Canadian Journal of Cardiology 31 (2015) 177e183

Review

Obesity and Atherosclerosis: Mechanistic Insights

Fina Lovren, PhD,a Hwee Teoh, PhD,a,b and Subodh Verma, MD, PhD, FRCSCa
a
b

Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St Michaels Hospital, University of Toronto, Toronto, Ontario, Canada

Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St Michaels Hospital, University of Toronto, Toronto, Ontario, Canada

ABSTRACT



RESUM
E

Obesity is a multifactorial chronic disease characterized by an accumulation of visceral and subcutaneous fat, which leads to a predisposition toward cardiometabolic diseases. A plethora of mechanisms,
including abnormalities in lipid metabolism, insulin resistance,
inammation, endothelial dysfunction, adipokine imbalance, and
inammasome activation have been suggested to underlie the relationship between obesity and atherosclerosis. More recent data point
toward an emerging role of impaired autophagy and altered gut
microbiome homeostasis as potentially contributing factors. This review provides an overview of this area.

site
 est une maladie chronique multifactorielle caracte
rise
e par
Lobe
rale et de graisse sous-cutane
e, qui
une accumulation de graisse visce
disposition aux maladies cardiome
taboliques. Une
entrane une pre
thore de me
canismes, dont les anomalies du me
canisme des liple
sistance, linammation, la dysfonction endothe
lial,
pides, linsulinore
se
quilibre des adipocytokines et lactivation de linammasome
le de
 te
 sugge
re
s pour e
tayer le lien entre lobe
site
 et lathe
roscle
rose.
ont e
es plus re
centes sugge
raient comme rle e
mergent la
Des donne
cience de lautophagie et lalte
ration de lhome
ostasie du
de
microbiome intestinal dtre des facteurs potentiellement contributifs.
sente revue donne un aperu de ce domaine de recherche.
La pre

Obesity is a major risk factor for atherosclerotic vascular disease and cardiometabolic syndrome. Various mechanisms have
been suggested to link obesity to atherosclerosis. These are
detailed in Table 1 and are reviewed herein.

protein kinase, and via an increase in the expression of peroxisome proliferator-activated receptor-a target genes such as
CD36, acyl-coenzyme oxidase, and uncoupling protein 2.2
The adiponectin receptors, AdipoR1 and AdipoR2, are
responsible for mediating the metabolic actions of adiponectin.
Adiponectin exerts its vasculoprotective effects through a
multitude of pathways. In vitro, adiponectin induces nitric oxide
(NO) production in human aortic endothelial cells via activation
of the 5-adenosine-monophosphate-activated protein kinase
pathway and enhancement of endothelial NO synthase (eNOS)
activity.3 Adiponectin additionally suppresses proliferation and
superoxide generation, and also enhances eNOS activity in
endothelial cells treated with oxidized low-density lipoprotein.4
Adiponectin has also been demonstrated to attenuate the
adhesion of monocytes to endothelial cells, primarily via a
mechanism that involves inhibition of tumour necrosis factor
(TNF)-a- and interleukin (IL)-8-induced synthesis of intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion
molecule 1 (VCAM1), and E-selectin.5 Adiponectin suppresses
the expression of class A macrophage scavenger receptors and
consequently reduces foam cell formation and decreases secretion of proinammatory cytokines.6 Notably, foam cell
formation is further reduced by adiponectin-induced downregulation of acyl-coenzyme A:cholesterol acyltransferase-1 in
macrophages, the enzyme that catalyzes the formation of
cholesteryl esters.7 Accordingly, adiponectin limits the initiation
of atherosclerotic plaque formation. Recent data point toward
the ability of adiponectin to prime monocyte differentiation
toward the anti-inammatory M2 macrophage lineage,8 and

Adipokine Imbalance
The visceral adipose tissue is a source of numerous
adipokines, most of which are deemed to be proinammatory.
Increasing evidence suggests that an imbalance between
proinammatory vs anti-inammatory adipokines (such as
adiponectin) might be responsible for the development of
insulin resistance and endothelial dysfunction and atherosclerosis in patients with obesity (Fig. 1).
Adiponectin is the most abundant anti-inammatory and
vasculoprotective adipokine secreted by adipose tissues.
Numerous studies have to date demonstrated that plasma levels
of adiponectin are lower in patients with obesity and/or diabetes. Adiponectin improves insulin sensitivity by increasing
energy expenditure and fatty acid oxidation through the
phosphorylation of 5-adenosine-monophosphate-activated
Received for publication November 18, 2014. Accepted November 25, 2014.
Corresponding author: Dr Subodh Verma, Division of Cardiac Surgery,
Keenan Research Centre for Biomedical Science, St Michaels Hospital, 30
Bond St, Toronto, Ontario M5B 1W8, Canada. Tel.: 1-416-864-5997;
fax: 1-416-864-5991.
E-mail: vermasu@smh.ca
See page 181 for disclosure information.

http://dx.doi.org/10.1016/j.cjca.2014.11.031
0828-282X/
2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

178

Table 1. Suggested mechanisms of obesity-induced atherosclerosis

Endothelial dysfunction
Adipokine imbalance
Vascular inammation
Macrophage NLRP3 inammasome activation
Altered gut microbiome
Loss of autophagic ux
Oxidative stress

that in states of adiponectin deciency (such as obesity),

monocytes might be primarily driven toward the proatherosclerotic M1 lineage. Physiological concentrations of adiponectin signicantly suppress the proliferation and migration of
human aortic smooth muscle cells induced by platelet-derived
growth factor BB in vitro9 by directly binding platelet-derived
growth factor-BB and inhibiting growth factor-stimulated
extracellular signal-regulated kinase signalling. These results
suggest that adiponectin might also prevent vascular remodelling
in atherosclerosis. In other studies, adiponectin has been shown
to selectively increase the expression of tissue inhibitor of
metalloproteinase-1 in human monocyte-derived macrophages,10 suggesting that it might favour plaque stabilization.
Via improving vascular function, adiponectin has been recently
implicated in protection against sepsis induced multiorgan
dysfunction.11 In vivo studies in mice have conrmed the
antiatherogenic properties of adiponectin. Adiponectindecient mice, compared with wild type controls, show neointimal thickening and increased proliferation of vascular
smooth muscle cells after mechanical injury to arteries.12
Adenovirus-mediated delivery of adiponectin in these mice
considerably attenuated the extent of neointimal proliferation.12
Furthermore, treatment of apolipoprotein E-decient mice
(ApoE/) with adiponectin-expressing adenoviruses reduced
atherosclerotic lesion formation compared with control mice.13

Canadian Journal of Cardiology

Volume 31 2015

Taken together, the balance of published information would

strongly associate low adiponectin levels in obesity as a causal
and/or permissive basis of atherosclerotic risk.
Resistin is a proinammatory adipokine that is released in
excess amounts in individuals with visceral adiposity. Resistin
profoundly upregulates the expression of TNF-a and IL-6 in
human peripheral blood mononuclear cells.14 Human resistin
has been reported to stimulate the synthesis of proinammatory cytokines such as TNF-a, IL-1, IL-6, and IL-12
in various cell types through a nuclear factor-kB-dependent
pathway.15 A positive correlation between resistin levels and
vascular inammation has been demonstrated in obese
humans.16 As further evidence of its proinammatory prole,
resistin upregulates the expression of adhesion molecules
VCAM1 and ICAM1, and induces chemokine (C-C motif)
ligand 2 and endothelin (ET)-1 release in human endothelial
cells.17 Indeed, we demonstrated that resistin directly triggered endothelial cell activation by promoting ET-1 release, in
part by inducing ET-1 promoter activity via the activator
protein-1 site. Furthermore, resistin upregulated the expression of adhesion molecules and chemokines and downregulated tumor necrosis factor receptor-associated factor-3,
an inhibitor of CD40 ligand signalling in endothelial cells.
Therefore, increased resistin levels might be another factor
that contributes to obesity-induced atherosclerosis.17
The adipokine, leptin, has a main function to control food
intake and energy expenditure.18 Levels of circulating leptin
uctuate; they are increased with overfeeding and decreased
with starvation. Mice with a mutation in the gene encoding
leptin (ob/ob mice) or the gene encoding the leptin receptor
(db/db mice) have obese phenotypes,19 and also exhibit
increased atherosclerosis.20 Leptin is considered to be a
proinammatory cytokine and is structurally similar to other
proinammatory cytokines such as IL-6, IL-12, and the

Figure 1. Anti- and proinammatory adipokines. AT, angiotensin II; CRP, C-reactive protein; EC, endothelial cell; ET-1, endothelin-1; ICAM, intercellular
adhesion molecule; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; NO, nitric oxide; oxLDL, oxidized lowdensity lipoproteins; PAI-1, plasminogen activator inhibitor-1; SMC, smooth muscle cell; TNF, tumour necrosis factor; VCAM, vascular cell adhesion
molecule. Reproduced from Lau et al.1 with permission from American Physiological Society. Copyright 2014, The American Physiological Society.

Lovren et al.
Obesity and Atherosclerosis: Mechanistic Insights

granulocyte colony stimulating factor.18 Leptin modulates the

T-cell immune response, stimulates the proliferation of Thelper cells, and increases production of proinammatory
cytokines by regulating different immune cells.21 Increased
production of leptin, therefore, modulates caloric intake and
atherosclerotic susceptibility.
Impaired Autophagy
Accumulating data suggest that loss of autophagy might be
an important determinant of atherosclerosis, particularly with
aging.22-25 One theory that is rapidly gaining popularity is that
loss of autophagy might be a central mechanism through which
cardiometabolic diseases arise. An intact autophagic machinery
is essential in limiting lipid uptake by macrophages. Autophagyrelated protein 7 (ATG7) is a critical autophagy gene and
macrophage specic ATG7-decient mice exhibit increased
susceptibility toward atherosclerosis25 via an increase in
macrophage low-density lipoprotein uptake and foam cell formation. Autophagic ux is compromised in obesity and the
metabolic syndrome. In a recent seminal paper, mice with
global haploinsufciency of ATG7 (Atg7/ mice) did not
show metabolic abnormalities but developed diabetes when
crossed with ob/ob mice. Atg7/-ob/ob mice show aggravated
insulin resistance with increased lipid content and inammatory changes, suggesting that autophagy haploinsufciency
impairs the adaptive response to metabolic stress.26 Furthermore, intracellular lipid content and insulin resistance after lipid
loading are increased as a result of autophagy insufciency, and
there is increased inammasome activation in Atg7/-ob/ob
mice.26 These results suggest that systemic autophagy insufciency could be a factor in the progression from obesity to
diabetes, and associated inammation and atherosclerosis.
Oxidative Stress Links Obesity to
Atherosclerosis
Obesity is strongly associated with an increase in systemic
oxidative stress. The extent of fat accumulation in obese
humans closely correlates with the markers of oxidative
stress.27 Similarly, the oxidative stress is augmented in plasma
and adipose tissue from obese mice.27 Increased oxidant
production, through quenching NO, has been linked to
increased atherosclerosis susceptibility.
Oxidative stress results from an imbalance between the
production of free radicals and antioxidant systems. Increase
in reactive oxygen species (ROS) production by the adipose
tissue in obesity is accompanied with an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
expression suggesting that augmented NADPH oxidase contributes to increased ROS production in adipose tissue.27
Impaired expression of antioxidative enzymes, such as superoxide dismutase, glutathione peroxidase, and catalase in adipose tissue lead to increased ROS production.27 Furthermore,
in cultured adipocytes, it has been shown that increased levels
of fatty acids increase oxidative stress and augment the production of proinammatory cytokines. In obese mice, treatment with NADPH oxidase inhibitor reduced ROS
production in adipose tissue and strikingly augmented adiponectin production, attenuated proinammatory cytokine
release, and improved insulin-sensitivity and hepatic steatosis.

179

Gut Microbiome as a Link Between Obesity and

Atherosclerosis?
The resident gut microbiota have crucial roles in host
functioning, and subsequently in health and disease. Most
bacterial species in the human and mouse gut belong to the
phyla Bacteroidetes and Firmicutes and to a lesser extent
bacterial phyla, such as Actinobacteria, Proteobacteria, and
Verrucomicrobia, and methanogenic archaea, mainly Methanobrevibacter smithii.28 The gut microbiota possess a variety
of functional properties and affect host physiology within and
outside the gut.
Some of the essential functions of the gut microbiota are
normal development and homeostasis of the immune system
in the gut, modulation of epithelial cell proliferation, protection against pathogenic bacteria, and modulation of villus
architecture and angiogenesis within the intestine.29 Studies in
humans and mice have shown that altered gut microbiota are
associated with several diseases, including obesity, diabetes,
inammation, and atherosclerosis.
The rst report of gut microbial difference between obese
and lean phenotypes was reported in leptin-decient (ob/ob)
mice.30 This study showed differences in gut microbial
composition with fewer phylum Bacteroidetes and more
phylum Firmicutes in obese ob/ob mice than in their lean
littermates. Because both groups of mice were fed the same
diet, the results suggested that obesity could be due to the
difference in gut microbial composition. Similarly, a decrease
in Bacteroidetes proportion with an increase in Firmicutes
proportion was found in obese human twins.31
Furthermore, the transfer of microbiota, harvested from
not only obese mice32 but also from lean or obese individuals,31 into germ-free mice reproduces the corresponding
phenotype demonstrating that the obese phenotype was
transferred by the microbiota.33 It has also been reported that
obese children already have different gut microbiota compared
with lean children.34 However, some conicting ndings have
been observed recently, showing no association35 or an
opposite association with an increase in Bacteroidetes in obese
individuals.36
Obese gut microbiota have been demonstrated to induce
chronic low-grade inammation in the host gut.37,38 A highfat diet in rats led to changes in the composition of the gut
microbiota and activation of toll-like receptor 4 signalling in
the gut epithelia and might aggravate gastrointestinal inammation associated with the obese phenotype.37
In a recent seminal report by Karlsson et al.,39 shotgun
sequencing of the gut metagenome was performed to
demonstrate that the genus Collinsella was enriched in patients with symptomatic atherosclerosis, dened as stenotic
atherosclerotic plaques in the carotid artery leading to
cerebrovascular events, whereas Roseburia and Eubacterium
were enriched in healthy control subjects. Further
characterization of the functional capacity of the metagenomes revealed that patient gut metagenomes were
enriched in genes encoding peptidoglycan synthesis and
depleted in phytoene dehydrogenase; patients also had
reduced serum levels of b-carotene. These ndings suggest
that the gut metagenome is associated with the inammatory
status of the host and patients with symptomatic atherosclerosis harbour characteristic changes in the gut
metagenome.39

180

Endothelial Dysfunction
Animal and human studies have demonstrated impaired
endothelial function in obesity.40 Several mechanisms lead to
diminished NO production and availability in obesity. These
include decreased expression of eNOS,41,42 or increased
inactivation of eNOS (secondary to increased production of
ROS). Plasma levels of asymmetric dimethylarginine are
increased in obese patients43 and in obese subjects with
metabolic syndrome. Asymmetric dimethylarginine serves as a
stoichiometric inhibitor of eNOS and might be yet another
mechanism through which obesity reduces the bioavailability
of NO.
In addition to NO, alterations in endothelium-derived
prostacyclin and thromboxane have also been implicated in
obesity. Obesity increases prostanoid-dependent vasoconstriction and vascular thromboxane receptor gene expression.44 These changes are likely to promote the development
of vascular disease, hypertension, and thrombosis associated
with obesity. An impaired cyclooxygenase pathway, with an
increase in the release of the thromboxane A2 metabolite
thromboxane B2, has been reported in microvessels from
obese spontaneous hypertensive rats.45 Likewise in obese
Zucker rats, the release of prostacyclin is attenuated46 and
activity of prostacyclin and eNOS in arterial endothelial cells
was decreased because of oxidation of fatty acids.47
The endothelium is the source of the potent vasoconstrictor peptide ET-1. ET-1 augments the vascular actions of
other vasoactive peptides such as angiotensin-II, norepinephrine, and serotonin, participates actively in leukocyte and
platelet activation, and facilitates a prothrombotic and proatherogenic phenotype. Obesity is associated with enhanced
ET-1-mediated vascular tone. In obesity, increased ET-1mediated vasoconstriction contributes to diminished
endothelium-dependent vasodilation.48 Increased ET-1
plasma levels have been found in normotensive and hypertensive obese subjects.49 Additionally, in experimental obesity,
there is an increase in gene and protein expression of ET-1 in
the cardiovascular system.44 ET-1-mediated vasoconstriction
might therefore promote hypertension, atherosclerosis, and
thrombosis, conditions frequently observed in obese patients.
Obesity-induced vascular dysfunction is observed in the
macrovascular and microvascular beds. In humans, reduced
endothelium-dependent vasodilation to methacholine was
demonstrated in the leg microcirculation of obese patients.50
Similarly, a progressive decline in endothelial function was
described in the forearm microcirculation of overweight and
obese patients.51 In the same study, intra-arterial infusion of
ascorbic acid improved acetylcholine responses, suggesting a
role of oxidative stress in obesity-related endothelial dysfunction.51 Furthermore, small resistance arteries from obese patients are characterized by a signicantly impaired
endothelium-dependent relaxation compared with lean control subjects.52,53 These data demonstrate that small arteries
from obese patients are characterized by a marked endothelial
dysfunction as result of decreased NO availability.
It has been established that endothelial cell activation is a
crucial early step in inammation. However, the role of
overweight and obesity, and, in particular, the association
between specic fat depots and endothelial activation, has not
been fully determined. It has been shown that the release of
free fatty acid by adipose tissue directly induced endothelial

Canadian Journal of Cardiology

Volume 31 2015

dysfunction.54 Subjects with upper body obesity have higher

levels of free fatty acid than subjects with obesity in the lower
extremities,55 thus suggesting that visceral fat has a more
prominent effect on endothelial dysfunction than fat stored in
other sites of the body. Furthermore, infusion of free fatty acid
at concentrations similar to those observed in obese subjects
increased plasma ICAM1 and VCAM1 levels in healthy subjects, thus indicating a direct effect of free fatty acid on endothelial cell activation.56 Similar ndings have already been
reported in animal models of obesity in which surgical removal
of visceral fat resulted in decreased concentrations of free fatty
acid in rat plasma,57,58 suggesting that visceral adiposity plays
an important role in the regulation of free fatty acid levels. The
removal of abdominal fat in humans by liposuction leads to a
decrease in concentrations of free fatty acid.59 Conversely,
removal of only subcutaneous fat fails to show any improvement in inammation or decrease in free fatty acid concentrations60 linking visceral fat and free fatty acid levels.
Children and adolescents with obesity-related hypertension
have a heightened systemic inammatory response with evidence of endothelial activation relative to normotensive obese
subjects.61 Recently, it has been shown that adiposity is
associated with higher levels of insulin resistance, E-selectin,
and VCAM1 even in healthy normal-weight children at a
young age of 2-3 years, and such associations are evident even
in children with relatively low levels of adiposity.62 These
studies therefore strongly argue that overweight and obesity
are associated with endothelial activation and it is possible that
adiposity in the visceral region might be a stronger predictor
of endothelial activation than overall adiposity.
Inammasome Activation in Obesity and
Atherosclerosis
Inammation might be one of the most important common threads to link obesity with atherosclerosis.63 Accumulating data now suggest that the nucleotide-binding
oligomerization domain-like receptor family pyrin domain
containing 3 (NLRP3) inammasome, largely within macrophages, might be stimulated by various cardiovascular risk
factors, including crystalline cholesterol. NLRP3 inammasome activation is responsible for the eventual conversion of
pro-IL-1b into IL-1b. During obesity, circulating levels of free
fatty acids are increased and lipids such as ceramide and
palmitate activate the cells of the innate immune system and
trigger inammasome activation.64 Lipopolysaccharideprimed macrophages stimulated with ceramide display
NLRP3-dependent caspase-1 activation and lead to production of IL-1b at relatively low levels.65 More recently, another
lipid, the saturated fatty acid palmitate, has been shown to
activate the NLRP3 inammasome.66 Palmitate is one of the
most abundant free fatty acids in plasma and is highly
increased in obesity. Several studies demonstrated that the
NLRP3 inammasome in obesity is an important mechanism
that participates in the development of insulin resistance.65-67
Likewise, the NLRP3 inammasome has been demonstrated
to be essential in the development of atherosclerosis,68 making
it a very attractive common mechanism (and potential target)
of cardiometabolic risk.
Obesity-induced inammation has been linked to the
activation of adipose tissue macrophages, T cells, and B cells

Lovren et al.
Obesity and Atherosclerosis: Mechanistic Insights

within fat deposits.69 The mechanisms that regulate the

activation of these immune cells in adipose tissue are still
largely unknown, however, a recent study found that obesity
itself induced the assembly of the NLRP3 inammasome in
adipose tissue macrophages.65 Moreover, inammasomemediated caspase-1 activation in adipose tissue and liver has
been shown to impair insulin signalling and glucose homeostasis.67 In free-feeding mice given a normal chow diet,
increased expression of NLRP3 and IL-1b in visceral adipose
tissue has been found to correlate directly with body weight
and adiposity. Direct involvement of NLRP3 in obesity has
been also conrmed in NLRP3 gene-decient mice fed a high
fat diet. In these mice, caspase-1 activation and pro-IL-1b
expression in adipose tissue, and loss of serum IL-18 production were profoundly reduced compared with their wild
type counterparts. Moreover, NLRP3- and caspase-1-decient
mice are more protected from high-fat diet-induced insulin
resistance. Similar observations were reported in humans.
Weight loss in obese diabetic patients is associated with a
decrease in NLRP3 and IL-1b expression in subcutaneous
adipose tissue.65,67

181

7. Furukawa K, Hori M, Ouchi N, et al. Adiponectin down-regulates acylcoenzyme A:cholesterol acyltransferase-1 in cultured human monocytederived macrophages. Biochem Biophys Res Comm 2004;317:831-6.
8. Lovren F, Pan Y, Quan A, et al. Adiponectin primes human monocytes
into alternative anti-inammatory M2 macrophages. Am J Physiol Heart
Circ Physiol 2010;299:H656-63.
9. Arita Y, Kihara S, Ouchi N, et al. Adipocyte-derived plasma protein
adiponectin acts as a platelet-derived growth factor-BB-binding protein
and regulates growth factor-induced common postreceptor signal in
vascular smooth muscle cell. Circulation 2002;105:2893-8.
10. Kumada M, Kihara S, Ouchi N, et al. Adiponectin specically increased
tissue inhibitor of metalloproteinase-1 through interleukin-10 expression
in human macrophages. Circulation 2004;109:2046-9.
11. Teoh H, Quan A, Bang KW, et al. Adiponectin deciency promotes
endothelial activation and profoundly exacerbates sepsis-related mortality.
Am J Physiol Endocrinol Metab 2008;295:E658-64.
12. Matsuda M, Shimomura I, Sata M, et al. Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol
Chem 2002;277:37487-91.
13. Okamoto Y, Kihara S, Ouchi N, et al. Adiponectin reduces atherosclerosis in apolipoprotein E-decient mice. Circulation 2002;106:2767-70.

Conclusions
Obesity leads to increased cardiovascular risk through
various mechanisms. Although it is impossible to dissect out
the unique mechanistic contribution of obesity (vs the associated features of the metabolic syndrome) toward atherothrombotic risk, several important themes have emerged.
These relate to alterations in adipokines, inammation, and
inammasome activation, gut microbiota, oxidative stress, and
endothelial dysfunction. The most compelling contemporary
mechanism that might help tie all of these facets together is
inammation, and signalling via the NLRP3 inammasome.
Disclosures
The authors have no conicts of interest to disclose.
References
1. Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines:
molecular links between obesity and atheroslcerosis. Am J Physiol Heart
Circ Physiol 2005;288:H2031-41.
2. Yamauchi T, Kadowaki T. Adiponectin receptor as a key player in healthy
longevity and obesity-related diseases. Cell Metab 2013;17:185-96.
3. Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ.
Adiponectin stimulates production of nitric oxide in vascular endothelial
cells. J Biol Chem 2003;278:45021-6.
4. Motoshima H, Wu X, Mahadev K, Goldstein BJ. Adiponectin suppresses
proliferation and superoxide generation and enhances eNOS activity in
endothelial cells treated with oxidized LDL. Biochem Biophys Res
Comm 2004;315:264-71.
5. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial
adhesion molecules: adipocyte-derived plasma protein adiponectin.
Circulation 1999;100:2473-6.
6. Ouchi N, Kihara S, Arita Y, et al. Adipocyte-derived plasma protein,
adiponectin, suppresses lipid accumulation and class A scavenger receptor
expression in human monocyte-derived macrophages. Circulation
2001;103:1057-63.

14. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an

adipokine with potent proinammatory properties. J Immunol
2005;174:5789-95.
15. Silswal N, Singh AK, Aruna B, et al. Human resistin stimulates the proinammatory cytokines TNF-alpha and IL-12 in macrophages by NFkappaB-dependent pathway. Biochem Biophys Res Comm 2005;334:
1092-101.
16. Choi HY, Kim S, Yang SJ, et al. Association of adiponectin, resistin, and
vascular inammation: analysis with 18F-uorodeoxyglucose positron
emission tomography. Arterioscler Thromb Vasc Biol 2011;31:944-9.
17. Verma S, Li SH, Wang CH, et al. Resistin promotes endothelial cell
activation: further evidence of adipokine-endothelial interaction. Circulation 2003;108:736-40.
18. La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev
Immunol 2004;4:371-9.
19. Friedman JM, Halaas JL. Leptin and the regulation of body weight in
mammals. Nature 1998;395:763-70.
20. Wu KK, Huan Y. Diabetic atherosclerosis mouse models. Atherosclerosis
2007;191:241-9.
21. Lord GM, Matarese G, Howard JK, et al. Leptin modulates the T-cell
immune response and reverses starvation-induced immunosuppression.
Nature 1998;394:897-901.
22. Chen WQ, Zhong L, Zhang L, et al. Oral rapamycin attenuates
inammation and enhances stability of atherosclerotic plaques in rabbits
independent of serum lipid levels. Br J Pharmacol 2009;156:941-51.
23. Hill BG, Haberzettl P, Ahmed Y, Srivastava S, Bhatnagar A. Unsaturated
lipid peroxidation-derived aldehydes activate autophagy in vascular
smooth-muscle cells. Biochem J 2008;410:525-34.
24. Mueller MA, Beutner F, Teupser D, Ceglarek U, Thiery J. Prevention of
atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice
despite severe hypercholesterolemia. Atherosclerosis 2008;198:39-48.
25. Ouimet M, Franklin V, Mak E, et al. Autophagy regulates cholesterol
efux from macrophage foam cells via lysosomal acid lipase. Cell Metab
2011;13:655-67.

182

Canadian Journal of Cardiology

Volume 31 2015

26. Lim YM, Lim H, Hur KY, et al. Systemic autophagy insufciency
compromises adaptation to metabolic stress and facilitates progression
from obesity to diabetes. Nat Commun 2014;5:4934.

45. Mendizabal Y, Llorens S, Nava E. Reactivity of the aorta and mesenteric

resistance arteries from the obese spontaneously hypertensive rat: effects
of glitazones. Am J Physiol Heart Circ Physiol 2011;301:H1319-30.

27. Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in

obesity and its impact on metabolic syndrome. J Clin Invest 2004;114:
1752-61.

46. Hodnett BL, Dearman JA, Carter CB, Hester RL. Attenuated PGI2
synthesis in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol
2009;296:R715-21.

28. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial ora. Science 2005;308:1635-8.

47. Du X, Edelstein D, Obici S, et al. Insulin resistance reduces arterial

prostacyclin synthase and eNOS activities by increasing endothelial fatty
acid oxidation. J Clin Invest 2006;116:1071-80.

29. Sommer F, Backhed F. The gut microbiotaemasters of host development

and physiology. Nat Rev Microbiol 2013;11:227-38.
30. Ley RE, Backhed F, Turnbaugh P, et al. Obesity alters gut microbial
ecology. Proc Natl Acad Sci U S A 2005;102:11070-5.
31. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome
in obese and lean twins. Nature 2009;457:480-4.
32. Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and
altered gut microbiota in mice lacking Toll-like receptor 5. Science
2010;328:228-31.
33. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an
anti-inammatory commensal bacterium identied by gut microbiota
analysis of Crohn disease patients. Proc Natl Acad Sci U S A 2008;105:
16731-6.
34. Kalliomaki M, Collado MC, Salminen S, Isolauri E. Early differences in
fecal microbiota composition in children may predict overweight. Am J
Clin Nutr 2008;87:534-8.
35. Fukuda S, Toh H, Hase K, et al. Bidobacteria can protect from
enteropathogenic infection through production of acetate. Nature
2011;469:543-7.

48. Weil BR, Westby CM, Van Guilder GP, et al. Enhanced endothelin-1
system activity with overweight and obesity. Am J Physiol Heart Circ
Physiol 2011;301:H689-95.
49. Parrinello G, Scaglione R, Pinto A, et al. Central obesity and hypertension: the role of plasma endothelin. Am J Hypertens 1996;9:1186-91.
50. Steinberg HO, Chaker H, Leaming R, et al. Obesity/insulin resistance is
associated with endothelial dysfunction. Implications for the syndrome of
insulin resistance. J Clin Invest 1996;97:2601-10.
51. Perticone F, Ceravolo R, Candigliota M, et al. Obesity and body fat
distribution induce endothelial dysfunction by oxidative stress: protective
effect of vitamin C. Diabetes 2001;50:159-65.
52. Grassi G, Seravalle G, Scopelliti F, et al. Structural and functional
alterations of subcutaneous small resistance arteries in severe human
obesity. Obesity 2010;18:92-8.
53. Virdis A, Santini F, Colucci R, et al. Vascular generation of tumor
necrosis factor-alpha reduces nitric oxide availability in small arteries from
visceral fat of obese patients. J Am Coll Cardiol 2011;58:238-47.
54. Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic
lipolysis in human obesity. J Clin Invest 2004;113:1582-8.

36. Macfarlane S, Macfarlane GT, Cummings JH. Review article: prebiotics

in the gastrointestinal tract. Aliment Pharmacol Ther 2006;24:701-14.

55. Martin ML, Jensen MD. Effects of body fat distribution on regional
lipolysis in obesity. J Clin Invest 1991;88:609-13.

37. de La Serre CB, Ellis CL, Lee J, et al. Propensity to high-fat diet-induced
obesity in rats is associated with changes in the gut microbiota and gut
inammation. Am J Physiol Gastrointest Liver Physiol 2010;299:
G440-8.

56. Mathew M, Tay E, Cusi K. Elevated plasma free fatty acids increase
cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects. Cardiovasc Diabetol 2010;9:9.

38. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates
obesity and insulin resistance. Diabetes 2007;56:1761-72.

57. Kim YW, Kim JY, Lee SK. Surgical removal of visceral fat decreases
plasma free fatty acid and increases insulin sensitivity on liver and
peripheral tissue in monosodium glutamate (MSG)-obese rats. J Korean
Med Sci 1999;14:539-45.

39. Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in

European women with normal, impaired and diabetic glucose control.
Nature 2013;498:99-103.
40. Virdis A, Neves MF, Duranti E, Bernini G, Taddei S. Microvascular
endothelial dysfunction in obesity and hypertension. Curr Pharm Des
2013;19:2382-9.
41. Kobayasi R, Akamine EH, Davel AP, et al. Oxidative stress and inammatory mediators contribute to endothelial dysfunction in high-fat
diet-induced obesity in mice. J Hypertens 2010;28:2111-9.
42. Sansbury BE, Cummins TD, Tang Y, et al. Overexpression of endothelial
nitric oxide synthase prevents diet-induced obesity and regulates adipocyte phenotype. Circulation Res 2012;111:1176-89.
43. Krzyzanowska K, Mittermayer F, Kopp HP, Wolzt M, Schernthaner G.
Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women. J Clin Endocrinol Metab 2004;89:
6277-81.
44. Traupe T, Lang M, Goettsch W, et al. Obesity increases prostanoidmediated vasoconstriction and vascular thromboxane receptor gene
expression. J Hypertens 2002;20:2239-45.

58. Gabriely I, Ma XH, Yang XM, et al. Removal of visceral fat prevents
insulin resistance and glucose intolerance of aging: an adipokinemediated process? Diabetes 2002;51:2951-8.
59. Ybarra J, Blanco-Vaca F, Fernandez S, et al. The effects of liposuction
removal of subcutaneous abdominal fat on lipid metabolism are independent of insulin sensitivity in normal-overweight individuals. Obesity
Surg 2008;18:408-14.
60. Klein S, Fontana L, Young VL, et al. Absence of an effect of liposuction
on insulin action and risk factors for coronary heart disease. N Engl J
Med 2004;350:2549-57.
61. Garanty-Bogacka B, Syrenicz M, Syrenicz A, et al. Serum markers of
inammation and endothelial activation in children with obesity-related
hypertension. Neuro Endocrinol Lett 2005;26:242-6.
62. Castro C, Tracy RP, Deckelbaum RJ, Basch CE, Shea S. Adiposity is
associated with endothelial activation in healthy 2-3 year-old children.
J Pediatr Endocrinol Metab 2009;22:905-14.
63. Verma S, Gupta M, Ridker PM. Therapeutic targeting of inammation
in atherosclerosis: we are getting closer. Can J Cardiol 2012;28:619-22.

Lovren et al.
Obesity and Atherosclerosis: Mechanistic Insights
64. De Nardo D, Latz E. NLRP3 inammasomes link inammation and
metabolic disease. Trends Immunol 2011;32:373-9.
65. Vandanmagsar B, Youm YH, Ravussin A, et al. The NLRP3 inammasome instigates obesity-induced inammation and insulin resistance.
Nat Med 2011;17:179-88.
66. Wen H, Gris D, Lei Y, et al. Fatty acid-induced NLRP3-ASC inammasome activation interferes with insulin signaling. Nat Immunol
2011;12:408-15.

183

67. Stienstra R, Joosten LA, Koenen T, et al. The inammasome-mediated

caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 2010;12:593-605.
68. Duewell P, Kono H, Rayner KJ, et al. NLRP3 inammasomes are
required for atherogenesis and activated by cholesterol crystals. Nature
2010;464:1357-61.
69. Odegaard JI, Chawla A. Mechanisms of macrophage activation in
obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab
2008;4:619-26.