Centre for Metabolic FitnessOptimising Health • Reducing Obesity • Modifying Lifestyles

OmegaOmega--3 fatty acids, 3 fatty acids, exercise and exercise and

metabolic fitnessmetabolic fitness

Peter Howe PhD

Director, Nutritional Physiology Research CentreDirector, ATN Centre for Metabolic Fitness

University of South Australia

Melbourne31st October, 2006

Functional capacityFunctional capacity (physical & mental fitness)(physical & mental fitness)

Range of functionin individuals

Age

Early LifeGrowth and development

Adult LifeMaintaining highest

level of function

Older AgeMaintaining health and independence

Disability threshold

• genes

• diet

• lifestyle

Dietary Guidelines for Americans 2005 - Center for Nutrition Policy and Promotion, USDA

MetabolicSyndrome

Health benefits of Health benefits of ωω3 PUFA3 PUFAInfant development & growth Promoting fitness (physical, mental, reproductive)Counteracting disease (prevention, treatment)

Diabetesinsulin resistanceobesity?

Inflammatory disorderspsoriasis/dermatitis rheumatoid arthritis immune renal disease inflammatory bowel disease asthma? Behaviouraldepression, bipolar disorderschizophrenia? dementia? ADHD?

Cardiovascular diseaselipids (TG, HDL) blood pressureplatelet aggregationendothelial functionarterial complianceheart rate variabilityatherosclerosis arrhythmias heart failurekidney damage strokeCancer

Excess energy (food) intake Insufficient physical activity

Genetic predisposition

Metabolic SyndromeMetabolic Syndrome

ObesityObesity

highblood

pressure

high blood fatsCardiovascular diseaseCardiovascular disease

$1.4B p.a.$1.4B p.a.DiabetesDiabetes$1.2B p.a.$1.2B p.a.

Bioactive nutrients

tailored exercise

programshighblood glucose,insulin

Inflammation

Physical disabilities Physical disabilities $0.9B p.a.$0.9B p.a.

Relative risks of allRelative risks of all--cause and cardiovascular cause and cardiovascular mortality in 3757 men with metabolic syndromemortality in 3757 men with metabolic syndrome

Katzmarzyk P et al, Diabetes Care 2004

Tertiles of cardiorespiratory fitness (maximal treadmill exercise test)Tertiles of cardiorespiratory fitness (maximal treadmill exercise test)

All Causes Cardiovascular Disease

Outcomes

Inputs nutrientsfunctional foods

Goals

physical activityexercise

enhanced circulatory and metabolic functions

National Research PriorityPromoting & maintaining health

Physical fitnessBody shape & composition

Energy (CHO, fat) utilisation Cardiovascular healthPhysical performance

Mental fitnessMood

Cognitive function

Preventive healthcareevidence-based strategies to promote health and prevent disease through• adoption of healthier lifestyles and diet • development of health-promoting foods

motivational strategiestraining programs, CBT

ATN Centre for Metabolic Fitness

Unifying ConceptUnifying Concept

Arterial FunctionArterial Function

Ultrasound assessment of Ultrasound assessment of dilatory capacity of arteriesdilatory capacity of arteries

Compliance Compliance (elasticity)(elasticity)of arteriesof arteries

Differential regulation of blood supplyDifferential regulation of blood supply

Local demands are met bymetabolic influences on endothelial dilatation(autoregulation)

Systemic Circulation

neural control autoregulation

autoregulation

Cognition,

behaviour

Cardiac output

Physical activity

autoregulation neural control β2 dilatation

Fisher N et al, J Cardiovasc Pharmacol 2006;47:S210

Regulation of cerebral blood flowRegulation of cerebral blood flowvasodilator response of middle cerebral artery to breathing 5% Cvasodilator response of middle cerebral artery to breathing 5% COO22

Female 73 yrs Female 69 yrs

characterised by:-• Impaired endothelial vasodilatation (acute)• Inflammatory mediators (cytokines, adhesion molecules)• Vascular remodelling reduced arterial compliance (chronic)

Endothelial dysfunction in the metabolic syndromeEndothelial dysfunction in the metabolic syndrome

high blood pressue insulin resistance high blood lipids

G Born & C Schwartz: Vascular Endothelium

Obese Lean p

Impaired Endothelial Dilatation in ObesityImpaired Endothelial Dilatation in Obesity

Subjects 9 M, 18 F 8 M, 18 F

Age (yr) 49.6 ± 1.6 50.1 ± 1.3 0.80

Height (m) 1.69 ± 0.02 1.67 ± 0.02 0.54

Mass (kg) 100.9 ± 3.4 63.0 ± 1.5 <0.001

BMI (kg/m2) 35.3 ± 0.9 22.5 ± 0.3 <0.001

Body fat (%) 43.5 ± 1.2 27.2 ± 1.6 < 0.001

FMD (%) 3.2 ± 0.4 5.7 ± 0.7 < 0.01

SBP (mmHg) 127.0 ± 2.6 118.6 ± 3.1 < 0.05

DBP (mmHg) 72.4 ± 2.0 67.0 ± 1.8 < 0.05

Large art. compliance 16.5 ± 0.9 15.5 ± 0.6 0.36

Small art. compliance 7.0 ± 0.5 7.3 ± 0.5 0.67

Consequences of impaired blood flowConsequences of impaired blood flow

Impaired Circulation

Adipose tissue

reduced physical capacity

Cognitive impairment OmegAD, OPAL

depression

limited cardiac performance,

angina

liver

TG oxidation

TG synthesis, oxidation

TG storage, mobilisation

high blood TG

ββ--adrenergicadrenergicblockersblockers

nutrientsnutrientsexerciseexercise

Obesity – a circulatory disorder?

Obesity

Impaired blood vessel

function

• Does metabolically healthy obese = healthy circulation?

• Can we counteract obesity by adopting diet and exercise strategies that improve circulatory function?

Impaired fat burning capacity during exercise ?

a-Linolenic acidC18:3

Docosahexaenoic acidC22:6 DHA

Eicosapentaenoic acid C20:5 EPA

Linoleic acidC18:2

EICOSANOIDS2-series prostaglandins 3-series4-series leukotrienes 5-series

Arachidonic acid C20:4

Thrombosisvasoconstrictioninflammation

linseed,canolaNUTS

fish,fish oil

plants

inhibit

animals

promote

Docosapentaenoic acidC22:5

inhibits

fish

fish,fish oil

excessmay

Aspirin

Circulatory diseaseCirculatory disease

Omega 6Omega 6 Omega 3Omega 3

PUFAsPUFAs and and eicosanoideicosanoid balancebalance

Mechanisms of action of polyunsaturated fatty acidsMechanisms of action of polyunsaturated fatty acids

1) Eicosanoids

2) Substrate for enzymes

3) Peroxidation

4) Membrane- flexibility

5) Acylation of proteins

6) Transcription factors

Platelets W blood cell Chemotactic agent

CH3COOH

CH3COOH

Red blood cells

more flexible

Protein

FA

FA

n-3n-3

membrane

Protein

mRNANucleus

PromoterDNA

Regulation of metabolism

& cell proliferation

n-6n-6

A Rustan, personal communication

Endotheliumarterialdilatation

Improved Metabolic Fitness (Physical and Mental)

Bioactive Nutrients and Regular Exercise

↑ Blood flow to

exercising muscles

Aerobic Exercise Resistance Exercise

Improved Circulation↑ Vasodilatation

↑Cerebrovascular

Perfusion

↑ Arterial Compliance↓ Blood

Pressure

Fat MetabolismFat Metabolism

Omega 3 PUFA• DHAPolyphenols•Tea, Wine, Cocoa

Gene expression of enzymes involved in

• fatty acid synthesis ↓• fatty acid oxidation ↑

Improved Body Composition

↑ lean mass ↓ fat mass

Improved Cardiovascular

Profile

↓ Plasma TG ↑ HDL

CHO MetabolismCHO Metabolism

GI Modified FoodsLow GI Diet↑ Insulin Sensitivity↑ EnduranceHigh GI Diet↑ Acute Performance

↑ Alertness↑ Cognitive Function

↑ Mood

OmegaOmega--Exercise studyExercise study

AimAimInvestigate effects of Investigate effects of ωω3 PUFA3 PUFA supplementation and aerobic supplementation and aerobic exercise on exercise on metabolic syndromemetabolic syndrome risk factors including risk factors including lipids, lipids, blood pressure, blood vessel function and central adiposity.blood pressure, blood vessel function and central adiposity.

DesignDesignDoubleDouble--blind 2x2 factorial intervention trialblind 2x2 factorial intervention trial, , 12 wks duration12 wks duration

Subjects Subjects •• males or females males or females aged 25aged 25--65 years65 years

•• overweight/obese + additional CV risk factor(s) overweight/obese + additional CV risk factor(s)

•• randomised to one of four groups:randomised to one of four groups:--

FO: tuna fish oil (6g HiDHA/day) SO: sunflower oil FOX: FO + exercise (3x45min/wk) SOX: SO + exercise

Hill A, Murphy K, Buckley J & Howe P, ISSFAL 2006

Baseline CharacteristicsBaseline CharacteristicsFO FOX SO SOX

men 6 7 7 7

women 13 13 12 10

all subjects 19 20 19 17

BMI (kg/m2) 34.0 ± 6.1 34.6 ± 6.1 34.6 ± 6.1 35.1 ± 5.2% Body Fat 43.9 ± 6.6 43.5 ± 9.7 43.7 ± 8.2 41.5 ± 8.1

SBP (mmHg)DBP (mmHg)

128.8 ± 14.372.5 ± 10.2

132.4 ± 16.177.7 ± 10.4

128.0 ± 13.072.6 ± 7.8

131.0 ± 11.275.4 ± 8.5

Plasma cholesterol (mmol/L)

6.74 ± 1.31 6.07 ± 1.21 5.98 ± 2.09 6.75 ± 1.69

Plasma TG (mmol/L) 1.66 ± 0.75 2.04 ± 1.67 1.73 ± 0.86 1.85 ± 0.79

DHA Incorporation in RDHA Incorporation in RBCBCss

DHA as %total fatty acids

in RBC

0

1

2

3

4

5

6

7

8

FO FOX SO SOX

0 6 12 0 6 12 0 6 12 0 6 12

Weeks

Change in plasma Change in plasma lipidlipidss –– TG and HDLTG and HDL

0.0

0.2

0.4

0.6

0.8

0.0

0.2

0.4

*

p < 0.05

Change in HDL

mmol/L

-0.4

-0.2

0.0

FO SO

* p < 0.05

Change in TG

mmol/L

-0.6

-0.4

-0.2

0.0

0.2

FO FOX SO SOX

Effects of OmegaEffects of Omega--3 and Exercise on Arterial Function3 and Exercise on Arterial Function

Change in smallartery compliance

%

Change in FMD (endothelial

function) mm

p < 0.01

*

p = 0.05

0.000

0.004

0.008

0.012

0.016

FO FOX SO SOX0.000

0.004

0.008

0.012

0.016

FO SO

-10%

0%

10%

20%

30%

40%

0%

10%

20%

30%

40%

50%

Exercise Non-exercise

DEXA Assessment of Body CompositionDEXA Assessment of Body Composition

Nutritional Physiology Research Group

Energy intake, Energy intake, Weight & Body CompositionWeight & Body Composition

Change in body weight

kg

-3.0

-2.0

-1.0

0.0

1.0

2.0

FO FOX SO SOX

p = 0.06

Change in fat mass

kg

Change in lean mass

kg

-3.0

-2.0

-1.0

0.0

1.0

2.0

FO FOX SO SOX

-3.0

-2.0

-1.0

0.0

1.0

2.0

*p < 0.05

-3000

-2000

-1000

0

1000

2000

FO FOX SO SOX

Change in energy intake

kJ

Fat Fat UtilisationUtilisation

Changes in fat mass were attributed to changes in fat oxidation as indicated by RER

FO

FOX

SO

SOX

-0.20 RER

-6000 6000

0.25

Fat Mass (g)

R2 = 0.12

P < 0.01

• ω3 supplementation– Reduces TG, increases HDL– Improves endothelial dependent dilatation

• ω3 supplementation plus regular moderate exercise– Can improve body composition

- reduces fat mass through increased fat oxidation (RER) – Synergistic effect – not seen with FO or exercise alone

• Regular moderate exercise– Increases small (resistance) artery elasticity

• Overall impact in metabolic syndrome– Improved blood lipid profile– Improved arterial function– Improved body shape

ConclusionsConclusions

Change in High Frequency Power

(normalised units)

Sunflower Oil Fish Oil0.0

2.5

5.0

7.5

10.0Ch

ange

in

HFP

*

Effects of omegaEffects of omega--3 and exercise 3 and exercise on on Heart Rate VariabilityHeart Rate Variability

Ninio DM et al, J Cardiovasc Electrophysiol 2005;16:1189-94

Effects of omegaEffects of omega--3 fatty acids on cardiovascular risk, 3 fatty acids on cardiovascular risk, exercise performance and recovery in AFL playersexercise performance and recovery in AFL players

VLC

n-3

(% to

tal f

atty

aci

ds)

0

2

4

6

8

10

Sunflower oilFish Oil

Week 0 Week 5

*

Seru

m tr

igly

cerid

e co

ncen

tratio

n (m

M)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Sunflower oilFish Oil

Week 0 Week 5

*H

eart

rate

(bpm

)

0

20

40

60

80

100

120

140

160

180

Sunflower oilFish Oil

Week 0 Week 5

*

Tim

e to

exh

aust

ion

(s)

0

200

400

600

800

Sunflower oilFish Oil

Week 0 Week 5

*

Buckley JD et al, Asia Pac J Clin Nutr 2005;14:S57

Workload (watts)150 190 230 270 310 350 390 Peak

Mea

n he

art

rate

d

iffe

renc

e (b

pm

)

-25

-20

-15

-10

-5

0

5

10

15

20

Fish Oil Control

*p<0.001

Fish oil attenuates heart rate elevation in trained cyclists Fish oil attenuates heart rate elevation in trained cyclists without affecting performancewithout affecting performance

Peoples GE et al. 4th International Conference on Nutrition and Fitness, Olympia, 2000

Potential nutrient function claimsPotential nutrient function claims

Omega-3 fatty acid consumption, as part of a healthy lifestyle including regular exercise, can contribute to a

• healthy circulation

• healthy heart

• healthy mind

• healthy body shape/composition

Attaining optimal fitness

Counteracting obesity

ALA(g/day)

EPA+DHA (mg/day)

Recommendations by expert panels:

BNF (1992) ~2 200 - 1000

EANS (1997) ~2 200

ISSFAL (1999) ~2 650

ISSFAL (2004) 1.4 500

Adoption of recommendations:-

US/Canada (2002) Australia (NHF 2006)

1.4 ≥2

135 - 270 (optional)500

Australia (NHMRC 2006) 1 – 2 90 (f) - 160 (m) adequate intake430 - 610 target intake(EPA+DPA+DHA)

How much How much omegaomega--3 3 do we need?do we need?(general recommendations -

no attempt to distinguish between EPA, DPA and DHA)

0

0.2

0.4

0.6

0.8

1.0

1.2

LA AA ALA EPA DPA DHA Total LCn3

10

12

Current PUFA intakesCurrent PUFA intakesaverage intakes for Australian adults, g/day

Howe P et al APJCN 2003;12:S27

Other estimated intakesOther estimated intakes LNA EPA+DHAJapan (Dolocek, 1992) 2.1 g 1600 mgNorway (Drevon, personal communication) ~700 mgUnited States (Nelson, 1999) 1.3 g 150 mg

FoodFood sources sources of LC of LC ωω3 PUFA3 PUFA• fish and other seafoods

• fish or microalgal oils can be blended with vegetable oils or margarines or added in microencapsulated form to processed foods

• red meat

• animal products (eggs, poultry, pork)and fish can be enriched with LC ω3 PUFA by feeding fish oil, fishmeal, flax or algal biomass to livestock

0

2

4

6

8

10

LNA EPA DPA DHA EPA+DHA EPA+DPA+DHA

0 mths 6 mths

% of total fatty acids

Eating processed foods enriched with Eating processed foods enriched with ωω3 (1g/day) 3 (1g/day) increases increases ωω3 levels in red blood cells3 levels in red blood cells

Murphy KJ et al. Asia Pac J Clin Nutr. 2004;13:S51

8.1%

Greatest ProtectionGreatest Protection

Least ProtectionLeast Protection

GISSI-P2:≈ 9-10%

CHS3: 8.8%

DART4: ≈ 8-9%

SCIMO5: 8.3%

5 epi. studies: ≈ 8%

PHS6: 7.3%

Seattle7: 6.5%4%

8%

PHS6: 3.9%

Seattle7: 3.3%

6%

10%

1Nilsen. AJCN. 74:50, 2001; 2Marchioli. Circulation. 105:1897, 2002; 3Mozaffarian. Circulation.107:1372, 2003; 4Burr. Lancet. 2:757, 1989;

5von Schacky Ann Intern Med.130:554, 1999; 6Albert. NEJM. 346:1113, 2002; 7Siscovick. JAMA. 274:1363, 1995.

SCIMO5: 3.4%

Harris WS, Von Schacky C. Prev Med. 2004;39:212

Protection against Cardiovascular Disease

The Omega-3 Index™

EPA+DHA in red blood cells

How does this relate to effects on cardiovascular biomarkers?

0

1

2

3

4

5

6

7

8

9

0g/day 2g/day 4g/day 6g/day

Week 0Week 6Week 12

#

**

*

*

# #

##

Supplementation with DHASupplementation with DHA--rich tuna oil rich tuna oil increases DHA levels in red blood cellsincreases DHA levels in red blood cells

-- a biomarker for incorporation into tissuesa biomarker for incorporation into tissues

% oftotal fatty acids

(Coates AM, Milte C, Buckley JD & Howe PRC, unpublished)

Change in fasting plasma triglycerides after Change in fasting plasma triglycerides after 6 and 12 weeks of fish oil supplementation 6 and 12 weeks of fish oil supplementation

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0 2

0.65

4

1.3

6

2.0 g n3/day

g/day

(mmol/l)

Week 6 Week 12Baseline ~2.5 mmol/l)

(Coates AM, Milte C, Buckley JD & Howe PRC, unpublished)

Mozaffarian D & Rimm EBJAMA 2006;296:1885-1899

Moderate omegaModerate omega--3 intakes lower cardiovascular risk3 intakes lower cardiovascular risk

Enrichment of pork with LC nEnrichment of pork with LC n--3 3 PUFAsPUFAs from tuna fishmealfrom tuna fishmeal

Total long-chain omega-3 fatty acids

050

100150200250300350400450

Steak Diced Mince Sausage Stir fry

(mg/100g)Raw Regular PorkCooked Regular PorkRaw Omega-3 PorkCooked Omega-3 Pork

(Siourtis S, Coates A, Buckley J & Howe P, unpublished)

DHA in erythrocyte membranes after eatingDHA in erythrocyte membranes after eating~800g/week of omega~800g/week of omega--3 enriched pork3 enriched pork

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Steak Mince Sausage

% of total fatty acids

Week 0 Week 4 Week 8 Week 11

(Siourtis S, Coates A, Buckley J & Howe P, unpublished)

Change in fasting serum triglycerides after Change in fasting serum triglycerides after regularly eating omegaregularly eating omega--3 pork for 12 weeks3 pork for 12 weeks

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2

0 2 4 6 8 10 12

Time (Weeks)

Cha

nge

in s

erum

trig

lyce

ride

from

bas

elin

e (m

mol

.L-1

)

Omega-3 PorkRegular Pork

**

Potential nutrient function claimsPotential nutrient function claims

Omega-3 fatty acid consumption, as part of a healthy diet and lifestyle

including regular exercise, can contribute to a

• healthy circulation

• healthy heart

• healthy mind

• healthy body shape/composition

• desirable omega-3 status

Centre for Metabolic FitnessOptimising Health • Reducing Obesity • Modifying Lifestyles