Joslin Diabetes Center Advances in Diabetes and Thyroid Disease 2013 Brown Fat: What You Need to Know

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1 Advances in Diabetes and Thyroid Disease Aaron M. Cypess, MD, PhD, MMSc Assistant Investigator and Staff Physician Joslin Diabetes Center Assistant Professor of Medicine Harvard Medical School November 8, 2013 Conflict of Interest Disclosure Aaron M. Cypess, MD, PhD I am a recipient of a sponsored research grant from Chugai Pharmaceutical Co., Ltd, through Joslin Diabetes Center and received an honorarium to give a lecture to employees at Pfizer, Inc. Objectives 1. Distinguish the structural and functional differences between brown and white adipose tissue. 2. Identify which imaging modalities are available to study brown fat function. 3. List the interventions already shown to increase brown adipose tissue mass and activity. 4. Based on the currently available data, describe the likelihood that brown adipose tissue will be a treatment target for obesity and diabetes. 1

2 Too Much Fat is Highly Morbid Two Types of Fat and Brown is Good White (WAT) Brown (BAT) Energy storage 50g contains kcal Cold-induced [NST] Diet-induced [DIT] Frontini A, Cinti S.(2010) Cell Metab. 7;11:253 ; Tran T et al. (2008) Cell Metab. 7:410; Lowell BB et al. (1993) Nature 366:740. Rothwell NJ, Stock MJ. (1983) Clin Sci (Lond ) 64:19.; Feldmann HM et al. Cell Metabolism 2009;9:203; Ouellet V et al. J Clin Invest. 2012;122:545 Energy expenditure 50g consumes kcal/day (max) Thermogenesis via Uncoupling Protein-1 [UCP-1] How Brown Fat Generates Heat Sympathetic Neurons Norepinehprine Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center Plasma Glucose FFA Endogenous Lipids 2

3 Brown Fat May be Used for Treating Metabolic Dysregulation BAT in cold-acclimatized mice consumed more than half of ingested lipids and glucose. Bartelt A et al. Nat Med. 2011;17:200-5; Nedergaard J et al. Cell Metab. 2011;13: Rodent Brown Fat Derives From Multiple Lineages Mesenchymal Stem Cells Commitment Phase Myf5- Progenitor Myf5+ Progenitor White Systemic Preadipocyte Brown Preadipocyte Preformed Brown Preadipocyte Myoblast Differentiation Phase Tseng YH et al. Nat Rev Drug Discov 2010;9:465Sanch ez-gurmaches J et al Cell Metab. 16: Rosenwald M et al Nat Cell Biol 2013 Apr 28?? = White Adipocyte Systemic Brown Adipocyte Preformed Brown Adipocyte Myocyte How We Measure Brown Fat Activity CT = Computed Tomography, describes the tissue PET = Positron Emission Tomography, shows glucose uptake PET/CT = tells us the relative metabolic activity of each tissue CT PET PET/CT 3

4 Where is Normal Human Brown Fat? Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center One distinct region: In the neck, shoulders, and chest, both sides. Human BAT is a Mix of White and Brown Adipocytes Virtanen KA, et al. NEJM 2009;360:1518 Human BAT has Extensive Neuronal and Vascular Connections as well as Numerous Mitochondria Zingaretti MC et al. FASEB J. 2009;23:3113 4

5 Adult Human Brown Fat is a Glucose Sink Cold-activated human BAT takes up more glucose per gram of tissue than even insulin-stimulated skeletal muscle. Orava J et al. Cell Metab. 2011;14:272-9 Uptake of Glucose and Fatty Acids Correlate with Oxidative Metabolism 18 F-FDG 18 F-FTHA 11 C-acetate 11 C-acetate tissue kinetics showed significant coldinduced activation of BAT oxidative metabolism. BAT could account for the 250 ± 45 kcal expended during the 3-hour period of cold exposure. Ouellet V et al. J Clin Invest. 2012;122:545 Pediatric BAT is More Frequently Active than in Adults, in both Girls and Boys Cypess AM, et al. NEJM 2009;360:1509; Drubach LA et al. J Pediatr 2011;159: C 43.3 P= Prevalence of Detectable Brown Adipose Tissue (%) P< Male Adult Female Male Female Pediatric Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center 5

6 Pediatric BAT Activity Correlates Inversely with BMI% Drubach LA et al. J Pediatr 2011;159:939 Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center What Do We Know About Human Brown Fat? Predominantly in one region of the body as a heterogeneous mixture of brown and white adipocytes. We can measure its activity indirectly through noninvasive 18 F-FDG PET/CT. People with active brown fat are more frequently female, younger, and leaner, but cause and effect are not known. Mild cold exposure is effective at stimulating it for prospective studies, but no pharmacological activators have been identified yet. Its energy expenditure has great therapeutic potential. Cypess AM, et al. (2009), NEJM 360:1509; Marken Lichtenbelt et al. NEJM 2009;360:1500; Virtanen KA, et al. (2009) NEJM 360; 1518; Zingaretti MC, et al. FASEB J. (2009) 23:3113; Saito M, et al. (2009) Diabetes 58:1526. Translational Approaches to Understanding BAT Noninvasive Imaging Integrative Physiology Mass and Activity PET/CT MRI Ultrasound Infrared Human and Rodent Bioenergetics Proteomics Genomics Therapeutics Cold Hormone thyroid, β3-ar 6

7 Non-invasive Imaging How do we currently quantify human BAT? Whole-body BAT mass or activity could not be measured in humans until 2002 with the discovery the 18 F-FDG PET/CT could identify metabolically active adipose tissue. Problems with FDG PET/CT ionizing radiation; expensive; detects an unknown and variable fraction of total BAT volume since you see only FDG-avid tissue. Options: (1) MRI -- use water-to-fat ratio and high density of mitochondria and blood vessels. (2) Infrared to detect BAT thermogenesis PET/CT and MRI Both Detect Similar BAT Volumes For 4 volunteers, volumes were the same (repeated measures ANOVA P = 0.11) Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center Chen YI, Cypess AM et al. J Nuc Med 2013;54:1584 7

8 Infrared Thermal Imaging Can Detect BAT Activity Integrative Physiology Secreted Factors That Promote BAT Differentiation and Function Brain cbat Thyroid Factor: FGF21, BMP7, BMP8b Mechanism: Browning/Lipolysis Factors: BDNF, BMP8b, Orexin Factor: T3 Mechanism: Differentiation (DIO2) Heart Muscle Factor: ANP/BNP Mechanism: Browning (p38mapk/pgcs) Factor: Irisin (FNDC5) Mechanism: Browning (PGCs) Liver Factors: FGF21 Mechanism: Browning (FGFR1/ βklotho) Schulz T &Tseng YH. Biochem J. 2013;453:167 WAT Factor: Prostaglandin Mechanism: Browning (COX2) Pancreas Factor: Insulin Mechanism: Differentiation (Insulin Recptor) Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center 8

9 What Distinguishes Brown and Beige Fat Wu J et al. Gen Dev 2013; 27: Human BAT is Deep Within the Neck a Superficial depots Deep depots H&E staining UCP1 staining Cypess AM et al. Nature Medicine 2013;19:635 Human Neck Brown Fat Gene Expression Is Similar to Murine Constitutive BAT WAT-associated markers Beige/Brite BATassociated markers Classical BAT markers Cypess AM et al. Nature Medicine 2013;19:635 9

10 Neck BAT has a High Energy Expenditure and can be Grown from Precursors Cypess AM et al. Nature Medicine 2013;19:635 Where are the brown and beige fat depots? Wu,J. et al. Cell 2012;150: Sharp LZ et al. PLoS One. 2012;7:e49452 Cypess AM et al. Nature Medicine 2013;19:635 Lidell ME et al. Nature Medicine 2013;19:631 Jespersen NZ et al. Cell Metabolism 2013;17:798 Outline from blogspot.com/2012_0 5_01_archive.html Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center Therapeutics 10

11 Approaches to Increasing Brown Fat Thermogenesis as an Anti-Obesity therapy Tseng YH et al Nat Rev Drug Discov 2010;9:465 Therapeutics Increase BAT Activity and Induce Weight Loss Cold Hormone Ephedrine energy expenditure and FDG uptake in BAT Thyroid increases thermogenesis and BAT growth Marken Lichtenbelt et al. NEJM 2009;360:1500. Shekelle P et al. JAMA. 2003;289:1537. Baba S et al. J Nucl Med. 2007;48:98. Skarulis M et al. JCEM 2010;95:256. Activating Brown Fat Torriani M et al. JCEM 2012;97:E602; Cypess AM, et al. PNAS USA 2012;109:

12 Both Ephedrine and Cold Activated the SNS Change Cypess AM et al. PNAS USA 2012;109:10001 Ephedrine and Cold Increased Energy Expenditure and Fat Metabolism Cypess AM et al. PNAS USA 2012;109:10001 Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center Ephedrine Had Many Unfavorable Effects on Metabolites Cold Did Not Saline Ephedrine Cold Ephedrine Cold vs Mean SD Mean SD Mean SD vs Saline Saline Glucose < Lactic Acid < β-hydroxybutyrate Free Fatty Acids Insulin < C-peptide < Norepinephrine Epinephrine Free T Total T Ghrelin Cypess AM et al. PNAS USA 2012;109:10001 Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center 12

13 Only Cold Exposure Increased Brown Fat Activity Cypess AM et al. PNAS USA 2012;109:10001 Confidential Aaron M. Cypess, MD, PhD, Joslin Diabetes Center How Much of The Thermogenesis is From BAT? Cold increases whole body energy expenditure by 300 kcal/day, but BAT thermogenesis accounts for <25 kcal/day. 5 times more was in WAT! Muzik O et al. J Nuc Med 2013 Jan 29 Cold exposure causes a significant increase in energy expenditure that correlates positively with the change in skeletal muscle mitochondrial uncoupling (state 4). However Wijers SL et al. PLoS One. 2008;12;3:e1777 There is no evidence for any alternative adaptive adrenergic thermogenesis to that mediated by UCP1 in brown fat. Golozoubova V et al FASEB J. 2001;15:2048, Feldmann HM et al Cell Metab. 2009;9:203 Chronic Cold Exposure May Have Beneficial Metabolic Effects Through BAT 10 days of cold acclimation increased BAT activity. Subjects also felt more comfortable in cold van der Lans AA et al. JCI 2013;123:3395 Daily 2-h cold exposure (17 C) for 6 weeks resulted in a decrease in body fat mass. Yoneshiro et al. JCI 2013;123:

14 Treatment with Thyroid Hormone Increases BAT Activity TSH 97 BMI yf 3 months treatment with LT 4 head TSH 0.10 BMI 23.1 Brown fat heart Final Summary Brown fat can be found in a substantial proportion of adult humans ( 100%). Multiple imaging techniques [PET/CT, MRI, U/S, IR] can measure brown fat activity that have both research and clinical applications. Brown fat may impact human metabolism at three different levels energy balance, glucose metabolism, and hormonal regulation with much still be learned. Thank You Joslin Diabetes Center Integrative Physiology and Metabolism Carla Roberts-Toler Lauren Weiner Christie Sass Cathy Sze Nate Truchan Ashely Holman Alessandro Doria Michael Molla C. Ronald Kahn Cecile Vernochet Marcelo Mori Yu-Hua Tseng Tim Schulz Ruidan Xue Lian Huang Allison Goldfine Massachusetts General Hospital Ken Kwong Steven Grinspoon Iris Chen Martin Torriani Anna-Liisa Brownell Brigham and Women s Hospital Frank Kuo / SPIN-VSL Beth Israel Deaconess Medical Center Nuclear Medicine Gerald M. Kolodny Matthew Palmer YihChieh Chen Gethin Williams Sanaz Lehman Ilan Tal Jeff English Ke Wang Surgery Andrew White Per-Olof Hasselgren Aron Chacko Allison Glasgow Laura Deschamps Ashley Doyle Lyndsay Herder Kshitij Chaudhary Grant support: NIH DK087317, DK070722, DK46200, DK33201, DK55545, DK46200,RR25758, DK81604, DK36836, Clinical Investigator Training Program, & the Eli Lilly Foundation. 14

15 ARS #1 The following characteristics are typical of brown adipose tissue, but not white adipose tissue, except: A. It looks brown B. When activated, it can generate heat. C. The average adult has kg of it in the body. D. Its capacity for inducible glucose uptake is the highest of any organ. ARS #2 Based on the evidence available today, human brown fat can influence metabolism through the following mechanisms, except: A. Regulate metabolism by releasing brown adipokines B. Take up glucose and fatty acids C. Increase energy expenditure 15