Metabolic Flexibility and Obesity

Bret H. Goodpaster, Ph.D.

Senior Investigator,
Translational Research Institute for Metabolism and Diabetes
Professor, Sanford Burnham Medical Research Institute
Outline
Definitions - What is metabolic flexibility?
Substrate metabolism in healthy subjects during
exercise
Substrate metabolism in pathophysiology of obesity
and type 2 diabetes
Improvements in metabolic flexibility with weight
loss and exercise training
Potential mechanisms of metabolic flexibility and
implications for obesity, weight loss and maintaining
weight loss
Metabolic Flexibility
M
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Metabolic Inflexibility
Metabolic flexibility
rest exercise

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10 sec 30 sec 2 min 5 min +
Energy Transfer Systems and Exercise
Aerobic
Energy
System
Anaerobic
Glycolysis
ATP - CP
Fuel Reserves in a Typical 70 kg Man
Available Energy (kcal)
Organ Glucose or TG Protein
Glycogen
Blood 60 45 0
Liver 400 450 400
Brain 8 0 0
Adipose 80 135,000 40
Muscle 1,200 350 24,000
Christensen & Hansen, 1939
Effect of exercise intensity on fuel utilization
Romijn, J. A., E. F. Coyle, L. S. Sidossis, et al. Am. J. Physiol.1993.
Contribution of Plasma and Intramuscular Substrates
during 30 min of Exercise at Various Intensities
Substrate utilization during prolonged
exercise
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Moseley et al 2003
Exercise at 60%VO
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Substrate utilization during prolonged exercise
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Moseley et al 2003
Exercise at 60%VO
2
max

Ingestion of either
carbohydrate (CHO) or
water at regular intervals
during exercise
Water
CHO
CHO
Water
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Trained
Unrained
Effects of training on substrate utilization during
prolonged exercise
J Appl Physiol, 1994
VO
2
max
VO
2
max is the maximum capacity to transport and
utilize oxygen during maximal exercise.
It is also called maximal oxygen consumption or
maximal oxygen uptake.
VO
2
max is also known as aerobic capacity, which
reflects the overall physical fitness.
Exercise training
Resting metabolic rate
(indirect calorimetry)
~3.5 ml/kg/min
16 ml/kg/min
46 ml/kg/min
Bjorn Daehlie
96 ml/kg/min
Race horse
180 ml/kg/min
Iditarod sled dog
240 ml/kg/min
Hummingbird
Metabolic flexibility
fasting feeding
feeding fasting
fasting insulin
Pathophysiology of Type 2 Diabetes
Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.
Peripheral Tissues
(Muscle)
Glucose
Liver
Impaired insulin
secretion
Increased glucose
production
Receptor +
postreceptor defects
Insulin
resistance
Pancreas
Fasting: High FFA extraction and
oxidation by skeletal muscle
FFA
Glycogenolysis
FFA
Gluconeogenesis
glucose
FFA
Randle cycle or
glucose fatty acid cycle
vascular space
sarcolemma
sarcoplasm
mitochondrion
Mitochondrial
membranes
FFA
GLUT -4
Pi
GLUT - 4
HK
pyruvate
CoA
glucose
acyl-CoA CoASH
b-oxidation
pyruvate
PDH
glucose-1-P
glycogen
Phos
CPT I
translocase
CPT II
glucose-6-P
acetyl-CoA
citrate
isocitrate
fumarate
succinate
succinyl-CoA
2-oxo-glutarate
oxaloacetate
malate
acyl-CoA
(FFA)
CoASH
fructose-1,6-bi P
Phosphofructokinase
Randle et al. Lancet. 1: 785-789, 1963
What if Minkowski had been ageusic?
An alternative angle on diabetes
McGarry JD. Science. 1992;258:766-70.
**
+
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Controls NIDDM
Impaired lipid oxidation after
fasting in Type 2 Diabetes
**P< 0.01 insulin vs.
basal; +P< 0.05
controls vs. diabetics
Kelley, DE & Mandarino, L J. J Clin Invest. 86, 1999-2007, 1990
Glucose availability determines FFA utilization.
Thus, an impaired rate of glucose uptake leads to increased FFA ox (Wolfe, 1998).
Reverse Randle Cycle
acetyl-CoA
MCFA
octanoic acid
TCA-cycle
b-oxidation
13
CO
2

MCFA FA acyl-CoA
LCFA FA acyl-CoA
LCFA
palmitic acid
Hyperinsulinemia
Hyperglycemia
Malonyl-CoA
CPT I
AJP Endo 1999
Diabetes 2000
Kelley, Goodpaster, Wing & Simoneau, AJP 1999
0.70
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0.90
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Lean
*
Fasting Insulin Stimulated
Switching from Fat Oxidation to Glucose Oxidation
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0.90
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Lean
Obese
* *
*
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Fasting Insulin Stimulated
Kelley, Goodpaster, Wing & Simoneau, AJP 1999
Switching from Fat Oxidation to Glucose Oxidation
Substrate availability and capacity for utilization
Are Mitochondria Implicated in Metabolic Inflexibility?
Young
Lean
Old
Obese
Type 2 Diabetes
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LEAN OBESE T2DM
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Diabetes 2002
Mitochondria function and insulin
resistance and type 2 diabetes
Shulman and Lowell, 2005
Mitochondria content is associated with
higher fat oxidation
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Sedentary Sedentary Exercising Exercising
*P<0.01 vs. sedentary
*P<0.01 vs. sedentary
Can exercise reverse or prevent
aging or obesity effects?
Exercise-induced changes in total
mitochondrial ETC activity
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PRE
POST
* Different (P<0.05)
pre-post training;
paired t-test.
Menshikova et al. J. Gerontol Biol Sci. 2006
Goodpaster unpublished
Exercise and calorie restriction-induced weight
loss effects on mitochondria
Correction of Dysregulated
Metabolism in Obesity
Correction of Dysregulated
Metabolism in Obesity
Diet-induced weight loss Exercise
-4.0
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Change in post-absorptive fatty acid oxidation
(m gm in
-1
kg FFM
-1
)
r = 0.62, P<0.01
Goodpaster, Katsiaras and Kelley, Diabetes, 2003.
Variability in Respiratory Quotient
and its Impact on Weight Gain
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Energy Bal
% Body Fat
Sex
Within
Subject
Method
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Duration of Follow-up (years)
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60
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high RQ > 0.87
Low RQ < 0.82
Family
Acknowledgments
David Kelley, M.D. CTRC and ONRC staffs
Vladimir Ritov, Ph.D. Nichole Helbling, R.N.
Elisa Menshikova, Ph.D.
John Dub, Ph.D. Paul Coen, Ph.D.
Francesca Amati, M.D., Ph.D. Krista Clark
Andrea Rossi, M.D. Maja Stefanovic, M..D.
Fred Toledo, M..D. Steve Anthony, M.S.
Pete Chomentowski, Ph.D. Kazanna Hames, Ph.D.


Crossing Antarctica with Diabetes:
Taking Diet, Exercise and Diabetes
Management to the Extremes
The Expedition
Ambient temperature during the 61-day trek ranged between
27
o
C and 5
o
C, and altitude steadily rose from 824 m to 2,835
m at the South Pole.
Each man pulled
his own provisions
on a 70 kg sledge
an average of 8.9
hrs per day by
skis.

The Antarctic Diet







The diet goal was:

6,514 kcals, 352 gm fat (47.6% kcals from fat)
Energy Expenditure
Energy Intake
T1DM NOND
-5,590 -7,285

4,018 3,821

-1,572 -3,464 Energy
Balance
Kcal/day
Positive energy
balance = weight gain
Negative energy
balance = weight loss