Healthy LivingResearch into the interaction between diet 

and chronic disease

Professor Andy Salter on behalf of

The Division of Nutritional SciencesSchool of Biosciences

University of Nottingham

Blissful Ignorance!

Ancel Keys

Plasma Cholesterol & Saturated Fat IntakeSeven Countries Study

ΔTC = 1.35(2ΔSFA – ΔPFA) + 1.5 ΔCHOL1/2The Keys Equation

cis Polyunsaturated fatty acids

cisMonounsaturated fatty acids

transMonounsaturated fatty acids

Saturated fatty acids

Meta-Analysis of 60 Trials

Mensink et al., 2003

ΔCholesterol when 1% of carbohydrate energy is replaced with fatty acids

BAD GOOD

COMA reportFood Recommendations

• Two portion of fish/week (one oily)

• Reduced fat spreads & dairy products instead of full fat

• Saturated fats & oils replaced with MUFA ‐rich– olive oil, rape seed oil, “high oleic” sunflower oil

• Increase intake of vegetables, fruit, potatoes & bread by 50%

Intake of Beef, Lamb & Butter in Great Britain

0

50

100

150

200

250

1975 1980 1985 1990 1995 2000 2005

Consum

ption (g/w

eek) Beef

LambButter

Redrawn from:  www.heartstats.org

Intake of Milk in Great Britain

0

0.5

1

1.5

2

2.5

3

1975 1980 1985 1990 1995 2000 2005

Milk In

take (L/w

eek)

whole

skimmed

Redrawn from:  www.heartstats.org

Consumption of saturated fat, 1975‐2006, Great Britain

Redrawn from:  www.heartstats.org

0

5

10

15

20

25

1970 1975 1980 1985 1990 1995 2000 2005 2010

Saturated Fatty Acid Intake (%

 fod en

ergy)

0

50

100

150

200

250

300

70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 2010

Dea

ths

/100

,000

(age

-sta

ndar

dise

d)

Year

Death rates from CHD, stroke and all other diseases of the circulatory system, people aged under 75, 1969 to 2007, England, with "Our Healthier Nation"

milestone and target

Our Healthier Nation milestone

Our Healthier Nation target

www.heartstats.org.uk

Deaths prevented or postponed as a result of population risk factor changes in England & Wales 1981‐2000

Risk Factor % Change Proportion of overall Deaths prevented or

postponed (%)Smoking -34.0 48

Blood Pressure -7.7 9.5

Cholesterol -4.2 9.6

Deprivation -6.6 3.4

Physical Activity -30.6 -4.3

Obesity +186 -3.4

Diabetes +65.6 -4.7

TOTAL EFFECT 58

Unal et al (2004) Circulation 109, 1101-1107

Deaths prevented or postponed as a result of population risk factor changes in England & Wales 1981‐2000

Risk Factor % Change Proportion of overall Deaths prevented or

postponed (%)Smoking -34.0 48

Blood Pressure -7.7 9.5

Cholesterol -4.2 9.6

Deprivation -6.6 3.4

Physical Activity -30.6 -4.3

Obesity +186 -3.4

Diabetes +65.6 -4.7

TOTAL EFFECT 58

Unal et al (2004) Circulation 109, 1101-1107

Body mass index by sex and age, adults aged 16 and over, 2006, England

0

10

20

30

40

50

60

70

16‐24 25‐34 35‐44 45‐54 55‐64 65‐74 75+

%

age

Males

<18.5

18.5‐25

25‐30

30‐40

>40

0

10

20

30

40

50

60

70

16‐24 25‐34 35‐44 45‐54 55‐64 65‐74 75+

%

age

Females

<18.5

18.5‐25

25‐30

30‐40

>40

Underweight“Normal”OverweightObeseMorbidly Obese

24% of all adults have a BMI >30 (Obese)

www.heartstats.org.uk

Why are we getting fat?

1 Mars Bar = 1086kJ4 Mars Bars = 4 x 1086 = 4344kJTherefore in 1 year extra energy = 4344 * 52 = 225888kJ1g adipose tissue = 39.1kJ

Therefore you could gain 225888/39.1 = 5.77kg (12.7lb)of fat (or run for 12‐16 miles/per week)Over 5 years = 4.5 stone!

Perhaps most important question is not why do some people get fat but how most people stay thin?  Appetite is normally tightly regulated

+ reduced activity

Combination of sucrose +  energy –dense fat

Obesity is usually associated with insulin resistance

•Often able to maintain blood glucose within normal limits but need to produce much more insulin•Diabetes occurs when pancreas can no longer produce enough insulin to maintain blood glucose within normal levels

Typical glucose tolerance test in an obese individual

Insulin Resistance is often associated with a number of risk factors for CVD

•Hyperglycaemia (raised plasma glucose)•Hypertension (raised blood pressure)•Hypertriglyceridaemia (raised plasma triacylglycerol)•Low HDL (good) cholesterol•Proinflammatory state•Prothrombotic state•Elevated plasma free fatty acids

Commonly referred to as METABOLIC SYNDROME

Theory as to how Metabolic Syndrome develops

Accumulation of ‘Insulin‐ Resistant’ Adipose Tissue

↑ Pro‐Inflammatory Adipocytokines↓ Anti‐Infammatory Adipocytokines

↑ Fatty Acid Release

Muscle/Liver Insulin Resistance

Dyslipidemia, hypertension,impaired glucose tolerance

Type 2 diabetes

Atherosclerosis

Cardiovascular Disease

NAFLD

Diet rich in saturated fatty acids and sucrose

Two Examples of the research are we doing

• Increasing the amount of “good” fat in our food.

• Impact of Maternal Diet on development of metabolic syndrome and cardiovascular disease. 

“Good” Fatty Acids

A Mixture of CLA isomers produced from Sunflower Oil

Where do the “bad” fats come from

Cereals and Cereal products, 18

Milk & Milk Products, 22

Butter, 4

Fat Spreads, 4

Meat & Meat Products, 26

Vegetables, Potatoes, 7

Confectionery, 5

Sources of Saturated Fatty Acids26.1g/day (12.8% food energy)

NDNS 2009

0

5

10

15

20

25

30

g/10

0 g

fatty

aci

ds

C4:0-C10:0C12:0C14:0C16:0C18:0C18:1 cisC18:1 transC18:2C18:3CLA (c9,t11)

Fatty Acid Composition of Bovine Milk

Manipulating Fatty Acid Content of Milk

cis-9, trans-11 CLA

Conjugated Linoleic Acids (CLA)

Biological Effects

Anticarcinogenic effects (in vivo and in vitro)

Antiatherogenic properties

Altered nutrient partitioning and lipid metabolism

Antidiabetic (type II) and reduced hyperglycemia

Immune modulation

Improved bone mineralization

Production of CLA‐enriched  butter

0

5

10

15

20

25

30

g/10

0 g

fatt

y ac

ids

C4:0-C10:0C12:0C14:0C16:0C18:0C18:1 cisC18:1 transC18:2C18:3CLA (c9,t11)

control

CLA/VA

Control cows fed a corn‐based total mixed ration 

CLA/VA cows fed the same ration + 2% sunflower oil and 1% fish oil to produce a milk fat enriched with  cis‐9, trans‐11 CLA.  Cows producing highest level of CLA selected for butter production

Data from Lock et al 2005

Lock et al., 2005

Effect of VA/CLA‐Enriched Butter on Plasma Lipoproteins in Hamsters

Plasma Cholesterol

‐60

‐40

‐20

0

20

40

Total LDL HDL LDL/HDL

% Change from

 Con

trol

P<0.001 p<0.001P<0.01 n.s

0

5

10

15

20

25

30

g/10

0 g

fatt

y ac

ids

C4:0-C10:0C12:0C14:0C16:0C18:0C18:1 cisC18:1 transC18:2C18:3CLA (c9,t11)

control

CLA/VA

Fatty Acid Composition of VA/CLA‐enriched  Butter

F.D.A. Announces Label Requirement For Artery Clogger

By MARIAN BURROS (NYT)

“Food and Drug Administration will require food processors to include amount of artery-clogging trans fatty acids on nutrition labels. …………………Dr Walter Willett of Harvard School of Public Health suggests that fast food restaurants that serve foods high in trans fats with no warning label may be sued by customers who later have heart attacks; some scientists think trans fats, which are actively added to foods, are at least as bad as saturated fats, and some think trans fats are worse.”

Ruminant vs. Industrial Sources TFA

http://www.foodandnutritionresearch.net/index.php/fnr/article/viewFile/1651/1557/2120

Some Health Benefits of Omega ‐3 Fatty Acids

•Reduce risk of cardiovascular  disease•Alleviate symptoms of Metabolic Syndrome•Prevent or even reverse Non Alcoholic Fatty Liver Disease

Omega 3 Fatty AcidsC18:3, n‐3

↓C18:4, n‐3

↓C20:4, n‐3

↓C20:5, n‐3

↓C22:5, n‐3

↓C22:6, n‐3

Δ6 desaturase

Δ5 desaturase

Δ4 desaturase

α linolenic acid

eicosapentaenoic acid (EPA)

Marine Algae

docosahexaenoic acid (DHA)

Terrestrial Plantse.g. Flax/Linseed

Omega ‐3 Fatty Acids in Beef

Statistical significance is indicated when *P<0.05, **P<0.01 and *** P<0.001.

0

5

10

15

20

25

30

35

40

45

C12

:0

C14

:0

C14

:1

C15

:0

Pal

miti

c

C16

:1 c

is

C17

:0

C17

:1 c

is

Ste

aric

Vacc

enic

Ole

ic

Lino

leic

Lino

leni

c

Ara

chid

onic

EPA

DPA

DH

A

CLA

c9,

t11

Fatty

Aci

d %

Grass/Silage

Concentrate

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Lino

leic

Lino

leni

c

C20

:4n-

6 A

A

C20

:5n-

3 E

PA

C22

:5n-

3 D

PA

C22

:6n-

6 D

HA

CLA

c9,

t11

*** ******

*** ***

***

***

*

* *

*

**

**

**

***

***

Omega 3

ApoE*3 Leiden mouse modelMost mice, rats and hamsters are relatively resistant to developing atherosclerosis

Apolipoprotein E is a major regulator of plasma lipoprotein metabolism

Mutations in ApoE result in familial dyslipoproteinemia

ApoE*3 Leiden is a tandem duplication of codons 120‐126 in the human apoE gene

Presence of a single allele of this gene results in familial dyslipoproteinemia  and increased atherosclerosis in humans

Mice expressing the human Leiden mutation also develop hyperlipidemia and show increased susceptibility to diet‐induced aortic atherosclerosis.

0.0

0.5

1.0

1.5

2.0

2.5

Grass / Silage Concentrate

Trig

lyce

ride

(mm

ol/l)

0

5

10

15

Grass / Silage ConcentrateC

hole

ster

ol (m

mol

/l)*

Results ‐ Serum lipid concentrations

• No difference was observed in serum cholesterol concentration between groups.  However serum triglyceride concentration was significantly lower in animals on the grass/forage diet (P=0.02).

Histological analysis of the aorta

Positive staining regions were quantified using Image ProPlus software

No difference was seen between groups (P=0.47)

Lesion

Omega 3 Fatty AcidsC18:3, n‐3

↓C18:4, n‐3

↓C20:4, n‐3

↓C20:5, n‐3

↓C22:5, n‐3

↓C22:6, n‐3

Δ6 desaturase

Δ5 desaturase

Δ4 desaturase

α linolenic acid

eicosapentaenoic acid (EPA)

Marine Algae

docosahexaenoic acid (DHA)

Terrestrial Plantse.g. Flax/Linseed

Ultimate Transgenics?

Fetal Programming Or

Developmental Orgins if Health and Disease (DOHaD)

The Fetal Origins (Barker) Hypothesis

“.....fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease.”

Barker DJ (1995) BMJ 311, 171‐174

Epidemiological Evidence

The Dutch Hunger Winter

Offspring from women who were pregnant during famine 

Exposed in early gestationIncreased obesity (women)More atherogenic lipoprotein profileLDL:HDL ratio higher (13.9%; 95%CI: 2.6–26.4%)Increased CHD

Exposed in late gestationImpaired glucose tolerance

Roseboom et al (2000) Am J Clin Nutr 72, 1101‐1106

Many studies in a whole range of species •Particularly Rats, Sheep & Mice•Mainly global nutrient deficiency or protein‐restriction

On a range of disease risk factors including•Blood pressure•Plasma lipids•Obesity•Insulin Resistance

Generally, confirm that there are critical windows during fetal life where nutritional ‘insults’ can ‘program’ metabolic disease risk factors

Animal Studies

control 18mth

Low protein 18mth

0

5

10

15

20

25

30

35

40

45

50

1 9 18

hepa

tic TA

G (m

g/liver) 

time (months)

cont

l.p.

“Fetal Programming of Steatosis

Mother fed control (18%) or low protein (9%) dietsOffspring fed normal chow (low fat/high CHO)

Erhuma et al (2007) Am J Physiol 292:1702‐1714

How does Fetal Programming Work?Epigenetics?

• Epigenetics is a term in biology used today to refer to changes in gene expression that are stable over rounds of cell division, and sometimes between generations, but do not involve changes in the underlying DNAsequence of the organism.  The molecular basis of epigenetics involves modifications to DNA and the chromatin proteins that associate with it. 

http://en.wikipedia.org/wiki/Epigenetics