barbara cannon the wenner-gren institute , stockholm university

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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WT

WT

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Effect ofhigh fat diet

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WT

WT

WT

Withoutbrown fatmice becomefatter

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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!