Dr. Bret Goodpaster: Metabolic Flexibility and Obesity

8/12/2019 Dr. Bret Goodpaster: Metabolic Flexibility and Obesity

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Metabolic Flexibility and ObesityBret H. Goodpaster, Ph.D.

Senior Investigator,Translational Research Institute for Metabolism and Diabetes

Professor, Sanford Burnham Medical Research Institute


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Outline

Definitions - What is metabolic flexibility?

Substrate metabolism in healthy subjects duringexercise

Substrate metabolism in pathophysiology of obesityand type 2 diabetes

Improvements in metabolic flexibility with weightloss and exercise training

Potential mechanisms of metabolic flexibility andimplications for obesity, weight loss and maintaining

weight loss


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Metabolic Flexibility

M e t a b o l

i c c a p a c i

t y

Metabolic Inflexibility


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Metabolic flexibility

rest exercise


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100%

% C

a p a c i t y of E n

er g

y S y s t em

10 sec 30 sec 2 min 5 min +

Energy Transfer Systems and Exercise

AerobicEnergySystem

AnaerobicGlycolysis

ATP - CP


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Christensen & Hansen, 1939

Effect of exercise intensity on fuel utilization


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Romijn, J. A., E. F. Coyle, L. S. Sidossis, et al. Am. J. Physiol.1993.

Contribution of Plasma and Intramuscular Substratesduring 30 min of Exercise at Various Intensities


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Substrate utilization during prolonged exercise

0.0

0.5

1.0

1.5

2.0

2.5

0 60 120 180 240 300

C H O o x i

d a t

i o n

( g / m i n )

0.0

0.2

0.4

0.60.8

1.0

1.2

1.4

0 60 120 180 240 300Time (min)

F a

t o x

i d a

t i o n

( g / m i n )

Moseley et al 2003 Exercise at 60%VO 2max

Ingestion of eithercarbohydrate (CHO) orwater at regular intervalsduring exercise

Water

CHO

CHO

Water


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0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0 60 120 180 240 300Time (min)

F a

t o x

i d a

t i o n

( g / m i n )

Trained

Unrained

Effects of training on substrate utilization duringprolonged exercise


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Resting metabolic rate(indirect calorimetry)

~3.5 ml/kg/min


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16 ml/kg/min 46 ml/kg/min


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Bjorn Daehlie

96 ml/kg/min


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Race horse

180 ml/kg/min


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Iditarod sled dog

240 ml/kg/min


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Hummingbird


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Metabolic flexibility

fasting feedingfeeding fasting

fasting insulin


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Pathophysiology of Type 2 Diabetes

Saltiel AR, Olefsky JM. Diabetes . 1996;45:1661-1669.

Peripheral Tissues(Muscle)

Glucose

Liver

Impaired insulinsecretion

Increased glucoseproduction

Receptor +postreceptor defects

Insulinresistance

Pancreas


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Fasting: High FFA extraction andoxidation by skeletal muscle

FFA

Glycogenolysis

FFA

Gluconeogenesisglucose

FFA


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Randle cycle orglucose fatty acid cycle

vascular space

sarcolemma

sarcoplasm

mitochondrion

Mitochondrialmembranes

FFAGLUT -4

PiGLUT - 4 HK

pyruvate

CoA

glucose

acyl-CoA CoASH

-oxidat ion

pyruvatePDH

glucose-1-PglycogenPhos

CPT Itranslocase

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


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**+

L e g

R Q

Controls NIDDM

Impaired lipid oxidation afterfasting in Type 2 Diabetes

**P< 0.01 insulin vs.basal; +P< 0.05controls vs . diabetics

Kelley, DE & Mandarino, L J. J Clin Invest. 86, 1999-2007, 1990


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Glucose availability determines FFA utilization.

Thus, an impaired rate of glucose uptake leads to increased FFA ox (Wolfe, 1998).

Reverse Randle Cycle

acetyl-CoA

MCFAoctanoic acid

TCA-cycle

-ox idat ion

13 CO 2

MCFA FA acyl-CoA

LCFA FA acyl-CoA LCFApalmitic acid

HyperinsulinemiaHyperglycemia

Malonyl-CoA

CPT I


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AJP Endo 1999

Diabetes 2000


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Kelley, Goodpaster, Wing & Simoneau, AJP 1999

0.70

0.80

0.90

1.00

L e g R Q

Lean*

Fasting Insulin Stimulated

Switching from Fat Oxidation to Glucose Oxidation


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0.70

0.80

0.90

1.00

L e g R Q

Lean

Obese

* *

*

**

Fasting Insulin Stimulated

Kelley, Goodpaster, Wing & Simoneau, AJP 1999

Switching from Fat Oxidation to Glucose Oxidation


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Substrate availability and capacity for utilization


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0

0.2

0.4

0.6

0.8

1

1.2

LEAN OBESE T2DM

N A D H - o x

i d a s e

( U / m

U C K )

*

*

Diabetes 2002

f


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Mitochondria function and insulinresistance and type 2 diabetes

Shulman and Lowell, 2005


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Mitochondria content is associated withhigher fat oxidation


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0

100

200

300

400

500

600

0

100

200

300

400

500

600

C y t o c

h r o m e

o x

i d

a s

e

a c t

i v

i t y

(

l

0

20

40

60

80

100

120

0

20

40

60

80

100

120

S u c c

i n a t e

o x

i d

a s

e

a c t

i v

i t y

(

l

Sedentary SedentaryExercising Exercising

*P


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Can exercise reverse or prevent

aging

or obesity effects?


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Exercise-induced changes in totalmitochondrial ETC activity

0.00

0.05

0.10

0.15

0.20

0.25

0.00

0.05

0.10

0.15

0.20

0.25

S u c c

i n a t e : O

2

o x

i d

a s e

(

U /

m U

* PRE

PO ST

* Different (P


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Goodpaster unpublished

Exercise and calorie restriction-induced weightloss effects on mitochondria


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Correction of DysregulatedMetabolism in Obesity


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Correction of DysregulatedMetabolism in Obesity

Diet-induced weight loss Exercise


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-4.0

-2.0

0.0

2.0

4.0

6.0

8.0

10.0

-1.0 -0.5 0.0 0.5 1.0

Ch

a n

g e i ni n s

u l i n-

s ti m u

l a t e d

g l u c

o s e d i s p o s a l

( R d

;m g

mi

n-1

k g

FFM

-1 )

C hange in post-absorptive fatty acid oxidation-1

-1

r = 0.62, P


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Variability in Respiratory Quotient and its Impact on Weight Gain

C u m u

l a t i v e

I n c i

d e n c e o f a

5 k g B o d y

W e i g h

t G a i n

( % )

Energy Bal % Body Fat

Sex

Within Subject

Method

40

20

0

Duration of Follow-up (years)

0 0.5 1 1.5 2 2.5 3 0

20

40

60

80

high RQ > 0.87

Low RQ < 0.82

Family


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Crossing Antarctica with Diabetes:

Taking Diet, Exercise and DiabetesManagement to the Extremes


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The Expedition Ambient temperature during the 61-day trek ranged between 27 oC and 5oC, and altitude steadily rose from 824 m to 2,835m at the South Pole.

Each man pulledhis own provisionson a 70 kg sledgean average of 8.9

hrs per day byskis.


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The Antarctic Diet

The diet goal was:

6,514 kcals, 352 gm fat (47.6% kcals from fat)


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Energy Expenditure

Energy Intake

T1DM NOND

-5,590 -7,285

4,018 3,821

-1,572 -3,464Energy

Kcal/day

Positive energybalance = weight gain

Negative energybalance = weight loss

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Dr. Bret Goodpaster: Metabolic Flexibility and Obesity