Barbara Cannon The Wenner-Gren Institute, Stockholm University Human brown fat is on fire

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 LondonUniversity of CopenhagenUniversity of Ancona Valentina GburcikNaja Zenius JespersenMarie Cristina Zingaretti James A. TimmonsCamilla ScheeleSaverio Cinti Bente Klarlund Pedersen Therese Juhlin

A new organ in adult humans: brown adipose tissue

”in man, brown adipose tissue is only found in newborns” Before 2007:

An unexpected development from 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

Brown adipose tissue

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1 UCP1 is essential for norepinephrine-induced thermogenesis in brown adipocytes

1 Enerbäck//Kozak 1997 UCP1 is the sole mediator of classical nonshivering thermogenesis

Wild-type mice UCP1(-/-) mice

1 Enerbäck//Kozak 1997 UCP1 is the sole mediator of classical nonshivering thermogenesis

Wild-type mice UCP1(-/-) mice

Wild-type mice UCP1(-/-) mice

Wild-type mice UCP1(-/-) mice No cold-induced nonshivering thermogenesis without UCP1

JPNM/chetan/normals How with humans? Do we have classical nonshivering thermogenesis

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 BAT+ BAT- Muzik//Granneman kcal/day % increase

We clearly possess nonshivering thermogenesis! Yoneshiro//Saito 2011 BAT+ BAT- Muzik//Granneman kcal/day % 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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1 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 mechanism for extra energy dissipation”

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

”work” Food Heat fat ”special mechanism for 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 of high fat diet

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Without brown fat mice become fatter

WT Without brown fat mice become fatter 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

Chylomicrons Lipoproteins After some hours of activation

Chylomicrons Lipoproteins After some hours of activation Lipo- protein lipase

Bartelt//Heeren 2011

i.e. brown adipose tissue protects against hypertriglyceridemia

Bartelt//Heeren 2011 apoa5–/–

Bartelt//Heeren 2011 apoa5–/– cold

Brown adipose tissue as a possible ameliorator of the metabolic syndrome obesity hypertriglyceridemia hyperglycemia Implications from mice

Brown adipose tissue and glucose disposal….

Thermogenesis Glucose uptake log[NE] Marette & Bukowiecki 1991 Brown-fat cells:

Cooney et al. 1985

Brown adipocyte Blood vessel

+ nor- epinephrine

Brown adipocyte Blood vessel

When UCP1 is activated both lipids and carbohydrates are oxidised LIPID CARBOHYDRATE Brown fat mitochondria

Bartelt//Heeren 2011

Is brown fat of importance for glucose homeostasis?

Glucose tolerance test

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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?)

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” evidence for possible significance of brown fat in humans is genetic

The polymorphism

Nagai et al G/G A/A + A/G

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)

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 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?

Stress

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!