Brown Fat: What is it, and is it important in obesity and diabetes?

Courtney PriceApril 17, 2008

PAS 645Dr. Bruckner

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

What’s the difference?

Where is it?

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

Nonshivering Thermogenesis

Increase in metabolic rate not due to increased muscle activity

Triggered by exposure to coldAcute 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

Nonshivering Thermogenesis

Chronic Exposure to Cold

Long-TermOvereating =Diet-Induced Thermogenesis

Sympathetic Nervous System

Retinoic Acid

BAT and Obesity

In animal studies: denervation or excision of interscapular results in increased total body fatDiet-induced obesity reversed in rats treated with β3-AR specific agonist

Increases UCP1 expression in BAT cells

Controversial in humansIs there enough BAT present to make a difference?

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

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

Future Research/Conclusions…

New drugs to target BAT in treating obesity and diabetes?

Previous attempts failed

Metabolic syndrome connection under investigation

R-A-A

GeneticsInteresting, but not likely to become a major factor

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. p162-163Hansen, 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.

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 35:446–447www.cdc.gov accessed 2/25/08. “Diabetes.”www.cdc.gov accessed 2/10/08. “Overweight and obesity.”www.wikipedia.com accessed 2/26/08 “Peroxisome proliferating activating receptor.”www.wikipedia.com accessed 2/26/08 “Thiazolidinediones”www.nih.gov/diabetes accessed 2/29/08http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm accessed 3/1/08Dale D and Federman D. ACP Medicine. 3rd Ed. 2007. Vol 1. 651-65Purnell J: “Obesity” 714-728Riddle M and Genuth S “Type 2 Diabetes Mellitus” 651-65http://sportsci.org/encyc/adipose/adipose.html accessed 2/29/08http://www.who.int/hpr/NPH/docs/gs_obesity.pdf accessed 3/1/08Whitney E and Rolfes S. Understanding Nutrition. 9th ed. 2002.www.diabetes.org accessed 2/29/08http://www.ndep.nih.gov/diabetes/youth/youth_FS.htm#Statistics accessed 3/1/08