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The impact of obesity on the maternal metabolic adaptation to pregnancy
Dilys J FreemanInstitute for Cardiovascular and Medical SciencesUniversity of Glasgow
Dilys J Freeman
Disclosed no conflict of interest
Presenter Disclosure Information
• Healthy pregnancy
• Obese pregancy
• Complicated pregnancy (preeclampsia)
HealthyH
Healthy Pregnancy
Gestational hormonal changes
Paulev and Zubieta-Calleja, Textbook in Medical Physiology and Pathophysiology, 2nd Ed
Taggart (1967) Br J Nutr 21;439
Fat acquisition during pregnancy
Adipose tissue adaptation to pregnancy
First trimester gain in insulin sensitivity
Gain in fat
Mid-trimester loss of insulinsensitivity
Increased adipose
turnover
Fetal growth
Non-pregnant Mid gestation Term
Huda et al Clinical Lipidology 2009
NEFA
Plasma NEFA flux vs concentration
TG NEFA
AdiposeTissue
Plasma compartment
Liver/Placenta
Utilisation
TG NEFA Utilisation
Non-pregnant
Pregnant
SAT physiological storage depot in pregnancy
↑ NEFA release
pregnancy hormones
insulin resistance+
VLDL
Adipose tissue depots – relative contribution
Visceral(VAT)
Subcutaneous
Upper body(USAT)
Lower body(LSAT) total lipolysis net lipolysis
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
USAT
VAT
mm
ol/
L/u
g D
NA
gly
cero
l o
r N
EF
A
Huda et al submitted
P=0.005*
P=0.026*
USAT is more lipolytic than VAT in the third trimester of pregnancy
Ex-vivo basal adipocyte lipolysis experiments
Effect on lipolysis: + +- + + + -/?-+/?
Forrest et al unpublished
SAT and VAT lipolysis regulated differently
Receptor profile suggests: - in VAT pregnancy hormones reduce lipolysis- in SAT pregnancy hormones promote lipolysis and adrenergic-driven lipolysis is reduced
SAT as a reservoir of fatty acids in health
• Based on the functionality and size of the SAT depot, we would suggest that in healthy pregnancy plasma NEFA are derived from this depot
• In the non-pregnant (Jensen et al JCEM 2008), USAT is estimated to be the source of 60% of circulating NEFA, LSAT 15-20% and VAT 6-17%
• SAT provides a “safer” depot for gestationally-acquired fat as VAT releases NEFA into the portal circulation and hence directly to the liver
SAT vs VAT lipolytic and lipogenic function
insulin sensitivity0
10
20
30
40
50
60
70
80
90
100
USAT
VAT
per
cen
t in
hib
itio
n o
f IP
A s
tim
ula
ted
li
po
lysi
s %
P=0.046*
Ex-vivo basal adipocyte lipolysis experiments
Huda et al submitted
USAT and UVAT mRNA expressionInsulin sensitivity assessed as insulin suppression of isopreterenol-stimulated lipolysis
Exp
ressio
n r
ela
tive t
o P
PIA
(%
)
0
5
10
15
Subcutaneous
Visceral*
INSR
Exp
ressio
n r
ela
tive t
o P
PIA
(%
)0
50
100
150
200
***
LPL
Subcutaneous
Visceral
LPL is a lipogenic enzyme
Insulin receptor
Lipoprotein lipase
Improved vascular function is a keyadaptation to pregnancy
Endothelium-dependent microvascular function
Stewart et al JCEM 2007
P<0.001
Required for placental formation and perfusion
Hypertriglyceridaemia: the need for vascular protection
Rasmussen et al Scan J Clin Lab Inv 2009
Data compiled from different overlapping longitudinal studies
* Significantly different from baseline
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
0 5 10 15 20 25 30 35 40 45 50 55 60 65
weeks (gestation)
mm
ol/
L T
rig
lyce
rid
e
Triglyceride
** *
*
*
Mackay et al unpublished
Late gestational lipid metabolism
Huda et al Clinical Lipidology 2009
High Density Lipoprotein (HDL)
Reverse cholesterol transport
Delivery of cholesterol to steroidogenic tissues
Vascular protection:-
• Prevents LDL oxidation• Inhibits ROS generation and
inflammatory signalling• Inhibits apoptosis & necrosis• Promotes cell survival by
carrying protective agents such as S-1-P
1.00
1.20
1.40
1.60
1.80
2.00
2.20
0 5 10 15 20 25 30 35 40 45 50 55 60 65
weeks (gestation)
mm
ol/L
HD
L
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
mm
ol/L
tri
gly
ce
rid
e
HDL Triglyceride
HDL increases over gestation
Delivery30%
increase
Placental circulationestablished
Data compiled from different overlapping longitudinal studies
n=225
Mackay et al unpublished
HDL and endothelium-dependent vascular function in pregnancy
1.000.750.500.250.00-0.25-0.50
10000
5000
0
-5000
-10000
-15000
-20000
Gestational change in HDL (mmol/ L)
Gest
ational c
hange in
EDM
VF
(PU M
Ohm
.min
)
r=0.42, p=0.013, r2=18% independent of maternal age, parity and smoking status
Gestational change = Post natal HDL - T3 HDL
No significant association with endothelium-independent microvascular function
n=34 Mackay et al unpublished
Concentration vs function
But.............
HDL concentration tells us nothing about HDL function
10.07.55.02.50.0-2.5-5.0
2500
2000
1500
1000
500
0
-500
-1000
incremental AUC HDL (mmol/ L*weeks)
incr
em
enta
l AU
C p
ara
oxonase
(ug/m
L*w
eeks)
r=0.47, p=0.043, r2=17%
Paraoxonase – PON-1
• Responsible for most of the anti-oxidative effects of HDL
• Protects against atherogenesis• Synthesised in the liver, carried by
HDL• Hydrolytic activity decreases lipid
peroxides• Mixed data on the effect of gestation
on PON-1 activity
n=19
Mackay et al unpublished
Maternal Obesity
Maternal obesity and hormones
Meyer et al JCEM 2013
Huda et al unpublished
P=0.038
Progesterone Placental lactogen0
2
4
6
8
10
12
14
healthy overweight obese
Pro
ges
tero
ne
or
pla
cen
tal
lact
og
en
(ug
/mL
)
Jarvie et al unpublished
Fat acquisition during pregnancyin lean and obese women
0
5
10
15
20
25
30
35
40
45
50
15 25 35
gestation (weeks)
fat
mas
s (k
g)
lean
obeseLean 4.3 kgObese 4.0 kg
Lean and obese women accumulate similar mass of fat
See Ellie’s poster No. 15 for more detail on the contributory elements of energy metabolism to this fat gain in lean and obese women
Maternal BMI and triglyceride response to pregnancy
0
0.5
1
1.5
2
2.5
3
3.5
15 20 25 30 35 40 45
BMI (kg/m2)
Tri
gly
ceri
de
(mm
ol/
L)
Trimester 1 Trimester 2 Trimester 3 Postnatal
154%66%
Meyer et al JCEM 2013
Actually a larger TG response in healthy weight than obese women
Healthy weight women are more metabolically flexible
baseline
gestation(weeks)
metabolic marker(concentration)
Location of fat and adaptation to pregnancy
Metabolic marker
Fat depot
Pearson correlationcoefficientunivariate
Contribution to variance
multivariate
P value Adjusted†
contributionto variancemultivariate
Adjusted P value
VLDL-1 UVAT -0.23 19.3% 0.005 13.3% 0.026
USAT 0.15 14.4% 0.013 12.9% 0.028
VLDL-2 UVAT -0.32 13.1% 0.027 5.3% 0.075
Incremental area under the curve
† adjusted for maternal age, parity, smoking status, deprivation category and gestations at sampling
Jarvie et al unpublished
Metabolic flexibility in pregnancy
High UVAT/ USAT
Low UVAT/USAT
Sattar & Freeman Chpt 5; 45-55Maternal Obesity Ed Gillman & Poston
Obese pregnancy & microvascular function
Predictors of endothelium-dependent
microvascular function in obese
pregnancy:
• obesity, 19.3%, p<0.001• gestation, 11.2% p<0.001• IL-6, 4.0%, p=0.002• IL-10, 2.4%. P=0.018
Endothelium dependent
Endothelium independent
Stewart et al JCEM 2007
P<0.001
P=0.021
Baseline metabolic markers - independent association with fat depot
Metabolic marker
Fat depot
Pearson correlationcoefficientunivariate
Contribution to variance
multivariate
P value Adjusted†
contributionto variancemultivariate
Adjusted P value
Leptin USATUVAT
0.680.65
9.1%6.3%
0.0020.009
8.9%4.0%
0.0070.039
Adiponectin UVAT -0.46 8.4% 0.020 9.4% 0.018
IL-6 USAT 0.57 8.4% 0.009 8.2% 0.013
CRP USAT 0.55 11.2% 0.004 9.7% 0.007
End DepMicrovascularFunction
UVAT -0.43 7.7% 0.025 5.7% 0.062
† adjusted for maternal age, parity, smoking status, deprivation category and baseline gestation
Baseline
Jarvie et al unpublished
Hypertrophy vs hyperplasia of adipocytes
Increased flux of non-esterified fatty acids (NEFA)
Central obesityNon-obese or lower body obesity
macrophage infiltrationand adipokine secretion
lipolysis
Hypertrophy Hyperplasia
Ex-vivo maternal USAT adipocyte CRP secretion
USAT and UVAT adipocytes were prepared by collagen digestion from fat biopsies at C-section.
CRP secretion from these adipocytes was measured using a suspension array (Bioplex).
USAT, but not UVAT, adipocyte CRP secretion correlated with third trimester maternal plasma CRP levels.
3.02.52.01.51.0
1.2
1.0
0.8
0.6
0.4
0.2
0.0
log CRP basal release (SAT)
log m
ate
rnal C
RP (
pla
sma)
r=0.66
r=0.66, p=0.005
Huda et al unpublished
Pregnancy exposure to metabolic marker - independent association with
fat depot
Metabolic marker
Fat depot
Pearson correlationcoefficientunivariate
Contribution to variance
multivariate
P value Adjusted†
contributionto variancemultivariate
Adjusted P value
CRP USAT 0.47 7.6% 0.047 8.3% 0.037
End DepMicrovascularFunction
USAT -0.59 12.1% 0.007 13.3% 0.009
Total area under the curve
† adjusted for maternal age, parity, smoking status, deprivation category and gestations at sampling
Jarvie et al unpublished
Maternal BMI and HDL concentration
1
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2
15 20 25 30 35 40 45
BMI (kg/m2)
HD
L c
ho
lest
ero
l (m
mo
l/L
)
Trimester 1 Trimester 2 Trimester 3 Post natal
20%
12%
n=98
Mackay et al unpublished
Pregnancy Complications
O’Brien et al (2003) Epidemiology
1 BMI unit 0.5% PE prevalence
Torloni et al (2009) Obesity Rev
1 BMI unit 0.9% GDM prevalence
Maternal BMI and incidence of GDM and PE
Obesity and the development of type 2 diabetes in the non-pregnant
Excess dietary fat
NEFA spillover
pancreatic beta cell
muscle
liver
Hypertrophic obesity
Ectopic lipid accumulation
Adipocyte function in PE
FCISIcontrol vs. PE
FCIS
I (%
)
-50
0
50
100
150
Control ControlPE PE
SAT
VAT
0.04
FCISIControl vs. PE
Fat cell insulin sensitivity index (FCISI) – the ability of insulin to suppress beta adrenergic stimulated lipolysis
Huda et al unpublished
In PE, SAT adipocytes as insulin resistant as VAT
Plasma NEFA flux vs concentration
TG NEFA
AdiposeTissue
Plasma compartment
Liver/Placenta
Utilisation
TG NEFA Utilisation
TG NEFA Utilisation
lipolysis ↓ utilisation
Non-pregnant
Pregnant
Pregnant - pathological
Ectopic fat is the problem not obesity
Stefan et al Arch Intern Med 2008
Plasma markers of liver fat in the non-pregnant
• Fatty liver is a powerful determinant of plasma small dense LDL (Sugino et al J Atheroscler Thromb 2011;18:1-7)
• Fatty liver in type 2 diabetes is associated with increased small dense LDL (Toledo et al Diabetes Care 2006;29:1845-50)
• In NAFLD there is depletion of LC PUFA possibly via reduced 5- and 6-desaturase activities (Videla et al, Free Radic Biol Med 2004)
Increased small dense LDL in obese pregnancy
In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal weight women and 35% of obese, 14% of overweight, and none of the normal weight women displayed an atherogenic LDL subfraction phenotype.
Trimester 3
0%
20%
40%
60%
80%
100%
Healthy Obese
% LDL-III
% LDL-II
% LDL-I
P=0.004
P=0.005
Meyer et al JCEM 2013
Evidence for ectopic fat in PE - decreased LC PUFA synthesis
■ Maternal □ Cord
Maternal and cord blood LC PUFA concentrations
Subcutaneous adipose tissueenzyme mRNA expression
FADS1 - 5 desaturaseFADS2 - 5 desaturaseSCD - stearoyl coA desaturaseELOVL2- very long chain FA elongaseELOVL6 – long chain FA elongase
MacKay et al Hypertension 2012
Subcutaneous adipose tissue
0
2
4
6
8
10
12
14
FADS1 FADS2 SCD ELOVL2 ELOVL6mR
NA
exp
ress
ion
(sq
rt t
arg
et/P
PIA
)
Control
PE
IUGR
P=0.020
*P=0.001
*P=0.043
#
Excess dietary fat
pancreas placenta?liver
Hypertrophic obesity
Ectopic lipid accumulation
Ectopic sites of fat storage in pregnancy
NEFA
spillover
visceraladipose tissue
bloodvessel
Placental lipidomic analysis
Figure 1. A. Total placental lipid, ** P<0.05 vs control and IUGR and B. Placental phosphatidyl choline (PC) arachidonic acid (AA) content * P<0.05 vs control, mean (SEM), in healthy (n=70), preeclampsia (n=19) and IUGR (n=12) pregnancy.
Eather, Freeman, Brown, Mitchell, Meyer unpublished
University of Wollongong Placental lipids were extracted and analysed on a hybrid triple quadrupole, linear ion trap mass spectrometer (AB Sciex QTRAP 5500) equipped with an automated, chip-based nanospray source (Advion Triersa Nanomate).
PE placenta has higher total lipid content and arachidonic acid content than controls
Implications for placental function –inflammation?
Figure 1: Placental samples showing CD68 positive macrophages (brown) under magnification x 40. (A) BMI ≥35 kg/m2, (B) BMI <35 kg/m2. Scale bar (bottom right) represents 50m. Figure 1C: Boxplot comparing log macrophage counts in the BMI<35kg/m2 group compared to the BMI≥35kg/m2 group. Represented as median, inter-quartile range, maximum and minimum of log transformed data.
A
B
>or=35<35
3.5
3.0
2.5
2.0
1.5
1.0
0.5
BMI (kg/ m2 )Lo
g m
acr
ophage d
ensity
(co
unts
per field
)
p=0.004
Huda et al unpublished
Pavan et al Endocrin 2004
……probably via LXR activation
OxLDL inhibits trophoblast invasion…..
Implications for placental function –trophoblast function?
Decreased antioxidant defences in preeclampsia
0
50
100
150
200
250
300
Control PE IUGR
Par
aoxo
nase
act
ivity
(ug/
mL)
P=0.012
n=125 n=57 n=16
Lower paraoxonase activity in preeclampsia
Dysfunctional HDL?
Mackay et al unpublished
Maternal obesity - a perfect storm?
Maternal obesitylipolysis ’safe’ storage of TGinsulin resistance
oxidative stressoxidised lipids
ectopic fat accumulationlipotoxicity
placenta
NEFA
maternal endothelial /vascular
stress
trophoblast invasion? uteroplacental
insufficiency
altered development, fat metabolism & transport
& inflammation
offspring obesityadverse maternal
outcomeJarvie et al Clin Sci 2010
AcknowledgementsICAMS
Ellie Jarvie
Rachel Forrest
Ann Brown
Fiona Jordan
Vanessa Mackay (née Rodie)
Frances Stewart
Christopher Onyiaodike
Naveed Sattar
Muriel Caslake
Glasgow Collaborators
Bill Ferrell
Shahzya Huda
Scott Nelson
University of Manchester
Mike Mackness
Project students
Jack Bray
Sam Eather
Louise McKenna
Iain Martin
Nicole Patterson
University of WollongongBarbara MeyerTodd MitchellSimon Brown
University of SurreyBruce Griffin
University of UmeaGunilla Olivecrona