Managed by UT-Battelle for the Department of Energy 1 Mathematical Modeling of Fatty Acid Oxidation in Skeletal Muscle Cells Sheds New Light on Obesity

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


22

Outline

Background of fatty acid oxidation in skeletal muscle cells

– Health issues

– Previous research

Research objectives

Methods

Conclusion

Future Research


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


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


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+


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+


77

Research Objective

Find a mathematical model that

– explains the experimental data, and

– sheds light on biochemical processes affecting FAO

Allen, 2005Allen, 2005


88

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)


99

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


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


1111

Experimental Data vs. Computational Data

ControlControl LeucineLeucine NifedipineNifedipine Leucine + NifedipineLeucine + Nifedipine

TreatmentsTreatments


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


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


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


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


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.


1717

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


1818

Questions

18 Managed by UT-Battellefor the Department of Energy

If we know how fatty acid oxidation works then we will

be able to figure out how to control

obesity

Documents

Managed by UT-Battelle for the Department of Energy 1 Mathematical Modeling of Fatty Acid Oxidation in Skeletal Muscle Cells Sheds New Light on Obesity