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Managed by UT-Battellefor the Department of Energy
11
Mathematical Modeling of Fatty Acid Oxidation in Skeletal Muscle Cells Sheds
New Light on Obesity
Presented to Associate Director
of the Office of Science
Sara HaqueResearch Alliance in Math and Science
Computational Sciences and Engineering DivisionMentor: Kara Kruse M.S.E.
In collaboration with the Obesity Research Center at the University of Tennessee in Knoxville
August 13, 2008
Oak Ridge, Tennessee
Managed by UT-Battellefor the Department of Energy
22
Outline
Background of fatty acid oxidation in skeletal muscle cells
– Health issues
– Previous research
Research objectives
Methods
Conclusion
Future Research
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33
Obesity is a Growing Problem in the United States
Overall health of individuals is decreasing and health care costs are increasing
Factors affecting obesity are numerous
– i.e., heart disease, diabetes, high blood pressure
Understanding biochemistry may lead to new ways of controlling obesity
Biochemical cross-talk between skeletal muscle cells and adipocytes, fat cells, may be a key factor in fatty acid oxidation
Developing a model of fatty acid oxidation is the first step
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44
Background: previous experimental research
In Vitro experiments by Sun and Zemel (2007) with C2C12 myotubes and 3T3–L1 preadipoctyes cultures show:
Leucine, an essential amino acid, found in dairy increases fatty acid oxidation (FAO)
Calcitriol reduces FAO due to lack of dietary Calcium
Adiponectin, released by adipocytes, increases FAO
UCP3, a transport protein, regulated by leucine and calcitriol controls how much fatty acids enter the mitochondria for oxidation
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55FFA
FFA
FAC
Fatty acyl-CoA
FFC
Acetyl-CoA
FFA
CPT-II
CPT-I
Β-OxidationFAC
UCP-3
Adipo RAdiponectin
AMPK
Calcitriol
TGL
Ca2+
Ca2+
H+
Mitochondria Intermembrane Space
Matrix of Mitochondria
Cytosol
Skeletal Muscle Cell
?
ACC
H+H+H+ H+
H+
H+
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66FFA
FFA
FAC
Fatty acyl-CoA
FFC
Acetyl-CoA
FFA
CPT-II
CPT-I
Β-OxidationFAC
UCP-3
Adipo RAdiponectin
AMPK
Leucine
TGL
Mitochondrial Intermembrane Space
Skeletal Muscle Cell
Cytosol
Matrix of Mitochondria
ACC
H+H+
H+
H+
H+
H+
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77
Research Objective
Find a mathematical model that
– explains the experimental data, and
– sheds light on biochemical processes affecting FAO
Allen, 2005Allen, 2005
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Mathematical model must behave in a physiologically consistent manner
Different equations can fit the same time points
Consider the equations that are physiologically consistent
PD
GF
-BB
Fra
ctio
nP
DG
F-B
B F
ract
ion
Time (Days)Time (Days)
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Methods Analyzed data using Excel
Created a mathematical model based on lumped Michaelis-Menton enzyme kinetics
Developed UCP3 model first
Developed FAO model at three time points at separate steady state solutions
Utilized Mathematica® FindFit function to estimate model parameters
Compared model equations with experimental results
Revised model if discrepancy between results and model occur
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1010
Results Good fit for UCP3
FAO model provides a good fit at 12 and 24 hour data however ongoing work is being conducted for 48 hours
33
3
3
max
][1
][1
][
][1
1*
][
][3
NVD
L
VD
m
K
N
K
VDK
L
K
VDSK
SVUCP
3*
1
112
1
11
3
21
2
2
2
1
11UCP
K
VDK
AK
L
K
K
VD
K
A
K
N
FAOFAOBUCP
K
VD
A
L
VD
AN
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1111
Experimental Data vs. Computational Data
ControlControl LeucineLeucine NifedipineNifedipine Leucine + NifedipineLeucine + Nifedipine
TreatmentsTreatments
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1212
Fatty Acid Oxidation at 12 Hours
12 Hour Fatty Acid Oxidation
0
50
100
150
200
250
300
350
1 2 3 4
Data Points at 12 Hours
Fat
ty A
cid
Oxi
dat
ion
Experimental
Computational
ControlControlLeucineLeucine NifedipineNifedipine
Leucine + NifedipineLeucine + Nifedipine
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1313
24 Hour Fatty Acid Oxidation
0
50
100
150
200
250
300
350
400
450
500
Data Points 24 Hours
Fa
tty
Ac
id O
xid
ati
on
Experimental
Computational
Fatty Acid Oxidation at 24 Hours
ControlControl LeucineLeucine NifedipineNifedipine Leucine + NifedipineLeucine + Nifedipine
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1414
Conclusion
• Mathematical model incorporating steady state Michaelis-Menton inhibitory kinetics successfully describes the experimental data for UCP3
Leucine has a stimulating effect which is fairly consistent over time
Nifedipine has stimulatory effect which increases significantly over time
Adiponectin has initial stimulatory effect on nifedipine which goes away over time
Adiponectin has inhibitory effect on leucine which increases slightly over time
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1515
Future Research Long-term goal is to develop a mathematical model
describing biochemical cross-talk between skeletal muscle cells and adipocytes.
To accomplish this goal the following processes will be modeled – FAO and fatty acid synthesis (FAS) in adipocytes
– cross-talk between skeletal muscle cells and adipocytes
– effects of Interlukin-6 and Interlukin-15 on the cross-talk between the cells
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1616
Collaborations and References All biochemical expertise and experimental data was
provided by Dr. Zemel from the Obesity Research Center at the University of Tennessee in Knoxville– Sun, Xiaocun and Zemel, Michael. (2007).Leucine and Calcium
Regulate Fat Metabolism and Energy Partitioning in Murine Adipocyte and Muscle Cells. . Lipids,42(4), A328-A329.
Biochemical Modeling Approach– Allen,Nicholas.(2005). Computational Software for Building Biochemical
Reaction Network Models with Differential Equations.
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Acknowledgments
The Research Alliance in Math and Science program is sponsored by the Office of Advanced Scientific Computing Research, U.S. Department of Energy.
The work was performed at the Oak Ridge National Laboratory, which is managed by UT-Battelle, LLC under Contract No. De-AC05-00OR22725. This work has been authored by a contractor of the U.S. Government, accordingly, the U.S. Government retains a non-exclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. Government purposes.
Thank you to our sponsor at DOE, George Seweryniak
Especially thank you to Kara Kruse, my mentor
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