TEST BANK For Corporate Finance, 13th Edition By Stephen Ross, Randolph Weste...
Freeman o&p2013
1. The impact of obesity on the maternal metabolic
adaptation to pregnancy
Dilys J Freeman
Institute for Cardiovascular and Medical Sciences
University of Glasgow
7. Adipose tissue adaptation to pregnancy
First trimester gain in
insulin sensitivity
Gain in fat
Mid-trimester loss of
insulin
sensitivity
Increased adipose
turnover
Fetal growth
Non-pregnant Mid gestation Term
Huda et al Clinical Lipidology 2009
NEFA
9. SAT physiological storage depot in
pregnancy
↑ NEFA release
pregnancy hormones
insulin resistance
+
VLDL
10. Adipose tissue depots – relative
contribution
Visceral
(VAT)
Subcutaneous
Upper body
(USAT)
Lower body
(LSAT)
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
total lipolysis net lipolysis
mmol/L/ugDNAglycerolorNEFA
USAT
VAT
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
11. 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Forrest et al unpublished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
12. 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
13. SAT vs VAT lipolytic and lipogenic
function
0
20
40
60
80
100
120
insulin sensitivity
percentinhibitionofIPA
stimulatedlipolysis%
USAT
VAT
P=0.046
*
Ex-vivo basal adipocyte lipolysis experiments
Huda et al submitted
USAT and UVAT mRNA expression
Insulin sensitivity assessed as insulin suppression of
isopreterenol-stimulated lipolysis
ExpressionrelativetoPPIA(%)
0
5
10
15
Subcutaneous
Visceral
*
INSR
ExpressionrelativetoPPIA(%)
0
50
100
150
200
***
LPL
Subcutaneous
Visceral
LPL is a lipogenic enzyme
Insulin receptor
Lipoprotein lipase
14. Improved vascular function is a key
adaptation to pregnancy
Endothelium-dependent microvascular function
Stewart et al JCEM 2007
P<0.001
Required for placental
formation and perfusion
15. 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)
mmol/LTriglyceride
Triglyceride
*
* *
*
*
Mackay et al unpublished
17. 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
18. 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)
mmol/LHDL
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
mmol/Ltriglyceride
HDL Triglyceride
HDL increases over gestation
Delivery
30%
increase
Placental circulation
established
Data compiled from different overlapping longitudinal studies
n=225
Mackay et al unpublished
19. 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)
GestationalchangeinEDMVF(PUMOhm.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
21. 10.07.55.02.50.0-2.5-5.0
2500
2000
1500
1000
500
0
-500
-1000
incremental AUC HDL (mmol/L*weeks)
incrementalAUCparaoxonase(ug/mL*weeks)
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
23. Maternal obesity and hormones
Meyer et al JCEM 2013
Huda et al unpublished
P=0.038
0
2
4
6
8
10
12
14
16
Progesterone Placental lactogen
Progesteroneorplacental
lactogen(ug/mL)
healthy overweight obese
24. Jarvie et al unpublished
Fat acquisition during pregnancy
in lean and obese women
0
5
10
15
20
25
30
35
40
45
50
15 25 35
gestation (weeks)
fatmass(kg)
lean
obese
Lean 4.3 kg
Obese 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
25. 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)
Triglyceride(mmol/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
26. baseline
gestation
(weeks)
metabolic marker
(concentration)
Location of fat and adaptation to
pregnancy
Metabolic
marker
Fat
depot
Pearson
correlation
coefficient
univariate
Contribution
to variance
multivariate
P value Adjusted†
contribution
to variance
multivariate
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
27. Metabolic flexibility in pregnancy
High UVAT/ USAT
Low UVAT/USAT
Sattar & Freeman Chpt 5; 45-55
Maternal Obesity Ed Gillman & Poston
28. 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
29. Baseline metabolic markers -
independent association with fat depot
Metabolic
marker
Fat
depot
Pearson
correlation
coefficient
univariate
Contribution
to variance
multivariate
P value Adjusted†
contribution
to variance
multivariate
Adjusted
P value
Leptin USAT
UVAT
0.68
0.65
9.1%
6.3%
0.002
0.009
8.9%
4.0%
0.007
0.039
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 Dep
Microvascular
Function
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
30. Hypertrophy vs hyperplasia of adipocytes
Increased flux of non-esterified fatty acids (NEFA)
Central obesity
Non-obese or lower
body obesity
macrophage infiltration
and adipokine secretion
lipolysis
Hypertrophy Hyperplasia
31. 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)
logmaternalCRP(plasma)
r=0.66
r=0.66, p=0.005
Huda et al unpublished
32. Pregnancy exposure to metabolic
marker - independent association with
fat depot
Metabolic
marker
Fat
depot
Pearson
correlation
coefficient
univariate
Contribution
to variance
multivariate
P value Adjusted†
contribution
to variance
multivariate
Adjusted
P value
CRP USAT 0.47 7.6% 0.047 8.3% 0.037
End Dep
Microvascular
Function
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
35. 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
36. 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
37. Adipocyte function in PE
FCISI
control vs. PE
FCISI(%)
-50
0
50
100
150
Control ControlPE PE
SAT
VAT
0.04
FCISI
Control 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
39. Ectopic fat is the problem not obesity
Stefan et al Arch Intern Med 2008
40. 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)
41. 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
42. Evidence for ectopic fat in PE -
decreased LC PUFA synthesis
Maternal Cord
Maternal and cord blood LC PUFA
concentrations
Subcutaneous adipose tissue
enzyme mRNA expression
FADS1 - 5 desaturase
FADS2 - 5 desaturase
SCD - stearoyl coA desaturase
ELOVL2- very long chain FA elongase
ELOVL6 – long chain FA elongase
MacKay et al Hypertension 2012
Subcutaneous adipose tissue
0
2
4
6
8
10
12
14
FADS1 FADS2 SCD ELOVL2 ELOVL6
mRNAexpression(sqrttarget/PPIA)
Control
PE
IUGR
P=0.020
*
P=0.001
*
P=0.043
#
44. 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
45. 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 50 m.
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 )Logmacrophagedensity(countsperfield)
p=0.004
Huda et al unpublished
46. Pavan et al Endocrin 2004
……probably via LXR activation
OxLDL inhibits trophoblast invasion…..
Implications for placental function –
trophoblast function?
47. Decreased antioxidant defences in
preeclampsia
0
50
100
150
200
250
300
Control PE IUGR
Paraoxonaseactivity(ug/mL)
P=0.012
n=125 n=57 n=16
Lower paraoxonase activity in
preeclampsia
Dysfunctional HDL?
Mackay et al unpublished
49. Acknowledgements
ICAMS
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 Wollongong
Barbara Meyer
Todd Mitchell
Simon Brown
University of Surrey
Bruce Griffin
University of Umea
Gunilla Olivecrona
Editor's Notes
The anti-lipolytic alpha2 and the pro-lipolyic beta2 are more highly expressed in the subcutaneous depot.The beta-3 adrenoceptor is more highly expressed in the subcutaneous depot however, it’s physiological role is still debated as it isn’t thought to contribute to catecholamine-induced lipolysis in human adipocytes.B1 and B2 shown to be higher in visceral in non-pregnant – thought to be responsible for differences in catecholamine responses
