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Turning up the heat: brown adipose tissue as a new target in metabolic disease

Turning up the heat: brown adipose tissue as a new target in metabolic disease. Prof. dr. Patrick C.N. Rensen Leiden University Medical Center Department of Endocrinology and Einthoven Laboratory for Experimental Vascular Medicine P.O. Box 9600, 2300 RC Leiden p.c.n.rensen@lumc.nl.

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Turning up the heat: brown adipose tissue as a new target in metabolic disease

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  1. Turning up the heat: brown adipose tissueas a new target in metabolic disease Prof. dr. Patrick C.N. Rensen Leiden University Medical Center Department of Endocrinology and Einthoven Laboratory for Experimental Vascular MedicineP.O. Box 9600, 2300 RC Leiden p.c.n.rensen@lumc.nl

  2. Patrick C.N. RensenProfessor in Endocrinology Disclosure potential conflicts of interests Patrick Rensen 2

  3. ‘Metabolic Aspects of Vascular Diseases’novel player: brown adipose tissue (BAT) obesity ATP production storage heat heart muscle WAT BAT dyslipidemia TG↑ LDL-C↑ HDL-C↓ atherosclerosis fatty acids cholesterol LDL VLDL chylomicron steatosis HDL liver E E LDLr LDLr intestine Patrick Rensen 3

  4. Comparison between white and brown adipose tissue Boon et al., Ned Tijdschr Geneeskd 2013 Patrick Rensen 4

  5. BAT is physiologically activated by coldvia ß adrenergic receptors Hypothalamus SNS Transient receptor potential channels TRP (M8, A1, V1) Sensory nerves Cold Boon et al., Ned Tijdschr Geneeskd 2013 Patrick Rensen 5

  6. Physiology of the brown adipocyte:uncoupling electron transport chain and ATP synthesis through UCP-1 Boon et al., Ned Tijdschr Geneeskd 2013 Patrick Rensen 6

  7. BAT contributes largely to triglyceride clearance Bartelt et al., Nat Med 2011 Patrick Rensen 7

  8. Brown adipose tissue required for heat production by non-shivering thermogenesis in neonates Patrick Rensen 8

  9. glucose BAT is still present and active in adults, and BAT activity inversely correlates with obesity 18F-fluoro-deoxy-glucose PET-CT Tumor BAT obese lean Van Marken-Lichtenbelt et al., NEJM 2009; Cypess et al., NEJM 2009; Virtanen et al., NEJM 2009 Patrick Rensen 9

  10. Cold exposure recruits BAT, increases non-shivering thermogenesis and induces weight loss 15-16°C (6 h/day, 10 days) 17°C (2 h/day, 6 weeks) Capsinoids (CH-19 Sweet; 9 mg/day po, 6 wks) Van der Lans et al., J Clin Invest 2013 ; Yoneshiro et al., J Clin Invest 2013 Patrick Rensen

  11. Central hypothesis:BAT is a target to comBAT obesity, T2D and CVD obesity ATP production storage heat heart muscle WAT BAT dyslipidemia TG↑ LDL-C↑ HDL-C↓ atherosclerosis fatty acids cholesterol LDL VLDL chylomicron HDL steatosis liver E E LDLr LDLr intestine Patrick Rensen 11

  12. Research themes related to BAT • Ethnicity • Pharmacology • Biomarker discovery (Boon/Jazet/Smit/Pereira Arias-Bouda; Van Marken Lichtenbelt, MUMC) • Physiology (Heeren, Hamburg) • Pharmacology • Metformin/AMPK (Guigas) • Rimonabant/CB1 receptor (Jukema) • ß adrenergic receptors(Heeren, Hamburg) • BMP7 receptor (Ten Dijke) • MC4R, GLP-1 receptor (Jazet) • Glucocorticoid receptor (Meijer; Grefhorst, EMC) • Genetics • USF1 (Jauhiainen, Helsinki) • ABCD1 (Kemp, AMC) • Immune system • Innate vs adaptive (Yazdanbakhsh; De Winther & Lutgens, AMC) • Interleukins (Stienstra, Tack & Dinarello, WUR/Radboud UMC) • Biological clock (Biermasz/Meijer) Patrick Rensen 12

  13. South Asians • 20% of world population • South Asians have an unfavorable metabolic phenotype • South Asians have 6-fold higher prevalence rate of T2D than white Caucasians, and develop T2D at much younger age • South Asians have increased risk of developing CVD, and 50% increased age-adjusted mortality rate from CVD reviewed in: Bakker and Sleddering et al., Eur J Endocrinol 2013 Patrick Rensen 13

  14. South Asians have increased plasma triglycerides and glucose from birth cord blood Glucose Triglycerides Boon et al., J Pedriatrics 2012 Patrick Rensen 14

  15. South Asians have decreased energy expenditure and decreased non-shivering thermogenesis REE (thermoneutral) personal cooling (2h) REE (cold-induced) PET-CT scan n.s. Bakker and Boon et al., The Lancet Diabetes & Endocrinol 2014 Patrick Rensen 15

  16. South Asians have lower BAT volume and activity • South Asians have decreased BAT volume that correlates with REE • Decreased BAT activity may underlie unfavorable metabolic phenotype • South Asians may particularly benefit from BAT-targeted approaches Bakker and Boon et al., The Lancet Diabetes & Endocrinol 2014 Patrick Rensen 16

  17. Metformin • Metforminis first-line drug in the treatment of type 2 diabetes • Decreases hepatic glucose production by inhibitinggluconeogenesis Metformin Glucose • Decreases plasma triglycerides via unknown mechanism • Causes decrease in body fat and BMI in T2D patients and children • Does metformin activate BAT? Wollen et al., BP 1988; Argaud et al., EJP 1993; Foretz et al., JCI 2010 Wang et al., Curr Ther Res Clin Exp 2013; McDonagh et al., JAMA Pedriatrics 2014 Patrick Rensen Patrick Rensen 17

  18. APOE*3-Leiden.CETP transgenic mouse: Well-established model for human-like lipoprotein metabolism Human Cholesterol mainly as LDL-C Mouse Cholesterol mainly as HDL-C APOE*3-Leiden.CETP mouse Cholesterol mainly as (V)LDL-C APOE*3-Leiden.CETP mice • develop diet-induced hyperlipidemia and atherosclerosis • respond in human-like manner to lipid-lowering interventions • intact apoE-LDLr clearance pathway (unlike apoe-/- and ldlr-/- mice) De Haan et al., Circulation 2008; Bijland et al., J Biol Chem 2010; Kühnast et al., PLoS One 2013 Patrick Rensen 18

  19. Study set up 250 mg/day/kg 12-weeks-old female APOE*3-Leiden.CETP mouse * * Geerling and Boon et al., Diabetes 2014 Patrick Rensen Patrick Rensen 19

  20. Metformin does not reduce hepatic VLDL-TG production Triton WR-1339 Trans35S 4h-fast † -30 0 15 30 60 90 (n=7 / group) Control Metformin TG VLDL Geerling and Boon et al., Diabetes 2014 *, p<0.05 Patrick Rensen 20

  21. Metformin increases TG clearance by activating BAT Geerling and Boon et al., Diabetes 2014 Patrick Rensen 21

  22. Metformin increases AMPK signaling and lipolysis in T37i brown adipocytes Geerling and Boon et al., Diabetes 2014 Patrick Rensen 22

  23. Metforming activates AMPK signaling in BAT to enhance uptake of TG from plasma Patrick Rensen 23

  24. Rimonabant • Rimonabant, CB1R inverse agonist, given to obese patients: • sustained weight loss despite transient decrease in appetite • improvement of lipid profile (triglycerides ↓) • Withdrawn from market in 2008 due to psychiatric side effects • Mechanism underlying effects on lipid metabolism unknown • Does rimonabant activate BAT? Patrick Rensen 24

  25. Study set up 10 mg/kg/day p.o. 10-weeks-old male APOE*3-Leiden.CETP mouse 12 16 0 60% high fat diet Weeks Boon et al., submitted Patrick Rensen 25

  26. Rimonabant decreases body weight and fat mass, accompanied by increased energy expenditure DEXA scan fully automatic metabolic cage Boon et al., submitted Patrick Rensen 26

  27. Rimonabant reduces plasma TG via increased uptake by BAT control rimonabant Control Rimonabant Boon et al., submitted Patrick Rensen 27

  28. Hypothesis: BAT activation reduces atherosclerosis Cutting et al., J Clin Invest 1934 Patrick Rensen 28

  29. Hypothesis: BAT activation reduces atherosclerosis Cutting et al., J Clin Invest 1934 Dong et al., Cell Metab 2013 Patrick Rensen 29

  30. Study set up: Does BAT activation reduce atherosclerosis in APOE*3-Leiden.CETP mice? CL316243 (20 µg; 3x/week s.c.) APOE*3-Leiden.CETP mice † -5 0 4 7 10 n=13-19 per group Western-type diet (0.1% cholesterol) HE-staining BAT (15x) HE-staining WAT (10x) Control CL316243 Berbée, Boon and Bartelt et al., in progress Patrick Rensen 30

  31. CL316243 lowers plasma triglyceride and cholesterol levels and reduces atherosclerosis in APOE*3-Leiden.CETP mice Vehicle CL316243 Berbée, Boon and Bartelt et al., in progress Patrick Rensen 31

  32. Intact apoE-LDLr pathway for lipoprotein remnants clearance is required for anti-atherogenic effect heat BAT fatty acids cholesterol E VLDL E (V)LDL cholesterol LDLr Berbée, Boon and Bartelt et al., in progress Patrick Rensen 32

  33. Conclusions & take home messages → It is not that bad to be cold! • BAT plays a role in metabolism of glucose, TG and cholesterol • BAT volume is smaller is South Asians versus white Caucasians • Metformin and rimonabant reduce diet-induced dyslipidemia and weight gain by direct activation of BAT • BAT activation inhibits atherosclerosis development → Because of its fat-burningcapacity, BAT is anattractive target tocomBATobesityandrelated disorders includingatherosclerosis Patrick Rensen 33

  34. Acknowledgements Dept. Cardiology • Stella Trompet • Wouter Jukema Dept. Human Genetics • Sjoerd van den Berg • Ko Willems van Dijk Dept. Molecular Cell Biology • Peter ten Dijke • Claudia Coomans • Joke Meijer Dept. Nephrology • Anton Jan van Zonneveld • Ton Rabelink Dept. Parasitology • Bruno Guigas • Maria Yazdanbakhsh Dept. Pulmonology • Padmini Khedoe • Pieter Hiemstra Dept. Thoracic Surgery • Meindert Palmen Dept. Urology • Geertje van der Horst • Gabri van der Pluijm Rijnland Hospital (Leiderdorp) • Frits Smit • Lenka Pereira Arias - Bouda MUMC, Dept. Human Biology (Maastricht) • Wouter van Marken Lichtenbelt MUMC, Dept. Radiology (Maastricht) • Matthias Bauwens AMC, Dept. Medical Biochemistry (Amsterdam) • Esther Lutgens • Menno de Winther EMC, Dept. Internal Medicine (Rotterdam) • Anneke van den Beukel • Aldo Grefhorst Laboratory for Mineralized Tissues (Zagreb) • Slobodan Vukicevic University Medical Center Hamburg (Hamburg) • Alexander Bartelt • Jörg Heeren National Institute for Health and Welfare (Helsinki) • Pirkka-Pekka Laurila • Matti Jauhiainen Patrick Rensen 34 LUMC, Dept. Endocrinology Mariëtte Boon Leontine Bakker Andrea van Dam Edwin Parlevliet Sander Kooijman Janine Geerling Jimmy Berbée Onno Meijer Alberto Pereira Ingrid Jazet Nienke Biermasz Louis Havekes

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