Brown Fat’s Potential for Solving the Obesity Problem

1. Brown Fat’s Potential for Solving the Obesity Problem By: Connor Crowley, Colin Heim, Bruno dos Santos, Elizabeth Conkey, and Jessica Boazman

2. Introduction to Brown Fat

3. Brown Fat • Brown fat, also known as Brown Adipose Tissue, is one of two types of fat in humans and mammals. • Brown Fat’s primary function is to generate body heat in newborns and animals, especially those that are hibernating. • Mammals and Humans with higher levels of brown fat take longer to start shivering. • Newborns have high levels of brown fat while adults have lower levels of brown fat • As humans get older brown fat disappears and white fat increases, however there function is similar

4. Brown Fat vs. White Fat • White fat contains a single lipid droplet • Brown Fat contains numerous small lipid droplets as well as numerous mitochondria that contains high levels of iron • The dark color of brown fat is a result of high levels of iron • Brown Fat generally has more capillaries than white fat given its greater need for oxygen

5. Brown Fat vs. White Fat

6. “Cold but not sympathomimetics activates human brown adipose tissue in vivo”

7. Experimental Set Up • 10 healthy human volunteers were used to test the effects of ephedrine and mild cold on Brown Adipose Tissue activity • Each test subject was subject to a dose of ephedrine, mild cold, or a saline solution (control) • 18F-fluorodeoxyglucose PET-CT was used to measure BAT activity

8. Observations • Ephedrine • Increase in Systolic and Diastolic blood pressure (figure 1) • Increase in heart rate (figure 1) • No measurable effect on BAT activity (figure 3) • Cold • Increase in Systolic and Diastolic blood pressure (figure 1) • Decrease in heart rate (figure 1) • Substantially Increased BAT activity (figure 3)

9. Figures 1. 2. 3.

10. Results • Exposure to cold substantially increased BAT activity as measured by 18F-fluorodeoxyglucose PET-CT uptake, while the weight loss drug ephedrine had no measurable affect on the activity level of BAT

11. “Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans”

12. Case Study (Effect of Temperature) • Designed to determine if • Brown Adipose Tissue (BAT) is metabolically active • Contributes to cold-induced non-shivering thermogenesis • Test subjects placed in suits lined with tubing • Creating a water-bath to lower the body temperature

13. Results of Temperature Case Study • Inverse Relationship between BAT activity and energy expenditure • A cold exposure stimulus enhances BAT oxidative metabolism • BAT is involved in non-shivering thermogenesis

14. Data (Temperature Case Study)

15. “Retinaldehyde dehydrogenase 1 (Aldh-1a1) regulates a thermogenic program in white adipose tissue”

16. Retinaldehyde-1a1 • is a key determinant of WAT plasticity and the regulation of white vs. brown adipocyte characteristics

17. Retinaldehyde-1a1 • Predominately expressed in visceral fat

18. Aldh-1a1 deficiency induces a BAT gene program in WAT • Absence of Aldh-1a1 causes greater energy expenditure in WAT, similar to the mechanisms seen in BAT.

19. Aldh-1a1deficiency activates a thermogenic program in WAT • Increased mitochondrial uncoupling drives oxidative phosphorylation, enhancing cellular respiration. • Oxygen consumption rates  increased in WAT and GWAT but not in BAT.

20. Retinaldehyde promotes Ucp1 Transcription in White Adipocytes • Cell line stimulated by Rald induced Ucp1 gene/protein expression. • With Aldh inhibitor (DEAB) present, Ucp1 expression was again stimulated to the same extent  independent of Rald conversion to retinoic acid.

21. Retinaldehyde Regulates Ucp1 Expression through RAR and PGC-1α • Retinoids exert action by activating receptors such as RAR and RXR. • RAR antagonists stop expression of Ucp1 and other BAT marker genes. • Rats injected  lower body temp. compared to controls. • Rald also recruits PGC-1α already located in the mitochondria, activating Ucp1 transcription.

22. Aldh1a1 Antisense Treatment Induces a Thermogenic Program • Mice injected with antisense oligonucleotide (ASO) showed decreased Aldh1a1 nRNA/protein levels in liver and GWAT without changing these levels in BAT  increased Ucp1 expression. • Cold environment  core temp. maintained. • Aldh1a1 repression induces a thermogenic program.

23. Take-Home Message • Activation?  exposure to mild cold causes increased Brown Adipose Tissue activity, leading to weight loss. • WAT acting as BAT?  blocking RetinaldehydeDehydrogenase, through various mechanisms, activates Uncoupling Protein 1  promoting mechanisms in WAT similar to mechanisms found in BAT, without altering BAT activity/function.

24. Works Cited • Kiefer, F.W. et al., (2012). Nature Medicine. 18 (6), 918-925. • Brown Adipose Tissue Trichrome. N.d. Photograph. Blue Histology - Connective Tissues. The University of Western Australia, 08 June 2009. Web. 30 Oct. 2012. http://www.lab.anhb.uwa.edu.au/mb140/corepages/connective/connect.htm.> • White Adipose Tissue H&E. N.d. Photograph. Blue Histology - Connective Tissues. University of Western Australia, 08 June 2009. Web. 30 Oct. 2012. http://www.lab.anhb.uwa.edu.au/mb140/corepages/connective/connect.htm.> • ”JCI - Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans." JCI - Welcome . N.p., n.d. Web. 30 Oct. 2012. <http://www.jci.org/articles/view/60433>.