Transcript Brown Fat`s Potential for Solving the Obesity Problem

Brown Fat’s Potential
for Solving the Obesity
Problem
By: Connor Crowley, Colin Heim, Bruno dos Santos, Elizabeth
Conkey, and Jessica Boazman
Introduction to
Brown Fat
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
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
Brown Fat vs. White Fat
“Cold but not
sympathomimetics
activates human brown
adipose tissue in vivo”
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
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)
1.
Figures
2.
3.
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
“Brown adipose tissue
oxidative metabolism
contributes to energy
expenditure during acute
cold exposure in humans”
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
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
Data
(Temperature Case Study)
“Retinaldehyde
dehydrogenase 1 (Aldh-1a1)
regulates a thermogenic
program in white adipose
tissue”
Retinaldehyde-1a1
• is a key determinant of WAT plasticity and the regulation of
white vs. brown adipocyte characteristics
Retinaldehyde-1a1
• Predominately expressed in visceral fat
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.
Aldh-1a1 deficiency 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.
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.
Retinaldehyde Regulates Ucp1
Expression through RAR and PGC1α
• 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.
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.
Take-Home Message
• Activation?  exposure to mild cold causes increased Brown
Adipose Tissue activity, leading to weight loss.
• WAT acting as BAT?  blocking Retinaldehyde
Dehydrogenase, through various mechanisms, activates
Uncoupling Protein 1  promoting mechanisms in WAT
similar to mechanisms found in BAT, without altering BAT
activity/function.
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/co
nnect.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/co
nnect.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>.