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

2. 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

3. A new organ in adult humans: brown adipose tissue

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

5. An unexpected development from radiology

7. Barrington & Maisey 1996 Tense muscle?

8. ”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

9. 2007:

10. ” in man, brown adipose tissue is found in newborns and in (certain?) adults” After 2007:

11. Classically: keeping human newborns warm

12. Classically: keeping small mammals warm

13. Classically: awakening from hibernation

15. Brown adipose tissue

18. 1

19. 1

20. 1

21. 1

22. 1

23. 1 UCP1 is essential for norepinephrine-induced thermogenesis in brown adipocytes

24. 1 Enerbäck//Kozak 1997 UCP1 is the sole mediator of classical nonshivering thermogenesis

25. Wild-type mice UCP1(-/-) mice

26. 1 Enerbäck//Kozak 1997 UCP1 is the sole mediator of classical nonshivering thermogenesis

27. Wild-type mice UCP1(-/-) mice

28. Wild-type mice UCP1(-/-) mice

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

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

31. UCP1 presence confirmed

32. Two independent – but congruent – studies: Yoneshiro//Saito 2011

33. Two independent – but congruent – studies: Yoneshiro//Saito 2011

34. Two independent – but congruent – studies: Yoneshiro//Saito 2011 BAT+ BAT- Muzik//Granneman 2012 200-400 kcal/day 10-20 % increase

35. We clearly possess nonshivering thermogenesis! Yoneshiro//Saito 2011 BAT+ BAT- Muzik//Granneman 2012 200-400 kcal/day 10-20 % increase

36. We clearly possess nonshivering thermogenesis! Can we adapt to cold?

37. Saito//Tsujisaki 2009 Human brown fat can be recruited, just as in mice. Induced by cold (?) exposure.

38. 1

39. 1 burning away food

40. ”work” Food Heat

41. we can abstain - but what if we eat?

42. ”work” Food Heat ”work” Food Heat fat

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

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

45. ”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

46. What are the consequences of lack of brown fat thermogenesis?

47. 1

48. ”work” Food Heat fat brown fat with UCP1

49. ”work” Food Heat fat brown fat without UCP1 Thus, animals/humans without UCP1 should become obese

50. WT

52. Effect of high fat diet

53. WT

54. Without brown fat mice become fatter

55. WT Without brown fat mice become fatter at thermoneutrality!

56. ”work” Food Heat fat brown fat without UCP1 Thus, animals without UCP1 become obese!

57. ”work” Food Heat fat brown fat without UCP1 Thus, animals without UCP1 become obese! i.e. brown fat protects against obesity

59. After some hours of activation

60. Chylomicrons Lipoproteins After some hours of activation

61. Chylomicrons Lipoproteins After some hours of activation Lipo- protein lipase

63. Bartelt//Heeren 2011

64. i.e. brown adipose tissue protects against hypertriglyceridemia

65. Bartelt//Heeren 2011 apoa5–/–

66. Bartelt//Heeren 2011 apoa5–/– cold

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

68. Brown adipose tissue and glucose disposal….

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

71. Cooney et al. 1985

74. Brown adipocyte Blood vessel

76. + nor- epinephrine

77. Brown adipocyte Blood vessel

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

79. Bartelt//Heeren 2011

82. Is brown fat of importance for glucose homeostasis?

83. Glucose tolerance test

84. 1

86. Fasting glucose

88. Brown fat is of significance for glucose control in mice

89. i.e. brown adipose tissue is antidiabetic

90. Thus, brown adipose tissue protects against - obesity - hypertriglyceridemia - hyperglycemia

91. So, OK, brown fat is “anti-metabolic syndrome” in mice (good for them…) but we are humans…

92. Does it matter whether we have brown fat or not? (i.e. does lack of brown fat really make us obese?)

93. Zingaretti et al., 2009 Correlative evidence

94. Present in the younger and slimmer (!) Zingaretti et al., 2009 Correlative evidence

95. Present in the younger and slimmer (!) Zingaretti et al., 2009

96. Present in the younger and slimmer (!) Zingaretti et al., 2009

97. - obese because they lack brown adipose tissue - lack brown adipose tissue because they are obese? - or perhaps both correct? Only correlation

98. Vijgen//van Marken Lichtenbelt 2012 Before

99. Vijgen//van Marken Lichtenbelt 2012 Before After gastric bypass

100. Vijgen//van Marken Lichtenbelt 2012 Before After gastric bypass (Re)activation: physical or “chemical”

101. The only “functional” evidence for possible significance of brown fat in humans is genetic

102. The -3826 polymorphism

104. Nagai et al. 2003 G/G A/A + A/G

105. And as time goes

106. These substitutions accelerate age-related decrease in BAT activity, and thereby may associate with visceral fat accumulation with age. Yoneshiro//Saito, 2013)

107. Correlation of UCP1 genotype with obesity Evidence from man obeseslimmer

108. Thus, the A’s can both eat more than the G’s – and stay slim…

109. 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?

111. Stress

113. 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

114. 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!