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SCOPE School Dublin - Donal O'Shea
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Obesity, innate immunity and gut hormones
Donal O’SheaSt Columcilles & St Vincents University Hospitals, National Childrens Research Center & University
College Dublin, Ireland
July 12th 2013
Outline of talkBackground
Obesity and the immune system
Gastrointestinal hormones and immunity
Childhood obesity work
Obesity: like no previous epidemic• Diabetes • Cancer• Dementia• Cardiovascular Disease• Asthma• Arthritis
Causes 4000 – 6000 Deaths per year in Ireland (Pop 5 million)
8 times the number from suicide 486 (2011) and road traffic accidents 112 (2012) combined
World Economic Forum 2011
• 2009 World Health Spend was $5 trillion ($4.4 trillion spent in high income countries).
• Cumulative loss of output from NCD 2010 to 2030 will be $47trillion (70% World GDP 2010)
• Currently high income countries bear most cost but this will change to middle income/developing areas
Sturm and Hattori, Int J Obes 2012
Percentage increase in BMI categories since 1986
Body Mass Index 40 & 50
BMI 40 BMI 52
Body Mass Index 40 & 50
BMI 40Guess 32
BMI 52Guess 41
Case
• 45YO male
Case
• 45YO male• Referred for left knee
pain
Case
• 45YO male• Referred for left knee
pain• Osteoarthritis diagnosed
Case
• 45YO male• Referred for left knee
pain• Osteoarthritis diagnosed• On examination
Wt 235kgs (BMI 78)BP 110/70Glucose 5.3Cholesterol 4.6
Case
• May need knee replacement
• Ideally should loose weight first
Intervention
• Dietician• Physiotherapist• Psychologist
• Monthly for 10 months
Result
Wt 233.5kgs (-1.5kgs)BMI 78
BP 118/76Glucose 5.6Cholesterol 4.6
Extreme obesity must be prevented
Extreme obesity must be prevented
because it is practically irreversible
Outcomes for Service in SVUH/SCH
Gained Weight ( > 2%)
9%
Lost Weight (> 2%)63%
Weight Stable
(+ or - 2%)28%
Societal influencesIndividual psychology
Biology
Activity environment
Individual activityFood
ConsumptionFood Production
TOXIC ENVIRONMENT
How much insulin would you advise?
They tell you what they do..
Nutrition in pregnancy vital
Albert Einstein (1879 - 1955)
I fear the day when the technology overlaps with our humanity.
Albert Einstein (1879 - 1955)
I fear the day when the technology overlaps with our humanity. The world will only have a generation of idiots.
Times and play have
changed….
Sedentary Time
Now 4th leading preventable cause of death
“Lack of activity destroys the good condition of every human being, while movement and methodical physical exercise save it and preserve it.”
Sedentary Time
Now 4th leading preventable cause of death
“Lack of activity destroys the good condition of every human being, while movement and methodical physical exercise save it and preserve it.” - Plato
American Diabetes Association
Childhood Obesity in Ireland (and Europe)
• 25% 3 year olds overweight/obese• 25% 9 years olds overweight/obese
• low self image, concept and self esteem
Growing up in Ireland 2009
Median BMI for each 5-year rise in age of onset of overweight
O’Connell et al JPHN 2011
• Study cohort - 6328 subjects (2961 male) – mean age 11.4 ± 4.0 years at baseline – mean length of follow-up 23.1 ± 3.3 years
• 5554 subjects normal weight as children– 812 (15%) were obese as adults
• 774 subjects overweight or obese as children– 500 (65%) were obese as adults
• 147 subjects obese as children– 121 (82%) were obese as adults
Juonala et al, NEJM 2011
This
Becomes this
BMI 51 BMI 52
Becomes this (82% chance)
BMI 51 BMI 52
Consumption of free sugar has soared
Sports Drinks• Growing Up Today Study II• Large Prospective Study• 5995 girls/4906 boys• 9-16 years old • Consumption of sports
drinks strongly associated with weight gain(Field et al, Consumption of Sports Drinks Prospectively Associated with Greater Weight Gain among Adolescents, Obesity Society Meeting 2012)
Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct. Diabetologia. 2013 Apr 26th
“This study corroberates the evidence between incidence of type 2 diabetes and high consumption of sugar sweetened drinks”
Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct. Diabetologia. 2013 Apr 26th
“This study corroberates the evidence between incidence of type 2 diabetes and high consumption of sugar sweetened drinks”
GSK decision to sell Ribena and Lucozade.
Outline of talkBackground
Obesity and the immune system
Gastrointestinal hormones and immunity
Childhood obesity work
Obesity causes and worsens outcome in……
• Diabetes • Cancer• Dementia• Sleep Apnoea• Asthma • Everything
• Suggests a common mechanistic fault• Focussed our research on the circulating immune
system
• Natural Killer cells
• Invariant Natural Killer T cells
• Dendritic cells
• Macrophages
• All cell types characterised by different cell surface markers
Studied four cell types to date
Flow cytometry
6B11
CD
3
Various cell types – with different surface markers
6B11
CD
3
Flow cytometry
Flow cytometry
Various cell types – with different markers
6B11
CD
3
• Key cell in attacking viruses and cancer cells
• Involved in a range of autoimmune conditions
Natural Killer Cell - foot soldier of the immune system
NK
cel
ls (
% t
otal
lym
ph
ocyt
es)
0
2.5
5
7.5
10
12.5
15
17.5
20
22.5
25
27.5
obese lean
*
n = 110, p = 0.006
Decrease in circulating natural killer cells in obesity
Smoking machine
Invariant Natural Killer T (iNKT) cell
A key cell in the innate immune system
Represents 0.2% - 1.2% of circulating T cells
Interacts with other immune cells to determine the downstream immune response:
Pro-inflammatoryAnti-inflammatoryCytotoxic
Cytokine
Cytotoxicity
NK cells
DCs
B cells
Macrophages
Chemokines
T cells
Invariant Natural Killer Cell – Swiss army knife of immune system
iNKT cells & Obesity
The invariant natural killer T cell is significantly depleted in severe obesity
***
iNKT
(% T
cel
ls)
0.0
0.15
0.30
0.45
0.60
0.75
0.90
Obese Lean
NKT
cel
ls (%
T c
ells
)
Lean Obese
Cross-sectional
Lynch et al, Immunity 2012
iNKT cells in obesity
RYGB restores iNKT cell number in humans
Longitudinal
010203040506070
iNKT
**
pre-op post-oppre-op post-op
BMI
0.0
0.1
0.2
0.3
0.4
0.5
0.6
**
NKT
cel
ls (%
T c
ells
)
Body
Mas
s In
dex
Gastric Bypass restores iNKT cell population in humans
What happens if you get rid of iNKT cells?
• Mouse model
• 0-12 weeks High Fat Diet (60% of kcals from fat) in wild type or iNKT knockout mouse
• Look at weight, metabolic status and inflammation
What happens if you get rid of iNKT cells in mice?
Ja18
Lean
mas
s (g
)
WT0
5
10
15
20
0
1
2
3 *
**
SFD WT Ja18
Wei
ght (
g)
Fat padsFat pads
WTJa18KO
0 1 2 3 4 5 6 7 8 920
25
30
35
40
**
***
****
*
***
***
***
weeks
Wei
ght (
g)W
eig
ht
(g)
0
2
4
6
8
10
12 *
HO
MA-
IR
WT Ja18KO WT HFD Ja18KO HFD
Liver
85
90
95
100
105
Adip
ocyt
e di
amet
er
m)
WT Ja18
*
iNKT cell KO mice get fatter & more severe metabolic disease on HFD
iNKT
obese Ja18KO mouse
iNKTiNKT continue on HFD for 4 days
PBS T NKT-2
-1
0
1
Wei
ght c
hang
e (g
) ***
PBS T NKT85
95
105
115
125
135***
**
*
Dia
met
er
m
SFDPBS T NKT0
1
2
3
Fat (
g)
*** **
100140180220260300340380420460500540580
PBS
NKTT cells
SFD
0 15 30 45 60 90
IL-4 & IL-10 dependent mechanismAlso re polarization of ATMReduction in serum inflammation
Adoptive transfer of iNKT cells but not T cells improves metabolism &weight
Conclusion
• Weight dysregulates the immune system
• Immune sytem regulates weight
IL-4 & IL 10 drive macrophages to switch on thermogenesis (UCP-1)
• Factors that affect IL-4 & IL-10 production will impact on thermogenesis and weight
IL-4 Producing iNKT cells
T3Control
iNKT cells
Stimulation +CSE
IL-4
pg/
ml
Looked at thyroid hormone and cigarette smoke
iNKT cells
Stimulation +Cortisol
iNKT cells +Stimulation
+Olanzapene
D.
Looked at cortisol and antipsycotic medication
Outline of talkBackground
Obesity and the immune system
Gastrointestinal hormones and immunity
Childhood obesity work
Gave GLP-1 to a diabetes patient with psoriasis
• Itch went within days and slept through for first time in 46 years
GLP-1 and the incretin effect
McIntyre et al. Lancet.1964
- 10’ 30’ 90’ - 90’ GLP-1
- - - - 30’ 30’ LPS
IB: pCREB
IB: CREB
IB: β-Actin
Time
Was it a consistent effect?Before After
PASI reduced by average of 38% (p - 0.008) DLQI reduced by average of 46% (p - 0.014)
Ahern et al, n=10 JEADV 2012
What about other inflammatory conditions?
0
1
2
3
4
5
6
7
8
1 2 3
Timepoints
DA
S28
0 6/52 12/52
All lost mean 4kg, HBa1C ↓
GLP-1 as a immunomodulator
• Looked at 12 T2DM starting GLP-1:
Circulating cytokines
Soluble CD163 (shed by macrophages)
iNKT levels
POST THERAPY
PBMCLPS
+-
++
+-
++
PRE THERAPY
GLP-1 regulates cytokine production and capacity for production
Pre Post
GLP-1 regulates adipokine production
LPS 0 10 30 90 0 10 30 90
Pre GLP-1
IB: pCREB
IB: p-p65
Post GLP-1
IB: p65
IB: CREB
IB: β-Actin
GLP-1 therapy restores p65 signalling pathway in human PBMC’s
Soluble CD163 in T2DM
GLP-1 therapy and soluble CD163
Is it just weight loss and glycaemia?
GLP-1 therapy restores depleted circulating iNKT cell populations in
patients with T2DM
GLP-1 summary
• Anti-inflammatory
• Restores innate immune population and function
• Immune effects at least part independent of weight and glycaemic actions
PYY receptor expression and intracellular signalling in iNKT cells
IB: p-IκBα
IB: IκBα
IB: β-Actin
PYY (time) - 10’ 30’ 90’iNKT cells + + + +
IB: pCREB
IB: CREB
IB: β-Actin
PYY (time) - 10’ 30’ 90’iNKT cells + + + +
b. c.a.
iNKT cellsC1R cellsαGalCerNative PYY
++--
+++
0ug
+++
ug
iNKT cellsC1R cellsαGalCerNative PYY
++--
+++
0ug
+++
ug
e.d.
iNKT cellsC1R cellsNative PYY
++-
++
ug
++
ug
++
ug
f.
PYY: cytokine production and tumour killing capacity of iNKT cells
PYY: restores killing capacity of NK from obese individuals
Y59 – longacting PYY analogue: cytokine production by iNKT cells
iNKT cellsC1R cellsY-59
+--
++-
++
100ngc. d.
Y-59
Y59 – Tumour growth and tumour killing by iNKT cells
Con
PYY summary
• System-wide regulation of innate immunity
• Different effects to GLP-1
• Looks more anti-tumour potential than anti-inflammatory
Outline of talkBackground
Obesity and the immune system
Gastrointestinal hormones and immunity
Childhood obesity work
Childrens Baseline Data
Lean Obese
Age 12.6 yrs old 11.9 yrs old
Number 20 30
Weight 52kgs 90kgs
Glucose 4.9 5.1
Insulin
Childrens Baseline Data
Lean Obese
Age 12.6 yrs old 11.9 yrs old
Number 20 30
Weight 52kgs 90kgs
Glucose 4.9 5.1
Insulin 21 149
Reduction in iNKT cells number and NK function already present in obese children.
Gene expression for diabetes and heart disease
Gene expression for Cancer defencemiR 34a – Tumour Suppressor
KICKBUSCH DUBLIN 2013
We have been here before
SanitaryRevolution HIAP
Revolution
What we have chosen to forget• 19th century:
• Sanitary surveys proved that a relationship exists between communicable disease and filth in the environment, and it was said that safeguarding public health is the province of the engineer rather than of the physician.
• The Poor Law Commission argues in 1838,
• “The expenditures necessary to the adoption and maintenance of measures of prevention would ultimately amount to less than the cost of the disease now constantly engendered.”
KICKBUSCH DUBLIN 2013
Conclusion
• Weight regulates immune system
• Immune system regulates weight
• Gut hormones differentially regulate both
• Obesity in childhood must be prevented
GLP-1 and the incretin effect
McIntyre et al. Lancet.1964
Most recently focussed on Dendritic Cell
Key cell in the response to viral illnessCytokine
Cytotoxicity
NK cells
DCs
B cells
Macrophages
Chemokines
T cells
CD11c
HLA
-DR
obese non obesea.
Circulating DCs are depleted in obesity
obese non obese
The Obese Dendritic Cell
• Loss of CD83
• Loss of IL-12 secretion
• Increase in IL-10 secretion
• Increase in anti-inflammatory transcription factor activation – CREB
• Drive Th2 response from healthy T cells
O’Shea et al IJO 2013
Myeloid DC don’t upregulate CD83 in response to viral or bacterial stimuli
Obese NT LPS
Non obeseNT LPS
CD
83
% M
FI
CD
83
% M
FI
Non obeseNT Poly I:C
Obese NT Poly I:C
Myeloid DC don’t upregulate CD83 in response to viral or bacterial stimuli
Obese NT LPS
Non obeseNT LPS
CD
83
% M
FI
CD
83
% M
FI
Non obeseNT Poly I:C
Obese NT Poly I:C
CD86 is upregulated
Obese NT LPS
Non obeseNT LPS
CD
86
% M
FI
As is CD54, HLA-DR, CCR7
Obese DCs produce significantly less IL-12
Obese NT LPS
Non obeseNT LPS
Non obeseNT Poly I:C
Obese NT Poly I:C
Obese DC produce significantly higher levels of IL-10 in the
absence or presence of stimulus
Obese NT LPS
Non obeseNT LPS
Non obeseNT Poly I:C
Obese NT Poly I:C
Obese DCs have increased CREB phosphorylation
pCREB
CREB
Obese Non Obese
LPS - + - + Obese NT LPS
Non obeseNT LPS
k.
Obese DC skew naïve T cells to Th2 phenotype
Lean DCObese DCLPST cells
+-++
-+++
Side effects of anti-inflammatories
• Steroids
Weight gain
Hypertension
High glucose
Immune suppression
?Cancer
• GLP-1
Weight loss
Lower blood pressure
Lower glucose
Immune “restorative”
?Cancer