1. Brown Fat: What is it, and is it important in obesity and diabetes? Courtney Price April 17, 2008 PAS 645 Dr. Bruckner

2. Fat…we all have it. WAT Stores triglycerides when food is consumed Secretes FA for ATP formation when food not available Secretes leptin BAT Lots of mitochondria Nonshivering thermogenesis Stimulated by norepinephrine

3. What’s the difference?

4. Where is it?

5. Fun facts… Found in mammals More prominent in newborns Usually diminishes with age Can persist as an adaptation to cold- induced thermogenesis BAT develops postnatally in mice, prenatally in humans

6. Nonshivering Thermogenesis Increase in metabolic rate not due to increased muscle activity Triggered by exposure to cold Acute vs chronic Mechanism: UCP1→ influx of H+ into mitochondrial matrix, bypasses ATP synthase, uncouples oxidative phosphorylation and energy is dissipated as heat instead of making ATP

7. Nonshivering Thermogenesis Chronic Exposure to Cold Long-Term Overeating = Diet-Induced Thermogenesis Sympathetic Nervous System Retinoic Acid

8. BAT and Obesity In animal studies: denervation or excision of interscapular results in increased total body fat Diet-induced obesity reversed in rats treated with β3-AR specific agonist Increases UCP1 expression in BAT cells Controversial in humans Is there enough BAT present to make a difference?

9. BAT and Diabetes Also controversial PPARγ responsible for adipocyte differentiation TZDs target PPARγ In mice: Induce UCP1 expression in BAT BAT hyperplasia Brown adipocytes in WAT depots

10. NE Stimulation of BAT PET scan of 50 y/o M with right adrenal pheochromocytoma Top: Pre-op uptake of FDG in brown fat Bottom: 5 days post-op

11. Future Research/Conclusions… New drugs to target BAT in treating obesity and diabetes? Previous attempts failed Metabolic syndrome connection under investigation R-A-A Genetics Interesting, but not likely to become a major factor

12. References Braitman, L, et al. 1985. “Obesity and caloric intake: the National Health and Nutrition Examination Survey of 1971-1975 (HANES I).” J Chron Dis. 38:727-32. Campbell, et al. Biology. 5th ed. Menlo Park (CA): Benjamin Cummins; 1999. Dallner, O. 2006. “B3-adrenergic receptors stimulate glucose uptake in brown adipocytes by two mechanisms independently of glucose transporter 4 translocation.” Endocrinology. 147(12): 5730- 5739. Engeli, S, et al. 2003. “The adipose-tissue rennin-angiotensin-aldosterone system: role in the metabolic syndrome?” Int J Biochem Cell Biol. 35(6):807-825. Gropper, SS, Smith JL, Groff, JL. Advanced Nutrition and Human Metabolism. 4th ed. Belmont (CA): Thompson Wadsworth; 2005. p162-163 Hansen, J and Kristiansen, K. 2006. “Regulatory circuits controlling white versus brown adipocyte differentiation.” Biochem J. 398(2): 153-168. Keen, H, et al. 1979. “Nutrient intake, adiposity, and diabetes.” Br Med J. 1:655-8. Klaus, S. 2004. “Adipose tissue as a regulator of energy balance.” Curr Drug Targets. 5(3):241-250. Nedergaard, J, et al. 2007. “Unexpected evidence for active brown adipose tissue in adult humans.” Am J Physiol Endocrinol Metab 293(2):444-452. Ortmann, S, et al. 2003. “Self-selected macronutrient diet affects energy and glucose metabolism in brown fat-ablated mice.” Obes Res. 11(12):1536-44. Schoeller, D. 2001. “The importance of clinical research: the role of thermogenesis in human obesity.” Am J Clin Nutr. 73(3):511-516. Teruel, T, et al. 2005. “Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive lipase and uncoupling protein-1, and down-regulates insulin-induced fatty acid synthase gene expression in brown adipocytes of Wistar rats.” Diabetologia. 48(6): 1180–1188.

13. References Valverde, A and Benito, M. 2005. “The brown adipose cell: a unique model for understanding the molecular mechanism of insulin resistance.” Min Rev Chem. 5(3): 269-278. Widmaier, E, et al. 2006. Vander’s Human Physiology. 10th ed. McGraw Hill. Yamaga L et al. 2008. “The effect of catecholamines on the glucose uptake in brown adipose tissue demonstrated by 18F-FDG PET/CT in a patient with adrenal pheochromocytoma.” Eur J Nucl Med Mol Imaging 35:446–447 www.cdc.govwww.cdc.gov accessed 2/25/08. “Diabetes.” www.cdc.govwww.cdc.gov accessed 2/10/08. “Overweight and obesity.” www.wikipedia.comwww.wikipedia.com accessed 2/26/08 “Peroxisome proliferating activating receptor.” www.wikipedia.comwww.wikipedia.com accessed 2/26/08 “Thiazolidinediones” www.nih.gov/diabeteswww.nih.gov/diabetes accessed 2/29/08 http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htmhttp://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm accessed 3/1/08 Dale D and Federman D. ACP Medicine. 3rd Ed. 2007. Vol 1. 651-65 Purnell J: “Obesity” 714-728 Riddle M and Genuth S “Type 2 Diabetes Mellitus” 651-65 http://sportsci.org/encyc/adipose/adipose.htmlhttp://sportsci.org/encyc/adipose/adipose.html accessed 2/29/08 http://www.who.int/hpr/NPH/docs/gs_obesity.pdfhttp://www.who.int/hpr/NPH/docs/gs_obesity.pdf accessed 3/1/08 Whitney E and Rolfes S. Understanding Nutrition. 9th ed. 2002. www.diabetes.orgwww.diabetes.org accessed 2/29/08 http://www.ndep.nih.gov/diabetes/youth/youth_FS.htm#Statisticshttp://www.ndep.nih.gov/diabetes/youth/youth_FS.htm#Statistics accessed 3/1/08