Endocrinology, 2023, 164, 1–13

https://doi.org/10.1210/endocr/bqad094
Advance access publication 8 June 2023
Mini-Review

Inflamed Adipose Tissue: Therapeutic Targets for

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Obesity-related Endothelial Injury
Wanlin Dai,1,2 Ziqi Liu,1,2 Shaojie Yang,3 and Jing Kong3
1
Innovation Institute, China Medical University, Shenyang, 110122, Liaoning, China
2
Health Science Institute, Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang,
110122, Liaoning, China
3
Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
Correspondence: Jing Kong, PhD, Department of General Surgery, Shengjing Hospital of China Medical University, Sanhao St, Shenyang, 110004, Liaoning,
China. Email: jingkong@cmu.edu.cn.

Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide and is primarily associated with obesity, visceral adiposity, and unhealthy
perivascular adipose tissue (PVAT). The inflammatory polarization of immune cells residing in adipose tissue and abnormal levels of adipose-
related cytokines are crucial factors contributing to the pathogenesis of metabolic disorders. We reviewed the most relevant papers in the
English literature regarding PVAT and obesity-related inflammation and CVD, aiming to explore potential therapeutic targets for metabolic
alterations related to CV health. Such an understanding will help determine the pathogenetic relationship between obesity and vascular injury
in efforts to ameliorate obesity-related inflammatory responses. In the context of obesity, dysregulation of adipose tissue immune function,
which consists of immune cells and adipose-derived cytokines, plays a crucial role in vascular injury and endothelial dysfunction, especially
the PVAT. Metabolic changes between typical VAT and PVAT in obese conditions would be beneficial in improving the risk of obesity-induced
endothelial dysfunction and CVDs.
Key Words: adipose immunity, endothelial dysfunction, insulin resistance, perivascular adipose tissue
Abbreviations: AdipoR1, adiponectin receptor 1; Ang II, angiotensin II; BAT, brown adipose tissue; CVD, cardiovascular disease; EC, endothelial cell; EnNaC,
endothelial cell Na+ channel; ER, estrogen receptor; FFA, free fatty acid; HIF-1α, hypoxia-inducible factor-1α; IL-33, interleukin 33; IR, insulin resistance; MCP-1,
macrophage chemoattractant protein-1; MR, mineralocorticoid receptor; NK, natural killer; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase; PVAT,
perivascular adipose tissue; SAT, subcutaneous adipose tissue; Th17, T-helper 17 cells; TNF-α, tumor necrosis factor-α; UCP1, uncoupling protein 1; VAT,
visceral adipose tissue; WAT, white adipose tissue.

Introduction: Inflamed Perivascular Adipose
Tissue Is One of the Key Elements in the
Progression of Endothelial Injury Under
Obesity
Obesity is a major global health issue that must be addressed.
In recent decades, a dramatic increase in the prevalence of
obesity has been observed in all life stages. Evidence suggests
a strong association between the prevalence of obesity and the
growing incidence of metabolic disorders. Obesity, character­
ized by meta-inflammation, referred to localized inflamma­
tory responses within the adipose, considerably increases the
risk of metabolic disorders such as insulin resistance (IR),
endothelial dysfunction, and cardiovascular diseases (CVDs)
(1). Owing to excessive nutrition and inadequate physical ac­
tivity, obesity-related chronic inflammation affects people
worldwide, particularly in developed regions (2, 3). Under
conditions of obesity, the quantity and quality of adipocytes
changes. With an unhealthy expansion of adipose tissue, in­
sufficient angiogenesis results in an imbalance both in oxygen
supply and lipid metabolism (4). Existing evidence indicates
that cytokines derived from both adipocytes and immune cells
are associated with the immune function of adipose tissue. In
the obese state, the new formation of adipocytes and broad re­
cruitment of proinflammatory immune cells, especially M2
macrophages, give rise to a major source of proinflammatory
cytokines, contributing to adipose tissue meta-inflammation
(5). Furthermore, the accumulation of dysfunctional adipose
tissue leads to adipocyte apoptosis or death, metabolic stress,
and hypoxia, subsequently triggering a proinflammatory re­
sponse (6). The proinflammatory immune response within
adipose tissue induces high levels of inflammatory serum hall­
marks accompanied by endothelial dysfunction and vascular
stiffness, which are strongly related to CVDs (7). Given the
underlying relationship between obesity, low-grade inflam­
mation, and metabolic alterations, targeting imbalanced
metabolic pathways is a promising therapeutic approach to
avoid immune-metabolic alterations that contribute to the
progression of the metabolic complications of obesity (8).
Managing the number of immune cells residing in adipose
tissue (9, 10), inhibiting the pathogenic transition form of
proinflammatory subtypes (11-13), lowering the levels of in­
flammatory cytokines derived from the dysfunctional adipose
tissue (14, 15), and improving the systemic metabolic

Received: 4 February 2023. Editorial Decision: 4 June 2023. Corrected and Typeset: 19 June 2023
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2 Endocrinology, 2023, Vol. 164, No. 7
situation may be supportive for obesity therapy and CV
health, which is of great significance (16, 17).
In this review, we first analyze the current understanding of
the heterogeneity of adipose tissue and metabolic alterations
of adipose tissue in the context of obesity, emphasizing the
role of adipose tissue-derived immune cells and cytokines in
inducing obesity-associated inflammatory responses. Second,
we highlight the importance of inflamed perivascular adipose
tissue (PVAT) in the progression of obesity-induced endothe­
lial dysfunction. Finally, we focus on the correlations between
abnormal levels of proinflammatory biomarkers and metabol­
ic alterations, including IR, endothelial dysfunction, and CV
health. Such an understanding will help determine the patho­
genetic relationship between obesity and CVD in efforts to
ameliorate obesity-related inflammation and identify poten­
tial therapeutic approaches that target specific immune-
metabolic dysregulation during obesity. Our paper aims to
systematically highlight the association of the inflammatory
phenotype of typical VAT and PVAT with a wide range of
metabolic alterations, especially hyperinsulinemia and IR,
and the increased risk of CVD in the presence of obesity.
White Adipose Tissue: A Crucial Regulator in
the Progression of Obesity-mediated
Inflammation
Histologically, there are 2 major subsets of adipose tissue:
white adipose tissue (WAT) and brown adipose tissue (BAT)
(Fig. 1). Based on the existing evidence, WAT plays an import­
ant role in energy homeostasis and endocrine homeostasis. It
is highly responsive to regulators such as hormones and cyto­
kines to store excessive energy as neutral lipids, release free
fatty acids (FFAs), and glycerol during nutrient deprivation.
In addition to energy homeostasis, WAT is considered a func­
tional endocrine or immune organ via cytokines or adipokines
derived from adipocytes and resident immune cells, such as
leptin and adiponectin (18, 19). In addition, owing to the dis­
tribution of WAT, we distinguished between subcutaneous
adipose tissue (SAT) found under the skin and visceral adipose
tissue (VAT) located in the abdominal area. Approximately
80% of the WAT is stored in subcutaneous regions located
in the gluteal, femoral, and abdominal regions in lean, healthy
individuals (20). In addition, the distribution of SAT follows
sex-dependent trajectories; healthy women tend to accumu­
late adipose in the lower part of the body, such as gluteofe­
moral SAT, and men in the abdominal SAT (21). VAT,
accounting for approximately 20% of the total adipose tissue,
surrounds internal organs and includes perirenal, retroperi­
toneal fat, and omental or mesenteric depots around the intes­
tines, which have essential roles in the metabolic
microenvironment of visceral organs (22, 23). Unhealthy ex­
pansion of visceral adipocytes may contribute to the impair­
ment of corresponding organs, which is also termed
adiposopathy, which includes cardiomyopathy, nephropathy,
and enteropathy (24).
Based on integrated single-cell and spatial transcriptomic
maps of human WAT, Massier et al (25) reported 4 major
cell classes, including adipocytes, fibroblasts, and adipogenic
progenitors, vascular, and immune cells. Adipocytes, the dom­
inant cell type in WAT, account for approximately 80% to
90% of the volume of the tissue and only a third of the cellular
composition. The rest of the adipose tissue—nonadipocyte
content, also known as a stromal vascular fraction, including
preadipocytes, fibroblasts, endothelial cells (ECs), adipose
tissue-derived stem cells, and adipose tissue-resident immune
cells—is highly involved in maintaining adipose tissue
homeostasis (26). Preadipocytes are crucial for regulating
adipocyte differentiation, such as WAT expansion and fat
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browning (27). Fibroblasts and ECs provide newly formed
capillaries and a vasculature microenvironment (28).
Adipose tissue–derived stem cells are ideal stem cell popula­
tions that have the potential to differentiate into various phe­
notypes regulated by bioactive molecules, which lay the
foundation for preventing de novo lipogenesis or obesity
(29). Immune cells in adipose tissue include natural killer
(NK) cells, NKT cells, monocytes, macrophages, dendritic
cells, mast cells, T cells, B cells, and plasma B cells. The great
abundance and variety of immune cells resident in the adi­
pose provides the possibility of the fat participating in im­
mune function and inflammatory responses. Existing
evidence has already shown that crosstalk mediated by adi­
pokines or cytokines between immune cells and adipocytes
plays an indispensable role in exerting immune functions
and regulating metabolic processes (25).
Brown Adipose Tissue: An Important
Regulator in Anti-Inflammatory Responses and
the Pathogenesis of Cardiovascular Risks
Adipose tissue is a dynamic organ characterized by the transi­
tion from WAT to BAT via the upregulation of peroxisome
proliferators-activated receptors (PPARα/γ), peroxisome
proliferators-activated receptor γ coactivator 1α (PGC-1α),
and PR domain-containing 16 (Prdm16), while the phosphor­
ylation of PPARγ plays an indispensable role in the transition
from BAT to WAT (30). BAT is a critical endocrine organ,
which is responsible for nonshivering thermogenesis and en­
ergy consumption, especially in infants or during cold expos­
ure, and activation of the sympathetic nervous system.
Current evidence has paid additional attention to its promis­
ing therapies for anti-inflammatory responses induced by
WAT under obese conditions (31). To put it simply, BAT
plays an influential role in enhancing metabolic levels and cor­
recting metabolic disorders and further exerts beneficial ef­
fects on obesity-related inflammation. Previous studies have
proposed potential therapeutic strategies for increasing the
proportion of BAT in the prevention of obesity and related
metabolic diseases. Gunawardana (32) also revealed the pos­
sibility for correcting type 1 diabetes via embryonic BAT
transplants. More important, Becher et al (33) have reported
that BAT was independently correlated with lower odds of
obesity-related metabolic disorders and cardiometabolic
risks. The protective role of BAT on CV health is of great im­
portance in individuals with overweight or obesity. However,
several recent studies have presented conflicting opinions that
BAT activation may be detrimental to the CV system (34).
Induction of BAT activation is associated with a significant in­
crease in heart rate to meet the need to maintain a balance be­
tween increased energy expenditure and elevated oxygen
demand levels. A chronic BAT activation via β-adrenergic sig­
naling pathway or thyroid hormone replacement is found to
be related to serious CV side effects, such as stroke or myocar­
dial infarction (35, 36). Additionally, Blondin et al (37) found
that β3-adrenergic receptor (β3-AR), which used to be
Endocrinology, 2023, Vol. 164, No. 7
Figure 1. Biological characteristics and function of different adipose tissue depots. Comparison of white adipose tissue, brown adipose tissue, and
perivascular adipose tissue with respect to their localization, morphology, and biological function in human-specific depots. Principal metabolic
alterations that occur in the context of obesity, together with adipose tissue remodeling, are highlighted.
thought to be responsible for the activation both of human
and rodent BAT, did not play such a critical function in human
beings, being displaced by β2-AR. We should note that most
of the mechanisms related to the activation of BAT are derived
from rodent studies; taking into account the notable differen­
ces between species, more clinical research is needed to
confirm the molecular theoretical basis of targeted BAT for
the treatment of obesity-related metabolic disorders.
Furthermore, given the conflicting conclusions on whether
BAT can be used as an intervention target to improve
obesity-related metabolic disorders, including CV risk factors,
BAT-targeted therapeutics should be carefully assessed to
avoid adverse effects.
Uncoupling protein 1 (UCP1) is a major regulator of brown
and beige adipocyte energy expenditure and metabolic
homeostasis (38). Cysteine-253 is a regulatory site on UCP1
that elevates protein activity on covalent modification. Lack
of C253 results in adipose tissue redox stress, which drives
substantial immune cell infiltration and systemic inflamma­
tory pathology in adipose tissues and liver of male, but not fe­
male, mice. Elevation of systemic estrogen reverses this
male-specific pathology (39). A decrease in proteins associated
with antigen processing and presentation, phagocytosis, and
B-cell signaling was observed in BAT from mice models fol­
lowing β-estradiol supplementation, due to estrogen’s roles
in suppressing inflammatory signaling in macrophages.(39)
Furthermore, the intact estrogen signal pathway plays a role
in increasing the resilience to nutritional/metabolic stress
and prevents adipose dysfunction via the regulation of key
genes involved in antioxidant processes. Estrogen receptors
(ERs), including ERα, ERβ, and GPR30, are found on the sur­
face of immune cells and can, thus, modulate the immune re­
sponse. 17-β Estradiol inhibits proinflammatory T-helper 17
cells (Th17) and M1 macrophage cell differentiation and en­
hances regulatory T cells and M2 macrophage expansion
(40). Estrogen expressed in adipocytes has been shown to epi­
genetically promote beiging in mice by promoting demethyla­
tion of the Adrb3 and Dio2 promoters, leading to increased
Ucp1 expression (41).
3
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Abnormal Immune Function in Unhealthy
Adipose Tissue Leads to Endothelial
Dysfunction: Focus on Typical Visceral Adipose
Tissue and Perivascular Adipose Tissue
In obesity, WAT expands unhealthily, leading to increased
oxygen consumption. Existing evidence indicates that ele­
vated expression of hypoxia-inducible factor-1α (HIF-1α) in
adipocytes mediated by hypoxia is a key trigger of
obesity-related inflammation. Furthermore, intracellular
proinflammatory signals, including c-Jun N-terminal kinase
(JNK) and nuclear factor κB are also activated in response
to excessive neutral lipids accumulated in adipocytes (42,
43). In addition, imbalanced cytokines or adipokines derived
from failed crosstalk between adipocytes and immune cells re­
sult in an initial inflammatory response within adipose tissue
(44). Here, we focused on the primary advances in the latest
data on the innate immune cells residing in and recruited to
adipose tissue, especially PVAT, during obesity (Fig. 2).
Notably, emerging evidence on innate immune function in
obese adipose tissue has shown that cytokine profiles secreted
by different subsets of immune cells have both anti-
inflammatory and proinflammatory effects on adipose tissue
in individuals with obesity. However, the mechanisms of
mediators or effectors upstream and downstream of proin­
flammatory phenotypes activation, proliferation, and polar­
ization in obese adipose tissue are still not fully understood.
That is, conflicting experimental data are still being observed
as predictive opinions are being proposed. Targeting these im­
mune cells and regulatory cytokines is expected to be a poten­
tial strategy for constraining obesity-associated adipose tissue
inflammation and systemic metabolic alterations.
In contrast to other typical fat depots, PVAT is character­
ized by dynamic and flexible functional properties between
white and brown adipocytes. Adipocytes in PVAT exhibit
more WAT histological properties while being less differenti­
ated and having less lipid storage capacity and advanced po­
tential to release cytokines or nutrient factors as compared
to typical WAT (45). Unhealthy PVAT is regarded as a key
4 Endocrinology, 2023, Vol. 164, No. 7

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Figure 2. Immune cells in typical visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT) during childhood obesity. During obesity,
unhealthy adipocytes experience increased quantity and quality. Crown-like structures surrounding dead or apoptotic adipocytes consist of Trem2+/
CD9+ macrophages and adipose tissue dendritic cells, which are the hallmarks of obese adipose tissue. Immune cells infiltrated in adipose tissue
contribute to oxidative stress activation and proinflammatory cytokines secretion, subsequently leading to systemic inflammation and other metabolic
alterations. In addition to the understanding of typical VAT, where the dominant role of infiltrating proinflammatory immune cells has received the most
attention, key regulatory models of accumulation immune cells contributing to vascular remodeling or stiffness via an impaired vasodilation state. In
contrast to other typical fat depots, PVAT is characterized by a significant accumulation both of PVAT M1 and PVAT M2 macrophages that have been
observed during metabolic-induced vascular diseases, which participates in proinflammatory responses and profibrotic responses separately.
Excessive B cells and immunoglobulin deposits lead to the formation of atherosclerotic plaques. Current understanding proposes that PVAT not only
interacts with typical VAT via endocrine proinflammatory signals, but also functions as a source of cytokines and chemokines. Taken together, the
dysfunction of immune cell-mediated adipose tissue remodeling plays an integral role in the development of obesity-related cardiovascular injury. CD,
cluster of differentiation; IFN-γ, interferon-γ; IL-1β, interleukin-1β; MAIT cell, mucosal-associated invariant T cell; NCR1, NK-cell–activating receptor; NK
cell, natural killer cell; Th1, major T helper 1; TNF-α, tumor necrosis factor-α; Trem2; triggering receptor expressed on myeloid cells-2.
Endocrinology, 2023, Vol. 164, No. 7
element involved in the microenvironment of the vasculature
system and plays an indispensable role in vascular pathologies
(7). While the previous view considered PVAT to provide sim­
ple mechanistic support and protection of vascular structures,
current knowledge has clarified the role of PVAT in regulating
the metabolic phenotype and physiological function of the
endothelium (46). Data have shown that both the quantity
and quality of PVAT change during the pathogenesis of
CVDs, characterized by altered cellular composition and
proinflammatory phenotypes. In obesity, PVAT dysfunction
depends on insufficient angiogenesis, oxidative stress, and in­
flammatory characteristics (47).
In the context of obesity, along with low-grade inflamma­
tion, a large number of immune cells infiltrate the blood ves­
sels. Stimulated by chemotaxis, immune cells are recruited
to and further accumulate in the PVAT at high frequency, as
well as in the vessel walls, which are critical in the pathogen­
esis of atherosclerosis and vascular disease during obesity
(47). Numerous differences in the innate and adaptive im­
munological properties of PVAT inflammation in vascular
pathologies, characterized by distinct cellular interactions be­
tween immune cells and the endothelium, have been found
when compared with classic meta-inflammation within the
VAT in the context of obesity (48). In addition to understand­
ing typical VAT, for which the dominant role of infiltrating
proinflammatory immune cells has received the most atten­
tion, key regulatory models of immune cell accumulation con­
tribute to hypertensive vascular remodeling via a profibrotic
phenotype. In contrast to the M2 polarization of adipose
tissue macrophages, which is responsible for a potent anti-
inflammatory effect, with a decreased frequency during obes­
ity, significant accumulation both of PVAT M1 and PVAT M2
macrophages has been observed during metabolic-induced
vascular diseases, which participate in proinflammatory re­
sponses and profibrotic responses, respectively (49). Data
also illustrate that increased B-cell activation in the PVAT dur­
ing obesity is involved in atherosclerotic pathogenesis, pos­
sibly related to aortic antibody deposition and B-cell
infiltration within atherosclerotic plaques (50). Chan et al
(50) also found that B-cell depletion prevents angiotensin II
(Ang II)-induced hypertension. In addition, perivascular eosi­
nophils play a vital role in mediating the effects of PVAT on
vascular health (51). Eosinophils are strongly involved in ad­
renergic signaling, nitric oxide (NO)-related vasodilation, and
adiponectin-dependent–positive mechanisms within PVAT
(52). Eosinophil dysfunction has been observed during obesity
or high-fat diet feeding, probably contributing to hyperten­
sion (52). According to animal model data, manipulating
the frequency of vascular eosinophils via interleukin 33
(IL-33) during obesity may be a valid target for obesity-related
vascular dysfunction and CV complications (53).
Furthermore, the obese state increases the amount of min­
eralocorticoid receptors (MRs) and circulating aldosterone,
which subsequently induces a chronic activation of Ang II
type 1 receptors and a suppression of epithelial nitric oxide
synthase (eNOS) activity, thus related to the decrease in NO
concentration and bioavailability (47, 54). In addition, ele­
vated levels of aldosterone significantly upregulate nicotina­
mide adenine dinucleotide phosphate oxidase (NAPDH
oxidase) components in various cell types (55). In terms of
the adipose tissue, an increase has been observed in the expres­
sion of proinflammatory cytokines such as IL-6 and tumor
necrosis factor-α (TNF-α), and the amplification of
5
inflammatory effects of the aldosterone appear to be related
to the induction of osteopontin release in proinflammatory
macrophages and T cells, while the UCP-1 transcription and
thermogenic activity decrease in BAT (56, 57). It is important
to note that, in the case of cardiovascular health, the activa­
tion of the aldosterone system induces an increase in oxidative
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stress and leads to adverse effects (57). Endothelial MR over­
activation under the condition of obesity leads to the overex­
pression of the intracellular adhesion molecule 1 (ICAM-1) in
a sex-specific manner, thereby enabling leukocyte adhesion to
coronary artery ECs (58).
As mentioned earlier, both the endocrine effect of classical
WAT and paracrine factors secreted from inflammatory cells
infiltrating the PVAT contribute to endothelial dysfunction,
which is characterized by decreased production or affected
sensitivity to vasoprotective regulators. In addition, excessive
concentrations of FAAs have been well accepted for their
effects on vascular IR through serine/threonine phosphoryl­
ation of insulin receptor substrates. These interfere with the
downstream activation of the phosphatidylinositol 3-kinase
(PI3K) signaling pathway, subsequently leading to the im­
pairment of insulin-related vasodilation (48). Consistent
with the prevailing view, studies have provided insight into
the direct action of FAAs on the eNOS enzyme, resulting in
impaired vasodilation (59).
In summary, available experimental results suggest that
PVAT plays an indispensable role in the development of endo­
thelial dysfunction. Furthermore, the current understanding
proposes that PVAT not only interacts with typical VAT
through endocrine proinflammatory signals but also functions
as a source of cytokines and chemokines. Given the limited
mechanistic studies on obesity-induced PVAT inflammation,
further studies should be performed to investigate the precise
function and underlying regulatory processes of inflamed
PVAT, which may help identify therapeutic targets for
obesity-related CV injury.
Metabolic Alterations Related to Adipose
Tissue Immune Dysfunction Play a Vital Role in
the Pathogenesis of Cardiovascular Diseases
Inflammatory Factors
Increasing observational evidence has focused on alterations
in circulating inflammatory factors in response to obesity
(60). Previous cross-sectional studies and longitudinal ana­
lyses of individuals with obesity showed that weight gain
was accompanied by increased levels of macrophage chemo­
attractant protein-1 (MCP-1), IL-6, and TNF-α, which are
largely related to vascular IR and endothelial dysfunction, es­
pecially proinflammatory factors derived from perivascular
adipocytes (Table 1) (61).
MCP-1 initiates various monocyte-mediated proinflamma­
tory signals and monocyte chemoattractant activities during
obesity. It has been established that ECs are well characterized
in response to MCP-1 stimulation by binding with CC chemo­
kine receptor 2, subsequently facilitating the formation of
foam cells and vulnerability to thromboembolism (62).
Importantly, reducing circulating MCP-1 levels has been pro­
posed as a promising therapeutic approach to ameliorate ath­
erosclerotic and thromboembolic risks (63). TNF-α is a potent
proinflammatory cytokine released by expansive adipocytes,
infiltrated macrophages, and lymphocytes that plays a vital
6 Endocrinology, 2023, Vol. 164, No. 7
Table 1. Changes in circulating inflammatory factors and adipokines during obesity and their potential role in endothelial dysfunction
Marker Change Biological process
Serum ↑ Monocyte chemoattractant activities
MCP-1
Serum IL-6 ↑ Pleiotropic but main
proinflammatory effects
Serum ↑ Proinflammatory effects, induce
TNF-α synthesis of acute-phase protein
Leptin ↑ Appetite regulation,
proinflammatory effects
Adiponectin ↓ Anti-inflammatory effects, insulin
sensitization
Abbreviations: AdipoR1, adiponectin receptor 1; CCR2, C-C motif chemokine receptor 2; eNOS, epithelial nitric oxide synthase; IL-6, interleukin-6; IRS-1,
insulin receptor substrate 1; MCP-1, macrophage chemoattractant protein-1; NO, nitric oxide; TNF-α, tumor necrosis factor-α.
role in mediating systemic inflammation, leading to the syn­
thesis and secretion of acute-phase proteins, such as high-
sensitivity C-reactive protein and fibrinogen. In addition,
TNF-α is responsible for activating obesity-induced oxidative
stress, leading to the inhibition of insulin signaling (63).
Schinzari et al (67) indicated that administering the monoclo­
nal antibody infliximab to neutralize TNF-α significantly im­
proved vascular IR. Elevated concentrations of circulating
and perivascular TNF-α in response to obesity-related inflam­
mation and IR interfere with insulin receptor substrate-1 and
Akt phosphorylation (68). Moreover, TNF-α has been widely
acknowledged for its ability to regulate the mitogen-activated
protein kinase (MAPK) pathway, directly impairing
endothelium-dependent vasodilation and vascular insulin sen­
sitivity (69). Lee et al (64) further suggested that TNF-α could
be a mediator of IL-6, functioning as a contributor to the
pathogenesis of endothelial dysfunction of coronary microcir­
culation in animal models of type 2 diabetes. Studies on IL-6
signaling in the context of obesity and obesity-related endo­
thelial dysfunction have initially focused on experimental ob­
servations (65, 66). Furthermore, IL-6 is largely associated
with a high risk of atherosclerosis via the upregulation of
the Ang II and renin-angiotensin system (80). Recent studies
have reported that IL-6 directly impairs coronary arteriolar
endothelium-dependent vasodilation in mice with type 2 dia­
betes via both overactivation of oxidative stress and inhibition
of eNOS enzyme phosphorylation, leading to attenuated
NO-signaling pathways within the endothelium (64).
Moreover, current evidence emphasizes the possible role of
the interactive relationship between TNF-α and IL-6 in vari­
ous vascular inflammation and endothelial dysfunction stages.
Two hypotheses for the interaction between TNF-α and IL-6
have been proposed: IL-6 expression could be regulated by
TNF-α stimulation, or IL-6 could be an essential upregulator
of TNF-α, indicating a strong relationship between IL-6 and
TNF-α that contributes to endothelial dysfunction (64).
More research is needed to elucidate the detailed mechanisms
of reciprocal inhibitory regulation at the molecular level. The
novel findings of the interactive possibility acting between
IL-6 and TNF-α as an inflamed regulatory site offer a potential
Potential role in endothelial dysfunction Reference
Increased circulating MCP-1 levels with obesity facilitate the (62, 63)
formation of foam cells and vulnerability to thromboembolism via
CCR2
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IL-6 depletion inverses the impairment of endothelial function. (64-66)
Increased circulating IL-6 levels inhibit eNOS phosphorylation and
reduce NO bioavailability, further impairing vasodilation
Increased circulating TNF-α levels interfere with IRS-1 and Akt (67-69)
phosphorylation, associated with vascular insulin resistance.
Interaction between TNF-α and IL-6 aggravates vascular
inflammation and vascular stiffness
Elevated leptin serum levels initiate systemic inflammation via (70, 71-
monocyte/macrophage chemotaxis. Leptin potentially functions as 73)
a protective element in cardiovascular tissues
According to animal models, adiponectin is highly involved in (74-79)
vasodilation and revascularization through T-cadherin and
transmembrane receptors AdipoR1 and AdipoR2
target for preventing or treating impaired endothelium-
dependent vasodilation in microcirculation induced by
obesity-related inflammation.
Abnormal Levels of Adipokines
Adipokines, also known as adipose-derived cytokines, are se­
creted by adipocytes or produced by immune and mesenchy­
mal cells in WAT. Adipokines are considered one of the
hallmarks of obesity and play prominent roles in the patho­
genesis of systemic low-grade inflammation and subsequent
metabolic alterations (70, 81). Here, we focus on major ad­
vances in the latest studies on leptin and adiponectin, the first
pair of adipokines to be extracted and identified, that act as
antagonistic mediators in regulating inflammatory responses
associated with adipose tissue activity (see Table 1). An imbal­
ance in circulating leptin and adiponectin levels has been ob­
served during obesity and is a typical biomarker of
metabolic alterations in individuals with obesity (82).
Leptin is a proinflammatory cytokine released from WAT.
Previous data have shown that in children and adults who
are overweight, leptin levels increase both in adipose tissue
and circulation, whereas the opposite is true in the case of
weight loss (71). In addition, based on data from clinical trials,
high baseline leptin levels are associated with a slight reduc­
tion in adipose mass in individuals with obesity, which is
closely related to IR (72). Furthermore, in obesity, leptin func­
tions as a potent monocyte/macrophage chemoattractant that
induces the increased release of proinflammatory cytokines
such as TNF-α, IL-6, and MCP-1 by monocytes and
macrophages (73). However, existing evidence demonstrates
that leptin activates the protective JAK-STAT and
AMP-activated protein kinase (AMPK) signaling pathways
in cardiovascular tissues (70). Recent studies have focused
on the effects of leptin deprivation on CV injuries. Hence, giv­
en the leptin-related direct supportive effects and collateral
adverse effects via obesity-related systemic inflammation in
CV tissues, further studies are required to reveal the relation­
ship between circulating leptin levels and CV tissue metabol­
ism in the context of obesity. Tissue-targeted therapeutic
Endocrinology, 2023, Vol. 164, No. 7
technologies may help address these contradictory metabolic
properties.
In contrast, adiponectin is largely associated with anti-
inflammatory responses, with reduced levels observed in
individuals with obesity. As circulating adiponectin levels
decrease in the obese state, recent data further suggest that
adiponectin administration alleviates diabetic cardiomyocyte
apoptosis, exerting a potent protective effect (74).
Adiponectin elicits multiple downstream AMPK and PI3K sig­
naling events, primarily through the transmembrane receptors
adiponectin receptor 1 (AdipoR1) and AdipoR2 (75, 76).
Studies have proposed that adiponectin may help prevent sys­
tolic and diastolic dysfunction from myocardial infarction and
ameliorate atherosclerotic plaque formation and cardiac
hypertrophy in the pathogenesis of hypertension (77). In add­
ition to AdipoR1 and AdipoR2, T-cadherin has been observed
in the vascular system and is responsible for the cardioprotec­
tive role of high-molecular-weight adiponectin (78). Previous
studies have indicated that following T-cadherin ablation, adi­
ponectin fails to exert its short-term and long-term cardiopro­
tective effects during hypertension, myocardial hypertrophy,
and myocardial ischemia-reperfusion injury (79).
In summary, increasing circulating adiponectin levels is a
promising therapeutic strategy for alleviating obesity, related
systemic low-grade inflammation, and subsequent obesity-
induced CVDs. However, owing to the limited sensitivity of
tissue-targeting techniques and potentially severe side effects,
drugs that are beneficial for adiponectin synthesis may not be
optimally suited for clinical treatment, leading to deviations in
experimental design and clinical management.
Hyperinsulinemia and Insulin Resistance
IR is the loss of the role of insulin in maintaining glucose and
lipid homeostasis. In the initial stage of IR, cells become less re­
sponsive to insulin and fail to efficiently use glucose for energy
metabolism, which in turn leads to increased blood glucose lev­
els. Pancreatic β cells compensate by producing more insulin to
moderate elevated blood glucose levels, resulting in hyperinsu­
linemia. As insulin sensitivity worsens, pancreatic β cells
respond to impaired glucose tolerance by continuously produ­
cing more insulin. Owing to constant overload, the ability of
pancreatic β cells to generate insulin is diminished, further lead­
ing to an increase in circulating glucose and, finally, IR (83).
It is generally accepted that obesity and long-term low-
density systemic inflammation are crucial factors in inducing
the affected insulin-signaling pathway, impaired glucose
homeostasis, and systemic IR. Existing data have shown
that unhealthy enlarged adipose tissue is a key source of in­
flammatory factors in the context of obesity (84). Several po­
tential mechanisms underlying the relationship between
obesity-related inflammation and IR have been proposed.
First, with the unhealthy expansion of adipose tissue, expan­
sive adipocytes release excess FAAs, reactive oxygen species,
and proinflammatory cytokines in response to an imbalance
in oxygen supply, which plays a key role in inducing the initial
stage of IR (85). Second, these inflammatory mediators not
only trigger meta-inflammation within adipose tissues, as
mentioned before, but also pass through the bloodstream
into other nonadipose organs or tissues, possibly leading to
lipotoxicity (86). In addition, toxic lipids such as ceramides
accumulate in affected tissues, including the liver, heart
muscle, and pancreas, further wearing out the cells (87).
7
Subsequently, dysfunction of organelles related to metabolic
balance, such as mitochondria, endoplasmic reticulum, and
lysosomes, has been observed in the progression of lipotoxic­
ity, with the regeneration of inflammatory mediators within
the affected tissues (88). Thereafter, several immune cells res­
iding in adipose tissue or other organs, both adaptive and in­
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nate immune cells, were found to be closely associated with
low-grade chronic inflammation and IR in obesity (89, 90).
In summary, an increasing number of studies have highlighted
the crucial role of adipose tissue inflammation and proinflam­
matory cytokines derived from obese adipose tissue as
contributors to hyperinsulinemia or IR or both (Fig. 3).
Obesity-related long-term low-grade systemic inflammation
impairs glucose tolerance and insulin sensitivity, which is
one of the initial triggers for individuals with obesity being
vulnerable to various chronic diseases or metabolic
alterations.
Current observational research has shown a higher CV risk
under obese conditions, or hyperinsulinemia with or without
insulin resistance, or both states, which are highly related to
endothelial injuries and heart failure with preserved ejection
fraction (91-93). A previous cohort study of children with
obesity reported that compared to a group of obese sedentary
children, obese children performing physical exercise exhib­
ited improvement in CV risk, estimated by blood pressure,
heart rate, and maximum volume of oxygen, and lower levels
of inflammatory biomarkers, such as white blood cells and
C-reactive protein (94). Similarly, Karason et al (95) also re­
ported that individuals with bariatric surgery showed a re­
duced obesity-related plasma protein profile, associated with
an increased risk of heart failure, compared to controls.
Trouwborst et al (96) revealed in a randomized controlled tri­
al the positive effects of improved muscle IR and liver IR on
cardiometabolic health through dietary modification.
Compared with healthy controls with normal serum insulin
levels, an experimental group with hyperinsulinemia was
more susceptible to coronary artery disease. More important,
both amelioration of insulin sensitivity and weight loss re­
versed the increase in CVD risk factors relative to baseline
(97). Studies have identified related alleles associated with ele­
vated fasting insulin levels or the preclinical stage of IR, which
increases the risk of hypertension and CVDs (98). Improving
insulin sensitivity via ketogenic diets reverses the genesis of
atherogenic dyslipidemia and systemic inflammation in
CVDs (99). In the vasculature, hyperinsulinemia and/or IR
play key roles in the development of atherosclerosis in re­
sponse to obesity and systemic low-grade inflammation (93).
According to current data from animal models, insulin is re­
sponsible for activating the endothelial cell Na+ channel
(EnNaC), which is highly associated with the stiffening and re­
modeling of the vasculature in a concentration-dependent
manner (100, 101). During feeding a diet rich in refined carbo­
hydrates and saturated fat, mice with EnNaC deletion showed
a significant improvement in vascular stiffness compared with
that in wild-type controls, while elevated serum insulin levels
were observed (100). Upregulation of EnNaC via overactivity
of insulin stimulation leads to reductions in bioavailable NO
through the activation of serum and glucocorticoid-regulated
kinase 1 signaling (100). Concisely, in the progression of low­
ering insulin sensitivity, the effects of insulin-mediated NO
production on vasodilation and further glucose utilization
are impaired, which underlies the pathogenesis of vascular
fibrosis, stiffness, and associated CVDs. In addition,
8 Endocrinology, 2023, Vol. 164, No. 7

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Figure 3. Proinflammatory components of perivascular adipose tissue (PVAT) and metabolic alterations during obesity in the regulation of vascular
homeostasis and vascular dysfunction via hyperinsulinemia or/and insulin resistance. In states of normal body weight (left), healthy PVAT plays a vital
role in maintaining systolic and diastolic activity of blood vessels. Both normal levels of vasodilators, such as adiponectin, and favorable insulin
sensitivity contribute to glucose homeostasis and vascular integrity during the anticontractile process. In the context of obesity (right), inflamed PVAT
and typical visceral adipose tissue (VAT) are highly involved in vascular dysfunction and endothelial stiffness. Increasing levels of free fatty acids,
reduced blood flow, localized hypoxia, apoptosis or necrosis of adipocytes, accumulation of immune cells, and massive production of proinflammatory
cytokines or vasoconstrictors impair insulin sensitivity and subsequently hyperinsulinemia and insulin resistance, resulting in vasoconstriction. In
addition, impaired endothelium shows a decrease in both eNOS activity and NO production, leading to dysfunction of endothelial-dependent
vasodilation. eNOS, epithelial nitric oxide synthase; FFA, free fatty acid; IL-6, interleukin-6; NO, nitric oxide; TNF-α, tumor necrosis factor-α; VAT, visceral
adipose tissue.

renin-angiotensin-aldosterone, and brain melanocortin sys­

tems appear to interact synergistically with direct atherogenic
effects in a state of hyperinsulinemia and/or IR, resulting in
CV system injury (93). In summary, insulin-related signaling
has the potential to provide new therapeutic targets for life­
style interventions and drug development at the intersection
of obesity, systemic inflammation, and CVD pathogenesis.

Outstanding Questions
The prevalence of obesity is particularly high worldwide. In
recent decades, a dramatic increase in the prevalence of obes­
ity has been observed in all life stages. At present, evidence
demonstrates a strong association between the prevalence of
obesity and the growing incidence of unhealthy CV events.
Based on the analysis of the underlying mechanisms or hy­
pothesis, some potential therapies can be attended or maybe
further improved (Fig. 4).

Intervening Early-Life Events Related to Adipose

Figure 4. Potential therapies for the prevention of obesity-related,
unhealthy cardiovascular events. Specific treatment strategies are
summarized in detail in the text.
hyperinsulinemia may lead to sympathetic overactivity and
renal sodium retention, further increasing blood pressure.
Excessive upregulation of the sympathetic nervous,
Immunity and Obesity-related Cardiovascular
Events: The Initial Step of Targeted Therapies
A lack of understanding of the roles of early-life events or child­
hood activities that result in high risks for obesity by influencing
adipose tissue immune dysfunction under the pathological con­
dition of obesity is a crucial factor of the incidence of
obesity-related CVDs, which occur at younger average ages
(102, 103). The increased occurrence of obesity during infancy
Endocrinology, 2023, Vol. 164, No. 7 9

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Figure 5. Overview of inflamed adipose tissue and systemic metabolic alterations involved in endothelial dysfunction and cardiovascular injury. First, as
unhealthy adipose tissue expands, hypertrophic adipocytes release excess free fatty acids, reactive oxygen species, and proinflammatory cytokines in
response to an imbalanced oxygen supply. Immune cell infiltration in inflamed adipose tissue is strongly associated with obesity-associated systemic
low-grade inflammation. In addition, toxic lipids, such as ceramides, accumulate in affected tissues, including the liver, heart, muscle, and pancreas,
further wearing out the cells. Second, against enormous nutrients during obesity, pancreatic β cells compensate by producing extra insulin to moderate
the elevated blood glucose levels, which is characterized by hyperinsulinemia. Owing to the constant overload of insulin and the progression of
lipotoxicity, the ability of pancreatic β cells to generate insulin is diminished, which further leads to a vicious cycle with the core of insulin resistance.
Finally, with the accumulation of proinflammatory factors, including vasoconstrictors, and impaired epithelial nitric oxide synthase (eNOS) activity of
endothelial cells, the diastolic process is destroyed, which eventually leads to vasoconstriction, paving the pathogenetic possibility for cardiovascular
disease.

or childhood results in a systemic inflammatory response that is
strongly associated with a range of metabolic alterations, in­
cluding unhealthy CV events during adolescence and even
into adulthood (104-106). Thus, early intervention taking
into account genetic predisposition, an obesogenic-nurturing
environment, and unhealthy lifestyles should receive attention
(105, 107). However, owing to the limitations of the relevant
techniques and the small number of samples from infants and
children, some interventions may not be fully processed, result­
ing in low sensitivity of data from some well-designed studies.
Further studies should shed light on potential regulators and
signaling pathways in childhood obesity and obesity-related
CV events. Simple interpretive language is necessary to facili­
tate the generalization of those optimal interventions.
Control of Inflamed Adipose Tissue in the Context of
Obesity via Regulating the Frequencies of Immune
Cells: The Advanced Step of Targeted Therapies
In the context of obesity, crown-like structures surrounding
dead or apoptotic adipocytes consist of Trem2+/CD9+ macro­
phages and adipose tissue dendritic cells, which are the hall­
marks of obese adipose tissue. Both typical VAT and PVAT
are responsible for obesity-related inflammation and subse­
quent inflammatory alterations within other organs (see
Fig. 2). In addition, inflamed PVAT may play a distinct role
in the progression of the pathology of endothelial injury and
vascular stiffness due to the specific location and morphology
of the fat depots, which is characterized by different frequen­
cies of infiltrated immune cells compared to typical VAT
(108). Currently, based on data from animal models, adoptive
transfer of anti-inflammatory immune cells to inflamed PVAT,
such as regulatory T cells, significantly improves endothelial
function and reduces blood pressure (109, 110). Moreover,
blocking interactions between proinflammatory immune cells
plays a vital role in ameliorating vascular dysfunction and
PVAT inflammation, including the crosstalk between macro­
phages, dendritic cells, NK cells, and T cells (108, 111).
However, given that mechanistic studies in inflamed perivas­
cular adipose tissue is still limited, more research should be
performed to investigate the precise relationship between ab­
normal adipose immunity during obesity and inflammatory
responses of cardiovascular system.
Restriction of Abnormal Circulating Inflammatory
Factors in the Context of Obesity: The Systemic Step
of Targeted Therapies
Alterations in circulating inflammatory factors or cytokines
are reported in previous cross-sectional studies and
10 Endocrinology, 2023, Vol. 164, No. 7

longitudinal analyses of individuals with obesity (see Table 1). Conclusion

Existing animal studies have suggested that TNF-α neutraliza­
In the context of obesity, dysregulation of adipose tissue im­
tion or blockade of TNF-α receptor can promote pathological
mune function, which consists of immune cells and adipose-
changes of myocardial damage, but clinical evidence is still
derived cytokines, plays a crucial role in vascular injury and
lacking. Additionally, leptin repletion possibly reverses
endothelial dysfunction, especially the PVAT (Fig. 5). An in-
ischemia-induced revascularization and the deleterious effects
depth understanding of the roles of adipose tissue immune

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of leptin deficiency. Nonetheless, further studies are required
dysfunction that triggers a series of metabolic alterations dur­
to reveal the relationship between circulating leptin levels
ing obesity, as well as the influence of these inflammatory re­
and CV tissue metabolism in the context of obesity, given
sponses on the pathogenesis of CVDs, will help to identify the
the leptin-related direct supportive effects and collateral ad­
underlying mechanisms involved in adipose tissue immune
verse effects via obesity-related systemic inflammation in CV
dysfunction and CVDs at the molecular level and in the devel­
tissues. Tissue-targeted therapeutic techniques may help ad­
opment of potential targeted therapy. Studies should further
dress these conflicting metabolic properties. Moreover, ac­
focus on the similarities and differences in metabolic changes
cording to data from animal models of adiponectin
between typical VAT and PVAT in obese conditions, which
insufficiency, adiponectin administration plays a critical role
would be beneficial in improving the risk of obesity-induced
in vasculoprotective and angiogenic properties. More basic
endothelial dysfunction and CVDs.
and clinical studies are still needed to identify whether the
beneficial effects of adiponectin repletion exert a direct effect
on cardiovasculature, given abnormal feeding behavior, un­ Search Strategy and Selection Criteria
healthy adipose tissue during obesity (112).
References for this review were identified through searches of
PubMed to identify relevant English-language papers pub­
Potential Aspects of Targeted Therapies: From a lished between January 1, 1980 and July 31, 2022. The search
Comprehensive Perspective term “perivascular adipose tissue” was used in combination
with the “AND” operator for the terms “obesity,” “cardio­
In this paper, we further highlight the potential role of the gut
vascular disease,” “endothelial dysfunction,” “childhood
microbiota and obesity-related metabolic disorders. The gut
obesity,” “obesity-related metabolic alterations,” “early life
microbiome, the largest bacterial colony in the human body,
events,” and “gut microbiota.” The final reference list was
appears to be strongly associated with metabolism (113,
generated based on originality and relevance to the broad
114). The regulatory axis between alterations in gut micro­
scope of this review, with a focus on the most recently pub­
biota and the development or function of adipose tissue may
lished papers.
be a key mediator that plays an essential role in ameliorating
obesity-related inflammation and circulatory risk factors
(115). We note that gut microbiota, under the influence of ex­ Funding
ternal perturbations or endogenous paradigms, could be con­
This work was supported by the Liaoning Science and
sidered as a factor bridging the gap between various lifestyle
Technology Plan Project (grant No. 2021JH2/10300118),
or genetic diversity and subsequent changes in metabolic traits
the Shenyang Science and Technology Innovation Talent
(116). Most CV risk factors, including aging, obesity, in­
Support Program for Youth and Midlife (grant No.
appropriate dietary patterns, and unhealthy lifestyles, have
RC200121), and The 345 Talent Project Program of China
been shown to induce gut dysbiosis, while certain alterations
Medical University Shengjing Hospital (grant No. 2019-40A).
in the gut microbiome further contribute to the pathogenesis
of endothelial injury via adipose tissue dysfunction, sympa­
thetic overactivation, and inflammatory responses in the cir­ Author Contributions
culatory system (117, 118). More important, specific
D.W., K.J., and L.Z. designed the overall study; D.W. and Y.S.
alterations in the gut microbiota under conditions of hyperlip­
collected information and prepared figures; D.W. and K.J.
idemia diets have been shown to result in the recruitment and
performed a systematic literature search and drafted the
activation of B2 cells in PVAT, followed by an increase in cir­
manuscript; and D.W., L.Z., Y.S., and K.J. revised the manu­
culating immunoglobulin G, promoting atherosclerosis (119,
script critically and approved its final version.
120). Studies to date have shown the significance of the com­
mensal microbes and obesity-induced circulatory risks, while
most of existing evidence remains at the phenomenological Disclosures
level (121). There is still a lack of mechanistic studies to ex­
The authors have nothing to disclose.
plore further, particularly in the light of the crosstalk with
PVAT, which is also crucial for estimating or ruling out previ­
ous observations and avoiding potential biases due to con­ Data Availability
founding. In addition, it remains to be further discussed
No new data were generated or analyzed in this research.
whether the study of WAT can be directly extended to
PVAT due to the tissue-specific nature of adipose tissue, and
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