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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