Turning up the heat brown adipose tissue as
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
Patrick C. N. Rensen Professor in Endocrinology Disclosure potential conflicts of interests Research contracts: None Consulting: Astellas Pharma B. V. Employment in industry: None Stockholder of a healthcare company: None Owner of a healthcare company: None Other: None Patrick Rensen 2
‘Metabolic Aspects of Vascular Diseases’ novel player: brown adipose tissue (BAT) ATP production heart muscle obesity storage heat WAT BAT dyslipidemia TG↑fatty LDL-C↑acids HDL-C↓ atherosclerosis cholesterol LDL E E chylomicron VLDL LDLr steatosis LDLr HDL intestine liver Patrick Rensen 3
Comparison between white and brown adipose tissue WAT BAT Amount <12 - >35 kg 100 -200 g Morphology Cells contain one large triglyceride (TG) droplet Cells contain multiple TG droplets of variable size Mitochondria Few Many Location Throughout body Fat pads along large vessels (c. BAT) Scattered between WAT (i. BAT) Function Storage of TG Combustion of TG into heat Boon et al. , Ned Tijdschr Geneeskd 2013 Patrick Rensen 4
BAT is physiologically activated by cold via ß adrenergic receptors Hypothalamus SNS Transient receptor potential channels TRP (M 8, A 1, V 1) Sensory nerves Cold Boon et al. , Ned Tijdschr Geneeskd 2013 Patrick Rensen 5
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
BAT contributes largely to triglyceride clearance Bartelt et al. , Nat Med 2011 Patrick Rensen 7
Brown adipose tissue required for heat production by non-shivering thermogenesis in neonates Patrick Rensen 8
BAT is still present and active in adults, and BAT activity inversely correlates with obesity glucose 18 F-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
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- Van der Lans et al. , J Clin Invest 2013 ; Yoneshiro et al. , J Clin Invest 2013 Patrick Rensen 10
Central hypothesis: BAT is a target to com. BAT obesity, T 2 D and CVD ATP production heart muscle obesity storage heat WAT BAT dyslipidemia TG↑fatty LDL-C↑acids HDL-C↓ atherosclerosis cholesterol LDL E E chylomicron VLDL LDLr steatosis intestine liver Patrick Rensen 11 HDL
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/CB 1 receptor (Jukema) • ß adrenergic receptors (Heeren, Hamburg) • BMP 7 receptor (Ten Dijke) • MC 4 R, GLP-1 receptor (Jazet) • Glucocorticoid receptor (Meijer; Grefhorst, EMC) • Genetics • USF 1 (Jauhiainen, Helsinki) • ABCD 1 (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
South Asians • 20% of world population • South Asians have an unfavorable metabolic phenotype • South Asians have 6 -fold higher prevalence rate of T 2 D than white Caucasians, and develop T 2 D 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
South Asians have increased plasma triglycerides and glucose from birth cord blood Glucose Triglycerides Boon et al. , J Pedriatrics 2012 Patrick Rensen 14
South Asians have decreased energy expenditure and decreased non-shivering thermogenesis REE (thermoneutral) personal cooling (2 h) REE (cold-induced) PET-CT scan n. s. Bakker and Boon et al. , The Lancet Diabetes & Endocrinol 2014 Patrick Rensen 15
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
Metformin • Metformin is first-line drug in the treatment of type 2 diabetes • Decreases hepatic glucose production by inhibiting gluconeogenesis Metformin Glucose • Decreases plasma triglycerides via unknown mechanism • Causes decrease in body fat and BMI in T 2 D patients and children • Does metformin activate BAT? Patrick Rensen Wollen et al. , BP 1988; Argaud et al. , EJP 1993; Foretz et al. , JCI 2010 Wang et al. , Curr Ther Res Clin Exp 2013; Mc. Donagh et al. , JAMA Pedriatrics 2014 17
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 apo. E-LDLr clearance pathway (unlike apoe-/- and ldlr-/- mice) De Haan et al. , Circulation 2008; Bijland et al. , J Biol Chem 2010; Kühnast et al. , PLo. S One 2013 Patrick Rensen 18
Study set up 250 mg/day/kg 12 -weeks-old female APOE*3 -Leiden. CETP mouse * Patrick Rensen * Geerling and Boon et al. , Diabetes 2014 19
Metformin does not reduce hepatic VLDL-TG production Trans 35 S Triton WR-1339 4 h-fast † TG -30 0 15 30 60 (n=7 / group) 90 VLDL Control Metformin Geerling and Boon et al. , Diabetes 2014 Patrick Rensen *, p<0. 05 20
Metformin increases TG clearance by activating BAT Geerling and Boon et al. , Diabetes 2014 Patrick Rensen 21
Metformin increases AMPK signaling and lipolysis in T 37 i brown adipocytes Geerling and Boon et al. , Diabetes 2014 Patrick Rensen 22
Metforming activates AMPK signaling in BAT to enhance uptake of TG from plasma Patrick Rensen 23
Rimonabant • Rimonabant, CB 1 R 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
Study set up 10 mg/kg/day p. o. 10 -weeks-old male APOE*3 -Leiden. CETP mouse 0 12 Weeks 60% high fat diet 16 Boon et al. , submitted Patrick Rensen 25
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
Rimonabant reduces plasma TG via increased uptake by BAT control Control rimonabant Rimonabant Boon et al. , submitted Patrick Rensen 27
Hypothesis: BAT activation reduces atherosclerosis Cutting et al. , J Clin Invest 1934 Patrick Rensen 28
Hypothesis: BAT activation reduces atherosclerosis Cutting et al. , J Clin Invest 1934 Dong et al. , Cell Metab 2013 Patrick Rensen 29
Study set up: Does BAT activation reduce atherosclerosis in APOE*3 -Leiden. CETP mice? CL 316243 (20 µg; 3 x/week s. c. ) APOE*3 -Leiden. CETP mice -5 n=13 -19 per group † 0 4 7 10 Western-type diet (0. 1% cholesterol) HE-staining BAT (15 x) HE-staining WAT (10 x) Control CL 316243 Berbée, Boon and Bartelt et al. , in progress Patrick Rensen 30
CL 316243 lowers plasma triglyceride and cholesterol levels and reduces atherosclerosis in APOE*3 -Leiden. CETP mice Vehicle CL 316243 Berbée, Boon and Bartelt et al. , in progress Patrick Rensen 31
Intact apo. E-LDLr pathway for lipoprotein remnants clearance is required for anti-atherogenic effect heat fatty acids BAT cholesterol E E VLDL (V)LDL cholesterol LDLr Berbée, Boon and Bartelt et al. , in progress Patrick Rensen 32
Conclusions & take home messages • 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-burning capacity, BAT is an attractive target to com. BAT obesity and related disorders including atherosclerosis → It is not that bad to be cold! Patrick Rensen 33
Acknowledgements Dept. Cardiology • Stella Trompet • Wouter Jukema Rijnland Hospital (Leiderdorp) • Frits Smit • Lenka Pereira Arias - Bouda Dept. Human Genetics • Sjoerd van den Berg • Ko Willems van Dijk MUMC, Dept. Human Biology (Maastricht) • Wouter van Marken Lichtenbelt Dept. Molecular Cell Biology • Peter ten Dijke • Claudia Coomans • Joke Meijer Dept. Nephrology • Anton Jan van Zonneveld • Ton Rabelink 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 Patrick Rensen 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 Dept. Parasitology • Bruno Guigas • Maria Yazdanbakhsh Dept. Pulmonology • Padmini Khedoe • Pieter Hiemstra Laboratory for Mineralized Tissues (Zagreb) • Slobodan Vukicevic Dept. Thoracic Surgery • Meindert Palmen University Medical Center Hamburg (Hamburg) • Alexander Bartelt • Jörg Heeren Dept. Urology • Geertje van der Horst • Gabri van der Pluijm National Institute for Health and Welfare (Helsinki) • Pirkka-Pekka Laurila • Matti Jauhiainen 34
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