Human brown fat is on fire Barbara Cannon

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

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UCP 1 is essential for norepinephrine-induced thermogenesis in brown adipocytes 1

UCP 1 is the sole mediator of classical nonshivering thermogenesis 1 Enerbäck//Kozak 1997

Wild-type mice UCP 1(-/-) mice

UCP 1 is the sole mediator of classical nonshivering thermogenesis 1 Enerbäck//Kozak 1997

Wild-type mice UCP 1(-/-) mice

Wild-type mice UCP 1(-/-) mice No cold-induced nonshivering thermogenesis without UCP 1

How with humans? Do we have classical nonshivering thermogenesis www. med. harvard. edu/ JPNM/chetan/normals

UCP 1 presence confirmed

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

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1 burning away food

Food ”work” Heat

we can abstain - but what if we eat?

Food ”work” Heat fat

Food Heat ”work” ”special mechanism for extra energy dissipation” Heat ”work” fat

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?

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brown fat with UCP 1 Food ”work” Heat fat

brown fat without UCP 1 Food ”work” Heat fat Thus, animals/humans without UCP 1 should become obese

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 UCP 1 Food ”work” Heat fat Thus, animals without UCP 1 become obese!

i. e. brown fat protects against obesity brown fat without UCP 1 Food ”work” Heat fat Thus, animals without UCP 1 become obese!

After some hours of activation

After some hours of activation Chylomicrons Lipoproteins

Aftersomehoursofofactivation Chylomicrons Lipoprotein lipase

Bartelt//Heeren 2011

i. e. brown adipose tissue protects against hypertriglyceridemia Bartelt//Heeren 2011

apoa 5–/– Bartelt//Heeren 2011

apoa 5–/– 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

Brown adipocyte Blood vessel

+ norepinephrine

Brown adipocyte Blood vessel

LIPID CARBOHYDRATE When UCP 1 is activated both lipids and carbohydrates are oxidised Brown fat mitochondria

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 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

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 UCP 1 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?

St r es s

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!