtenbelt 2012
Before
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Vijgen//van Marken Lichtenbelt 2012
Before After gastric bypass
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Vijgen//van Marken Lichtenbelt 2012
Before After gastric bypass
(Re)activation: physical or “chemical”
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The only “functional” evidencefor possible significance of brown fat in humans is genetic
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The -3826polymorphism
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Nagai et al. 2003
G/G
A/A + A/G
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And as time goes
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These substitutionsaccelerate age-related decrease in BAT activity, and thereby may associate with visceral fat accumulation with age.
Yoneshiro//Saito, 2013)
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Correlation of UCP1 genotype with obesity
Evidence from man
obeseslimmer
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Thus, the A’s can both eat more than the G’s– and stay slim…
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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?
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Stress
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Stress
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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
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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!
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