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Adiponectin and Hypertension


Abstract and Figures

Adipose tissue secretes a variety of bioactive molecules, also known as adipocytokines or adipokines. Obesity, in particular, visceral fat accumulation, is implicated in the dysregulated secretion of adipocytokines, which can contribute to the development of metabolic syndrome and cardiovascular diseases. Adiponectin is an adipocytokine that is exclusively secreted from adipose tissue, but its plasma levels are reduced in obese subjects, especially those with visceral fat accumulation. Adiponectin has a variety of protective properties against obesity-linked complications, such as hypertension, metabolic dysfunction, atherosclerosis, and ischemic heart disease. Adiponectin exerts the beneficial effects on vascular disorders by directly affecting components of vascular tissue. This review will discuss clinical and experimental findings that examine the role of adiponectin in regulation of hypertension and vascular function. American Journal of Hypertension advance online publication 7 October 2010;. doi:10.1038/ajh.2010.216
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nature publishing group
Obesity, in particular, visceral fat accumulation, causes a
cluster of hypertension, type 2 diabetes, and dyslipidemia, also
referred to as metabolic syndrome. e accumulated disor-
ders induced by visceral fat accumulation lead to cardiovascu-
lar disease, which is one of the leading causes of mortality in
western countries. Adipose tissue produces and secretes many
bioactive molecules,1–5 which are known as adipocytokines
or adipokines.3,6 Dysregulated production of adipocytokines,
such as tumor necrosis factor-α (TNF-α), leptin, and plasmino-
gen activator inhibitor type 1, is associated with the pathogen-
esis of metabolic syndrome and cardiovascular diseases.1–5
Adiponectin is almost exclusively expressed in adipose
tissue7,8 and exists abundantly at the range 3–30 µg/ml in
plasma. Interestingly, plasma adiponectin levels are decreased
in obese patients, particularly those with excess visceral fat,
and its plasma levels are inversely correlated with visceral
adiposity.9,10 Low concentration of adiponectin, so-called
hypoadiponectinemia, is closely associated with obesity-
related diseases including hypertension, type 2 diabetes, and
cardiovascular disease.11–14 Numerous experimental studies
have shown that adiponectin displays a variety of protective
actions on obesity-induced pathological conditions, including
hypertension, insulin resistance, hepatic steatosis, atheroscle-
rosis, and ischemic heart disease.15–19 Furthermore, adiponec-
tin exerts antiatherogenic and anti-inammatory eects by its
ability to act on vascular component cells including endothe-
lial cells and macrophages.20–26 In this review, we will focus on
the key role of adiponectin in regulating vascular homeostasis.
A number of clinical studies have demonstrated the rela-
tionship of plasma adiponectin concentration with
hypertension.11,12,27,28 Adamczak et al. showed for the rst
time that plasma adiponectin levels are signicantly lower
in patients with essential hypertension compared with those
in body mass index-matched normotensive subjects.11 An
inverse correlation is observed between adiponectin con-
centration and mean systolic and diastolic blood pressure.
Similarly, adipo nectin levels are negatively associated with
blood pressure in patients with type 2 diabetes and metabolic
syndrome.29 In addition, Iwashima et al. have demonstrated
that a hypoadiponectinemia is a risk factor for hypertension
independent of insulin resistance and diabetes.12
Adiponectin has been reported to associate with the pro-
gression of hypertension. Chow et al. for the rst time demon-
strated an inverse relation between plasma adiponectin
concentration and the future development of hypertension by
prospective analysis of Chinese subjects for 5 years.30 In this
study, 70 normotensive, nondiabetic subjects, who developed
hypertension by the end point, were compared with 140 age-
and sex-matched subjects who were normotensive during the
observed periods. Hypoadiponectinemia at baseline is a strong
predictor of future hypertension even aer adjusting the con-
founding factors such as mean blood pressure, C-reactive
protein, body mass index, and waist circumference. Subjects
with hypoadiponectinemia show three times higher morbidity
of future hypertension than those with normal range of
adiponectin levels.
Analysis of mutations in human adiponectin gene provides
further information about the link between adiponectin and
hypertension. Among several single-nucleotide polymor-
phisms of adiponectin gene, single-nucleotide polymorphism
at position 164 (TC genotype of the I164T) has been associated
Adiponectin and Hypertension
Koji Ohashi1, Noriyuki Ouchi1 and Yuji Matsuzawa2
1Department of Molecular Cardiology, Nagoya University Graduate School
of Medicine, Nagoya, Japan; 2Sumitomo Hospital, Emeritus Osaka University,
Osaka, Japan. Correspondence: Noriyuki Ouchi (
Received 12 August 2010; first decision 3 September 2010; accepted
3 September 2010.
© 2011 American Journal of Hypertension, Ltd.
Adipose tissue secretes a variety of bioactive molecules, also known
as adipocytokines or adipokines. Obesity, in particular, visceral
fat accumulation, is implicated in the dysregulated secretion of
adipocytokines, which can contribute to the development of
metabolic syndrome and cardiovascular diseases. Adiponectin is
an adipocytokine that is exclusively secreted from adipose tissue,
but its plasma levels are reduced in obese subjects, especially
those with visceral fat accumulation. Adiponectin has a variety of
protective properties against obesity-linked complications, such as
hypertension, metabolic dysfunction, atherosclerosis, and ischemic
heart disease. Adiponectin exerts the beneficial effects on vascular
disorders by directly affecting components of vascular tissue. This
review will discuss clinical and experimental findings that examine
the role of adiponectin in regulation of hypertension and vascular
Keywords: adiponectin; blood pressure; endothelial cell; hypertension;
macrophage; metabolic syndrome
American Journal of Hypertension, advance online publication 7 October 2010;
Adiponectin and Hypertension
with hypoadiponectinemia and high blood pressure in Japanese
population.12 I164T mutation is also related to metabolic syn-
drome and coronary heart disease.31,32 Hypoadiponectinemia
caused by I164T mutation is due, at least in part, to disturbance
of secretion of adiponectin into plasma.33
An experimental study also supports the notion that adipo-
nectin modulates blood pressure. Adiponectin-knockout
mice show no phenotype of hypertension under unstressed
conditions. However, aer high-salt diet feeding, adiponectin-
knockout mice exhibit signicantly higher levels of systolic
blood pressure compared with wild-type (WT) mice inde-
pendent of insulin resistance.15 Adiponectin replenishment
by adenovirus system ameliorates the high-salt diet-induced
hypertension of adiponectin-knockout mice. Adenovirus-
mediated overexpression of adiponectin dramatically reduces
the systolic blood pressure in a genetic mouse model of
obesity and hypertension. Furthermore, in aldosterone infu-
sion model with uninephrectomy, adiponectin-knockout
mice develop higher systolic blood pressure compared with
WT mice.34 Aldosterone-infused adiponectin-knockout
mice also show severer le ventricular hypertrophy and pul-
monary congestion compared with control mice. Analysis
of diastolic heart function by echocardiogram revealed that
adiponectin-knockout mice have severe diastolic dysfunc-
tion following aldosterone infusion.34 us, adiponectin-
deciency contributes to the development of hypertension
under conditions of stress.
Collectively, hypoadiponectinemia induced by visceral fat
accumulation is highly associated with hypertension.
Endothelial dysfunction is an important feature predispos-
ing to vascular disease and is closely associated with obesity-
linked complications including hypertension and insulin
resistance.35 Numerous studies have shown that adiponectin
is benecial for endothelial function. Plasma adiponectin level
is closely correlated with the vasodilator response to reactive
hyperemia in hypertensive patients.36 Likewise, plasma adipo-
nectin level is positively associated with the forearm blood
ow response during reactive hyperemia in apparently healthy
men.37 Furthermore, hypoadiponectinemia has been reported
to associate with impaired endothelium-dependent vasodila-
tion of the brachial artery in diabetic patients.38 In support of
these clinical data, adiponectin-knockout mice display impair-
ment of endothelium-dependent vasodilation in response to
acetylcholine compared with control mice when fed an athero-
genic diet.36
Endothelial nitric oxide synthase (eNOS) and nitric oxide
(NO) are crucial regulators of vascular homeostasis, in parti-
cular, endothelial function.39,40 Accumulating evidence indi-
cates that adiponectin functions as an endogenous modulator
of endothelial-derived NO production. Adiponectin-knockout
mice have lower levels of eNOS transcripts in aorta and NO
metabolites in plasma as well as higher blood pressure com-
pared with WT mice aer high-salt diet feeding.15 Systemic
administration of adiponectin to high salt-fed adiponectin-
knockout mice lowers the elevated blood pressure and restores
the reduced eNOS transcripts in aorta. Of importance, inhi-
bition of NOS reverses the reduction of blood pressure
caused by adiponectin in adiponectin-knockout mice. us,
adiponectin-deciency participates in salt-sensitive hyperten-
sion through modulation of eNOS function.
Nishimura et al. have shown that adiponectin-knockout
mice develop exacerbated cerebral ischemia-reperfusion
injury with reduced eNOS activation in ischemic brain tissue
and decreased NO metabolites in plasma compared with WT
mice.41 Kondo et al. reported that caloric restriction promotes
revascularization in response to tissue ischemia through an
adiponectin-mediated activation of eNOS.42 In another article,
adiponectin-knockout mice exhibit reduced levels of endothe-
lial NO in the vessel walls.43 ese ndings strongly suggest
that the favorable actions of adiponectin on vascular response
are mediated, at least in part, by its ability to activate eNOS.
A number of in vitro experiments reveal the important role
of adiponectin in regulating eNOS activity and NO production.
Adiponectin stimulates phosphorylation of eNOS at Ser-1177
in human endothelial cells through its ability to activate AMP-
activated protein kinase signaling.20 Adiponectin also stimu-
lates NO production in vascular endothelial cells through
phosphorylation of eNOS22 (Figure 1). e stimulatory eects
Endothelial cell function
Figure 1 | Protective actions of adiponectin on endothelial cell function.
Adiponectin ameliorates endothelial cell function through two independent
regulatory mechanisms within endothelial cells. Adiponectin enhances
eNOS activity and subsequent NO production through Adipo R1/R2-AMPK
signaling. Adiponectin stimulates cyclooxygenase-2 (COX-2) expression
and prostaglandin I2 (PGI2) production through calreticulin (CRT)/CD91-
dependent Akt signaling pathway. AMPK, AMP-activated protein kinase;
eNOS, endothelial nitric oxide synthase; NO, nitric oxide.
Adiponectin and Hypertension
of adiponectin on eNOS activity and NO production are
shown to be mediated through adiponectin receptors, Adipo
R1/R2 and their intracellular adaptor molecule APPL1.44 In
addition, treatment of bovine endothelial cells with globular
fragment of adiponectin increases eNOS mRNA and protein
expressions, leading to increased production of NO.45 us,
these results suggest that hypoadiponectinemia can cause
decreased endothelium-derived NO production and subse-
quent endothelial dysfunction, ultimately contributing to the
development of hypertension.
In addition to the above-mentioned signaling pathway, adi-
ponectin promotes endothelial cell function through another
mechanism. Endothelial cyclooxygenese-2 (COX-2) and its
metabolites play an important role in control of vascular func-
tions such as vascular tone and endothelial function.46–49
A recent report with mouse genetic experiments shows that
adiponectin promotes revascularization in response to tissue
ischemia through COX-2-dependent mechanism.24 Deletion of
COX-2 in an endothelial specic manner results in suppression
of adiponectin-induced revascularization response in ischemic
muscle. In cultured endothelial cells, recombinant adiponectin
treatment signicantly increases COX-2 expression and pro-
motes endothelial cell function via activation of Akt-dependent
COX-2 signaling pathway. Importantly, adiponectin-mediated
endothelial cell protection via Akt-COX-2 regulatory axis is
largely dependent on the ability of adiponectin to associate with
a newly recognized adiponectin-binding protein, calreticulin/
its adaptor protein CD91 on the surface of endothelial cells
(Figure 1). Consistent with these ndings, adiponectin pro-
motes a clearance of apoptotic body by macrophages through
a calreticulin/CD91-dependent pathway.50 Furthermore, adi-
ponectin-knockout mice display reduced levels of prostaglan-
din I synthase mRNA in aorta and circulating prostaglandin
I2 metabolite following high salt feeding.15 Adiponectin sup-
plementation using adenovirus system restores the reduced
levels of prostaglandin I synthase transcript in aorta and pros-
taglandin I2 metabolite in plasma in high salt-fed adiponectin-
knockout mice. ese observations indicate that adiponectin
improves endothelial cell function, at least in part, through
COX-2-prostaglandin I2-dependent pathway (Figure 1).
Taken together, adiponectin protects against endothe-
lial dysfunction via at least two regulatory pathways involv-
ing AMP-activated protein kinase-eNOS signaling and
COX-2-prostaglandin I2 signaling within endothelial cells.
Future researches with mouse genetic models are needed to
dissect the receptor-mediated signaling pathways involved in
the vascular protection by adiponectin.
A number of epidemiological studies have indicated that
plasma adiponectin concentration is negatively correlated
with the inammatory markers C-reactive protein and the
proinammatory cytokine interleukin-6 in blood stream.51–54
ese observations are in agreement with the experimental
data showing the protective properties of adiponectin against
inammation. Adiponectin has been reported to aect the
function and phenotype of macrophages by multiple mecha-
nisms, thereby displaying various anti-inammatory actions.
Adiponectin attenuates agonist-stimulated production of a
proinammatory cytokine TNF-α in cultured macrophages,
which is accompanied by diminished nuclear factor-κB
activation.55,56 Because TNF-α acts as a key modulator that
associates with the pathology of obesity-linked metabolic and
vascular disorders, the salutary actions of adiponectin on vari-
ous pathological processes may be mediated partly through
suppression of TNF-α production in macrophages. In line with
this notion, a recent report showed that adiponectin protects
against ischemia-induced vascular injury in retina via modu-
lation of TNF-α inammatory response.57
One of the crucial steps in atherogenesis is adherence of
monocytes to damaged endothelial cells and subsequent
monocyte-to-macrophage transformation. Adiponectin sup-
presses adherence of monocytes to TNF-α-stimulated endothe-
lial cells by inhibiting expression of adhesion molecules.4,14
Adiponectin also suppresses expression of class A scavenger
receptor in human macrophages and prevents transforma-
tion of macrophages to foam cells.58 Consistent with these
in vitro ndings, overexpression of adiponectin protects
against the development of atherosclerosis in a mouse model
of atherosclerosis.18,59 Furthermore, adiponectin promotes the
ecient removal of apoptotic debris from the body by mac-
rophages through a cell surface calreticulin/CD91 system on
macrophage, thereby preventing inammation and immune
system dysfunction.50
Recent evidence suggests that adipose tissue macro-
phages play an important role in the chronic inammatory
state and metabolic dysfunction associated with obesity.60,61
Interestingly, macrophages from fat tissue of lean sub-
jects express markers of the M2 or “alternatively activated”
macrophage, whereas obesity leads to a reduction of M2
markers and an increase of genes associated with the M1 or
classically activated” macrophage62 (Figure 2). M1 macro-
phage polarization causes inammation and tissue destruc-
tion, whereas the M2 macrophage is believed to display an
anti-inammatory phenotype and rather confer wound repair
and vascular protection (Figure 2).
A recent study has shown that peritoneal macrophages and
stromal vascular fractions (SVF), which include macrophages
and vascular components except for adipocytes, isolated from
adiponectin-knockout mice display an activated M1 pheno-
type.25 Conversely, adenovirus-mediated systemic delivery of
adiponectin promotes expression of arginase-1, a well-known
Adiponectin and Hypertension
M2 marker, in peritoneal macrophages and SVF in WT and
adiponectin-knockout mice. In vitro cultured experiments also
show that treatment of mouse peritoneal macrophages and
SVF with recombinant adiponectin protein leads to upregula-
tion of M2 markers including arginase-1, macrophage galac-
tose N-acetyl-galactosamine specic lectin-1 (Mgl-1) and
interleukin-10. In contrast, treatment with adiponectin protein
attenuates expression of M1 markers including TNF-α, inter-
leukin-6, and monocyte chemotactic protein-1 in cultured
mouse macrophage and SVF. e elevation of M2 markers and
suppression of M1 markers following adiponectin treatment
are also found in cultured human monocyte-derived macro-
phages and SVF (Figure 2). erefore, it is conceivable that
adiponectin ameliorates vascular disorders including endothe-
lial dysfunction by its ability to promote macrophage polari-
zation toward the anti-inammatory phenotype. However, the
molecular mechanism by which adiponectin regulates macro-
phage behavior has not been fully understood. Future studies
are necessary to elucidate the adiponectin signaling pathways
that are involved in changes in macrophage function and
e RAS plays a crucial role in cardiovascular homeo stasis
by regulating blood pressure and vascular function.63,64
Accumulating evidence indicates the important role of RAS in
regulation of adiponectin production. Watanabe et al. showed
that an antihypertensive drug angiotensin II type 1 receptor
blocker (ARB) losartan treatment for 3 months increases
plasma adiponectin concentration in patients with essential
hypertension. In contrast, treatment with a calcium blocker,
amlodipine, has no eect on adiponectin levels in this popu-
lation.65 Similarly, losartan treatment for 6 months increases
serum adiponectin levels in hypertensive patients with meta-
bolic syndrome.66 Furthermore, plasma adiponectin levels are
signicantly increased aer 8 weeks of treatment with an ARB
telmisartan in patients with essential hypertension.67 It has
also been shown that both telmisartan and another ARB irbe-
sartan increase circulating adiponectin levels in patients with
insulin resistance and hypertension.68 erefore, inhibition of
angiotensin II type 1 receptor-mediated signaling appears to
lead to elevation of adiponectin levels in hypertensive subjects.
Conversely, administration of angiotensin II to rats fed with
a high-fructose diet signicantly decreases plasma adipo nectin
levels.69 Interestingly, plasma adiponectin concentration
decreases before the blood pressure increase aer angiotensin
II infusion. Angiotensin II is known to stimulate generation
of reactive oxygen species. Furukawa et al. demonstrated that
the increased reactive oxygen species cause dysregulation of
adipocytokines including reduced levels of adiponectin and
that hydrogen peroxide, one of reactive oxygen species, inhib-
its adiponectin expression in adipose tissue.70 us, activa-
tion of RAS reduces adiponectin production partly through
enhancement of reactive oxygen species generation. To sup-
port this hypothesis, another ARB olmesartan has been shown
to restore decreased level of adiponectin in obese animals,
which is accompanied by decrease in oxidative stress in adi-
pose tissue.71
Benson et al. have shown that telmisartan functions to pro-
mote peroxisome proliferator-activated receptor-γ (PPAR-γ)
activity as a partial agonist for PPAR-γ.72 Treatment of 3T3-L1
adipocytes with telmisartan results in upregulation of aP2 and
CD36, which are target molecules of PPAR-γ. e administra-
tion of PPAR-γ ligands, thiazolidinediones, has been reported
to robustly increase the plasma adiponectin concentrations
in human and mouse studies.73 iazolidinedione treatment
has been shown to enhance expression and secretion of adipo-
nectin in cultured adipocytes.73–77 erefore, PPAR-γ acti-
vation by ARBs could be another mechanism of adiponectin
upregulation by these agents.78
Several clinical studies have demonstrated that, in addition
to blood pressure-lowering eects, ARBs have various bene-
cial actions including improvement of glucose and lipid metab-
olism and vascular function. In a double-blinded randomized
trial in patients with essential hypertension, losartan-treated
groups exhibit signicantly lower new-onset diabetes and
stroke compared to atenolol during mean 4.8-year follow-up
Endothelial cell
M2 M1
Arginase-1 TNF-α
Anti-inflammatory Proinflammatory Endothelial function
Vascular protection
Figure 2 | Potential mechanism of vascular protection by adiponectin.
Adiponectin attenuates the phenotype of M1 macrophages, which display
upregulation of proinflammatory cytokines including tumor necrosis factor-α
(TNF-α), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1).
Adiponectin promotes the phenotype of M2 macrophages, which show
upregulation of arginase-1 (Arg-1), interleukin-10 (IL-10), and macrophage
galactose N-acetyl-galactosamine specific lectin-1 (Mgl-1). Adiponectin
ameliorates endothelial cell function via increase in NO and PGI2 production
in endothelial cells. It is plausible that adiponectin exerts protective actions
on vascular function through its ability to improve function of macrophage
and endothelial cell. NO, nitric oxide; PGI2, prostaglandin I2.
Adiponectin and Hypertension
time.79 Valsaltan, another ARB, also reduces new-onset type 2
diabetes in nondiabetic hypertensive patients compared with
amlodipine.80,81 Telmisartan treatment decreases total and
low-density lipoprotein cholesterol levels and hemoglobin
A1c in patients with essential hypertension.82 In addition,
telmisartan improves the pulse-wave velocity accompanying
with a decreased levels of asymmetric dimethylarginine, an
endogenous eNOS inhibitor produced by vascular endothe-
lial cells.82 Considering the protective actions of adiponectin
on metabolic syndrome, multiple functions by ARBs could be
attributed to induction of adiponectin.
Collectively, these ndings suggest that adiponectin upregu-
lation by RAS inhibition is benecial for not only hypertension
but also various metabolic and vascular diosorders.
Adiponectin functions as an important adipocytokine link-
ing between adipose tissue and the vasculature. Adiponectin
directly acts on vascular endothelial cells and exerts salutary
eects on endothelial function through eNOS-dependent
and COX-2-dependent regulatory mechanisms. Adiponectin
can serve as a regulator of macrophage function and favor
anti- inammatory phenotype in macrophages, potentially
contributing to vascular protective properties. Clinical and
experimental studies indicate the causal relationship between
hypoadiponectinemia and hypertension. Blockade of angi-
otensin II type 1 receptor leads to elevation of circulating adi-
ponectin levels, which could confer the benecial pleiotropic
eects of ARBs including improvement of metabolic and
vascular function beyond antihypertensive actions. us, the
therapeutic strategies that enhance adiponectin production
or action have potential utility for prevention or treatment of
obesity-related vascular dysfunction such as hypertension.
Taken together, future studies are required to elucidate the
molecular and cellular mechanisms of adiponectin regulation
and function in more detail for comprehensive understanding
of the pathogenesis of metabolic syndrome.
Disclosure: The authors declared no conflict of interest.
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... Adiponectin, one of the adipocytokines mainly secreted from adipocytes [13], has been suggested not only to modulate lipid metabolism but also to regulate blood pressure [14]. Moreover, adiponectin could stimulate the endothelium production of nitric oxide (NO) [14], an important mediator of endothelial function such as vasodilation and angiogenesis [15,16]. The available evidence suggests that dietary β-conglycinin could modulate blood pressure by increasing serum adiponectin concentration. ...
... In the present study, the plasma adiponectin concentration was significantly higher in rats fed the β-CON diet than in those fed the Control diet, consistent with the results previously reported [11,23]. Ohashi et al. reported that the plasma adiponectin concentration was positively correlated with an endothelial vasodilation response in mice [15], suggesting that β-conglycinin exerts an antihypertensive affect through an increase in plasma adiponectin concentration. Although the type of dietary protein did not affect the visceral adipose tissue weights in the present study, the gene expression of Adipoq in the mesenteric adipose tissue was significantly higher, whereas that of Pparg tended to be higher in rats fed the β-CON diet than in those fed the Control diet. ...
... The β-conglycinindependent increase in plasma NOx concentration in the present study could be due to an increase in plasma adiponectin concentration. In this context, it has been reported that serum/plasma adiponectin contributes to reducing the blood pressure by upregulation of the gene expression of eNOS and by an increase in NO production in vascular endothelial cells [15,26]. Thus, increasing plasma adiponectin concentration by feeding of β-conglycinin was suggested to stimulate the production of eNOS in the aortic endothelium and, consequently, to exert an antihypertensive effect. ...
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Dietary β-conglycinin has been shown to increase plasma adiponectin concentration and decrease visceral adipose tissue weight in rats. Since adiponectin is one of the factors regulating blood pressure, as well as modulating lipid metabolism, we examined whether dietary β-conglycinin affects blood pressure in spontaneously hypertensive rats. The experimental diets were prepared according to the AIN-93G formula containing 20% protein, either casein (Control) or casein replaced with soy protein isolate (SOY) or β-conglycinin (β-CON) at the proportion of 50%. Male rats (SHR/Izm, 6 wk-old) were fed the diets for 7 weeks. The SOY compared with the Control significantly suppressed the blood pressure both at week 4 (p = 0.011, Control vs. SOY) and thereafter, and β-CON had even higher suppression (p = 0.0002, Control vs. β-CON). SOY and β-CON increased plasma adiponectin concentration followed by an increase in plasma nitric oxide and possibly a decreasing trend of gene expressions of angiotensinogen in the liver and renin in the kidney. The results indicated suppression by β-conglycinin of increasing blood pressure through an enhancement of plasma adiponectin, probably in combination with a regulation of the renin–angiotensin system in spontaneously hypertensive rats.
... As we already described above, adiponectin protects against endothelial dysfunction via several regulatory pathways. One pathway in endothelial cells involves enhancing of nitric oxide synthase (eNOS) ac tivity and NO production via AdipoR1/R2AMPKendothelial signaling and the other one is via cyclooxygenase2 (COX2) expression and prostaglandin I 2 (PGI 2 ) production through calreticulin/CD91dependent Akt signaling [143]. Furthermore, adiponectin is able to attenuate the pheno type of macrophages M1 (M1 activity is known to inhibit cell proliferation and tissue damage) and to promote the pheno type of macrophages M2 (M2 activity is known to promote cell proliferation and tissue repair). ...
... Furthermore, adiponectin is able to attenuate the pheno type of macrophages M1 (M1 activity is known to inhibit cell proliferation and tissue damage) and to promote the pheno type of macrophages M2 (M2 activity is known to promote cell proliferation and tissue repair). Therefore, it is plausible that adiponectin exerts protective actions on vascular func tions at least in part through improving functions (excuse the pleonasm here) of macrophages and endothelial cells [143]. ...
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Adipose tissue mostly composed of different types of fat is one of the largest endocrine organs in the body playing multiple intricate roles including but not limited to energy storage, metabolic homeostasis, generation of heat, participation in immune functions and secretion of a number of biologically active factors known as adipokines. The most abundant of them is adiponectin. This adipocite-derived hormone exerts pleiotropic actions and exhibits insulin-sensitizing, antidiabetic, anti-obesogenic, anti-inflammatory, antiatherogenic, cardio- and neuroprotective properties. Contrariwise to its protective effects against various pathological events in different cell types, adiponectin may have links to several systemic diseases and malignances. Reduction in adiponectin levels has an implication in COVID-19-associated respiratory failure, which is attributed mainly to a phenomenon called ‘adiponectin paradox’. Ample evidence about multiple functions of adiponectin in the body was obtained from animal, mostly rodent studies. Our succinct review is entirely about multifaceted roles of adiponectin and mechanisms of its action in different physiological and pathological states.
... Whether the sex difference in hypertension is genetic, hormonal, or environmental is unknown, but the potential protective effect of 2 X chromosomes and/or higher estrogen levels could be further explored by studying males with KS. For example, one of the mechanisms proposed for biological sex difference in hypertension is the protective effect of the adipocytokine adiponectin, with males having lower levels than females and lower levels often found in individuals with metabolic syndrome (43)(44)(45). Normal adiponectin levels have been reported in men with KS despite their poor cardiometabolic profiles, which would be congruent with a protective effect of adiponectin against hypertension (4). ...
Context Diabetes and cardiovascular diseases are common among men with Klinefelter syndrome (KS) and contribute to higher morbidity and mortality. Objective To determine if cardiometabolic-related diagnoses are more prevalent among youth with KS compared to matched controls in a large population-based cohort. Design Secondary data analysis from electronic health records Setting Six pediatric institutions in the United States (PEDSnet) Patients All youth with KS in the database (n=1,080) and 4,497 youth without KS matched for sex, age (mean 13 years at last encounter), year of birth, race, ethnicity, insurance, site, and duration of care (mean 7 years). Main outcome measures Prevalence of five cardiometabolic-related outcomes including overweight/obesity, dyslipidemia, dysglycemia, hypertension, and liver dysfunction Results The odds of overweight/obesity (OR 1.6 (95%CI 1.4-1.8)), dyslipidemia (3.0 (2.2-3.9)), and liver dysfunction (2.0 (1.6-2.5)) were all higher in KS compared to controls. Adjusting for covariates (obesity, testosterone treatment, and antipsychotic use) attenuated the effect of KS on these outcomes, however boys with KS still had 45% greater odds of overweight/obesity (CI 1.2-1.7) and 70% greater odds of liver dysfunction (1.3-2.2) compared to controls, and both dyslipidemia (1.6 (1.1-2.4)) and dysglycemia (1.8 (1.1-3.2)) were higher in KS but of borderline statistical significance when accounting for multiple comparisons. The odds of hypertension were not different between groups. Conclusions This large, population-based cohort of youth with KS had a higher odds of most cardiometabolic-related diagnoses compared to matched controls.
... It is characterized by low plasma levels of adiponectin (ADP). Low ADP levels are, in turn, associated with autoimmune diseases [4] and the development of hypertension [5]. Imbalanced diet [6], low physical activity [7], and genetic predisposition [8] are among the most common causes of obesity. ...
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Obesity is associated with chronic inflammation. While cold therapy influences the pro/antioxidative status of an individual, by affecting adipokine levels and the lipid profile, the effect of body mass index (BMI) on the response to cold exposure is unclear. We analyzed the link between BMI and the differences in effects of whole-body stimulation, depending on the number of treatments, on specific physiological parameters in men. Twenty-seven non-active men were divided into three groups: N (n = 9, BMI < 24.9), IOb (n = 9, BMI 30.0–34.9), and IIOb (BMI ≥ 35.0). The subjects participated in 20 3-min cryochamber sessions (−120 ◦C), 1/day, 5 days/week. Body composition was analyzed before and after treatment. Blood adiponectin (ADP), leptin (LEP), and tumor necrosis factor alpha (TNF-alpha) levels, and the lipid profile were analyzed three times: at baseline and up to 2 h after 10 and 20 sessions. The 20 treatments caused significant changes in body composition. Between 10 and 20 whole-body cryostimulation (WBC) sessions, a significant decreased was observed in the LEP and TNF-alpha levels. No significant changes in the lipid profile were noted. However, a positive tendency to regain the metabolic balance in adipose tissue was apparent in the IOb group in the tested period (decreased TG levels, increased HDL levels or the HDL/LDL ratio, and significantly decreased visceral adiposity index levels). Collectively, for people with obesity increasing the number of treatments above the standard 10 should be recommended.
... It has been found that APN could effectively promote the NO secretion and the subsequent anti-inflammation activity to maintain endothelium function in an APN deficient mice model. 23,24 Moreover, APN not only facilitated the eNOS activity and resulting NO secretion via improving the stability of eNOS mRNA and promoting the phosphorylation of eNOS at Ser1177 site, but also enhanced the interac-tion between eNOS and heat-shock protein 90 (hsp90). [25][26][27] Hence, the APN decreasing was considered as an unfavorable indicator for primary hypertension. ...
Objective: To investigate the potential mechanism of the vascular remodeling effect and provide additional information about anti-hypertension activity of Fufang Qima capsule. Methods: Spontaneous hypertensive rats (SHRs) were used to study the underlying mechanism of the anti-hypertension activity of QM. In this study, SHRs were randomly divided into 5 groups: model group, Telmisartan group (7.2 mg/kg, p.o.), and three QM groups (0.9298, 1.8596, and 3.7192 g/kg, p.o.). Wistar Kyoto rats (WKY) were used as normal control group. Blood pressure (BP), aorta, perivascular adipose tissue (PVAT) histology were investigated to evaluate the effect of QM. Nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) phosphorylation were measured. Adiponectin (APN) secretion, as well as APN signal pathway proteins including APN, adiponectin receptors (R1 and R2) and adenosine 5'-monophosphate-activated protein kinase (AMPK) were all analyzed. Results: QM significantly reduced BP and ameliorated the vascular pathological change, i.e. intima media thicken and collagen fiber hyperplasia. Meanwhile, QM increased concentration of NO and the phosphorylation of eNOS in the aorta. The anti-hypertensive and endothelia-protective effect of QM could be attributed to activating APN/ AMPK pathway by up-regulating the expression of APN in PVAT and APN Receptor 2, AMPKα and phosphorylated AMPKα in the aorta. Conclusion: The QM alleviation effect mechanism for primary hypertension was via modulating the APN/AMPK signal pathway.
... Waist circumference and waist:stature ratio increased in ARG group, reflecting insulin resistance [29], increased adiposity [30] or incidence of MES [31]. In particular, increased waist:stature ratio (a marker of abdominal obesity) was associated with cardiovascular diseases [32], type 2 diabetes mellitus [33,34] and MES [35,36]. In apparent support of this finding, TAG:HDL-chol ratio, another marker of abdominal obesity [1] increased in ARG-fed rats. ...
Objective. To assess the impact of adipose tissue dysfunction for target blood pressure levels achieving in arterial hypertension (AH) and chronic heart failure with preserved left ventricular ejection fraction (HFpEF) in real clinical practice. Materials and methods. We examined 91 elderly patients (> 75 y.o.) with AH and HFpEF during hospital admission. The mass and mass fraction of adipose tissue, serum levels of adipokines (adiponectin, leptin) and proinflammatory cytokines (TNFa and IL6) were assessed. Steady normotension at discharge was used as a marker of the target blood pressure level achievement possibility. Results. By the time of the planned discharge, stable normotension was recorded in 24.2% of patients. In senile patients with failure to achieve normotension, isolated systolic AH was most common - 55.1%. Patients with persistent hypertension at the time of the planned discharge were characterized by a low ability of adipose tissue to secrete adiponectin: 0.05 (0.03; 0.12) vs 0.37 (0.12; 0.5) μg/mL/kg (p = 0.037 ). The minimum values of adiponectin (corrected for adipose tissue mass) were in patients with systolic-diastolic AH (0.04 (0.03; 0.06) μg/ml/kg, Jonkhier-Terpstra test, p = 0.033). A regression model for achieving normotension in senile patients with HFpEF was built with a total percentage of correct classifications of 93.8% before bootstrap and 95.8% after: the maximum values of the Wald statistics were achieved with respect to the predictors "adiponectin", "TNF-a" and "heart rate". Conclusion. The development of adipose tissue dysfunction, accompanied by a decrease in the “rescue hormone” adiponectin synthesis, is associated with the failure to achieve normotension during medication of the inpatient treatment in senile patients with AH and HFpEF.
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Metabolic cardiovascular diseases have become a global health concern, and some of their risk factors are linked to several metabolic disorders. They are the leading causes of death in developing countries. Adipose tissues secrete a variety of adipokines that participate in regulating metabolism and various pathophysiological processes. Adiponectin is the most abundant pleiotropic adipokine and can increase insulin sensitivity, improve atherosclerosis, have anti-inflammatory properties, and exert a cardioprotective effect. Low adiponectin concentrations are correlated with myocardial infarction, coronary atherosclerotic heart disease, hypertrophy, hypertension, and other metabolic cardiovascular dysfunctions. However, the relationship between adiponectin and cardiovascular diseases is complex, and the specific mechanism of action is not fully understood. Our summary and analysis of these issues are expected to contribute to future treatment options.
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Adiponectin, an adipocyte-derived hormone, is a versatile player involved in the regulation of energy homeostasis, cardiovascular disease, and diabetes. Within adipocytes, adiponectin is retained in the lumen of the endoplasmic reticulum (ER) by binding to the thiol protein ER resident protein 44 kDa (ERp44), which is apparently regulated by the activation of nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma. However, the precise role of ERp44 in adiponectin secretion remains elusive. In the present study, we investigated the functional correlation between ERp44 and adiponectin in a pig model. The transcription of porcine ERp44 was regulated by PPARgamma, which was consistent with the finding of putative peroxisome proliferator response element sites within ERp44 promoter. Using chromatin immunoprecipitation and luciferase reporter assays, we demonstrated that the transcription of porcine ERp44 is repressed through binding of PPARgamma to a peroxisome proliferator response element site located between positions -981 and -1004 in its 5'-flanking region. In human embryonic kidney 293 cells stably transfected with cDNA encoding porcine adiponectin, the secretion of adiponectin was significantly up-regulated and the ERp44 mRNA was down-regulated observably, by either the treatment of PPARgamma agonist rosiglitazone or the overexpression of PPARgamma in these cells. Taken together, our results indicated that PPARgamma is an essential regulatory factor for the transcriptional activity of ERp44, which in turn controls the secretion of adiponectin.
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It is established that the adipocyte-derived cytokine adiponectin protects against cardiovascular and metabolic diseases, but the effect of this adipokine on macrophage polarization, an important mediator of disease progression, has never been assessed. We hypothesized that adiponectin modulates macrophage polarization from that resembling a classically activated M1 phenotype to that resembling alternatively-activated M2 cells. Peritoneal macrophages and the stromal vascular fraction (SVF) cells of adipose tissue isolated from adiponectin knock-out mice displayed increased M1 markers, including tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1 and decreased M2 markers, including arginase-1, macrophage galactose N-acetyl-galactosamine specific lectin-1, and interleukin-10. The systemic delivery of adenovirus expressing adiponectin significantly augmented arginase-1 expression in peritoneal macrophages and SVF cells in both wild-type and adiponectin knock-out mice. In culture, the treatment of macrophages with recombinant adiponectin protein led to an increase in the levels of M2 markers and a reduction of reactive oxygen species and reactive oxygen species-related gene expression. Adiponectin also stimulated the expression of M2 markers and attenuated the expression of M1 markers in human monocyte-derived macrophages and SVF cells isolated from human adipose tissue. These data show that adiponectin functions as a regulator of macrophage polarization, and they indicate that conditions of high adiponectin expression may deter metabolic and cardiovascular disease progression by favoring an anti-inflammatory phenotype in macrophages.
We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)—granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units—erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor α. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions.
Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.
Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPARgamma ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-alpha, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-alpha. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-alpha on the adiponectin promoter.
Our previous studies demonstrated that, in gracilis muscle arterioles of male mice deficient in the gene for endothelial nitric oxide synthase (eNOS), flow-induced dilation (FID) is mediated by endothelial PGs. Thus the present study aimed to identify the specific isoform of cyclooxygenase (COX) responsible for the compensatory mediation of FID in arterioles of eNOS-knockout (KO) mice. Experiments were conducted on gracilis muscle arterioles of male eNOS-KO and wild-type (WT) mice. Basal tone and magnitude of FID of arterioles were comparable in the two strains of mice. A role for COX isoforms in the mediation of the responses was assessed by use of valeryl salicylate (3 mM) and NS-398 (10 μM), inhibitors of COX-1 and COX-2, respectively. In eNOS-KO arterioles, valeryl salicylate or NS-398 alone inhibited FID (at maximal flow rate) by ∼51% and ∼58%, respectively. Administration of both inhibitors eliminated the dilation. In WT arterioles, inhibition of COX-2 did not significantly affect FID, whereas inhibition of COX-1 decreased the dilation by ∼57%. The residual portion of the response was abolished by additional administration of N ω-nitro-l-arginine methyl ester. Western blot analysis indicated a comparable content of COX-1 protein in arterioles of WT and eNOS-KO mice. COX-2 protein, which was not detectable in arterioles of WT mice, was strongly expressed in arterioles of eNOS-KO mice, together with an upregulation of COX-2 gene expression. Immunohistochemical staining confirmed the presence of COX-2 in the endothelium of eNOS-KO arterioles. In conclusion, COX-2-derived PGs are the mediators responsible for maintenance of FID in arterioles of eNOS-deficient mice.
Aldosterone infusion results in left ventricular hypertrophy (LVH) and hypertension and may involve profibrotic and proinflammatory mechanisms. In turn, hypertension is the major cause of diastolic heart failure (HF). Adiponectin, an adipose-derived plasma protein, exerts antiinflammatory and anti-hypertrophic effects and is implicated in the development of hypertension and systolic HF. We thus tested the hypothesis that hypoadiponectinemia in aldosterone-induced hypertension exacerbated cardiac remodeling and diastolic HF. Wild-type (WT) or adiponectin-deficient (APNKO) mice underwent saline or aldosterone infusion and uninephrectomy and were fed 1% salt water for 4 wk. Blood pressure was increased in aldosterone-infused WT (132 +/- 2 vs. 109 +/- 3 mm Hg; P < 0.01) and further augmented in APNKO mice (140 +/- 3 mm Hg; P < 0.05 vs. aldosterone-infused WT). LVH was increased in aldosterone-infused WT vs. WT mice (LV/body weight ratio, 4.8 +/- 0.2 vs. 4.1 +/- 0.2 mg/g) and further increased in aldosterone-infused APNKO mice (LV/body weight ratio, 6.0 +/- 0.4 mg/g). Left ventricular ejection fraction was not decreased in either aldosterone-infused WT or APNKO hearts. Pulmonary congestion however was worse in APNKO mice (P < 0.01). The ratio of early ventricular filling over late ventricular filling (E/A) and the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e'), measures of diastolic function, were increased in aldosterone-infused WT hearts and further increased in APNKO hearts (P < 0.05 for both). Renal function and cardiac fibrosis were no different between both aldosterone-infused groups. Aldosterone increased matrix metalloproteinase-2 expression in WT hearts (P < 0.05 vs. WT and P < 0.01 vs. APNKO). Myocardial atrial natriuretic peptide, interferon-gamma, and TNF-alpha expression were increased in aldosterone-infused WT hearts. Expression of these proteins was further increased in aldosterone-infused APNKO hearts. Therefore, hypoadiponectinemia in hypertension-induced diastolic HF exacerbates LVH, diastolic dysfunction, and diastolic HF. Whether or not adiponectin replacement prevents the progression to diastolic HF will warrant further study.
Aldosterone production causes vascular injury and may occur despite the long-term administration of angiotensin converting enzyme-inhibitors (ACE-I) (ie, aldosterone breakthrough). The angiotensin II receptor blocker (ARB) telmisartan can function as a ligand for peroxisome proliferator-activated receptor (PPAR) γ. Stimulation of PPAR γ has been demonstrated to raise adiponectin production and suppress angiotensin II type 1 receptor expression. Thus, we investigated the effect of the ACE-I perindopril erbumin (perindopril) and the ARB telmisartan on plasma levels of aldosterone and adiponectin. Patients with essential hypertension were randomly assigned to receive 48 weeks of perindopril (2-8 mg/d) or telmisartan (20-80 mg/d). We measured adiponectin, aldosterone, angiotensin II, and renin at weeks 0, 8, 24, and 48. A total of 53 subjects were randomized. Data on 51 subjects (25 in the perindopril group and 26 in the telmisartan group; mean age, 65.1 years) were available for analyses. Plasma aldosterone decreased significantly in both the telmisartan (69.9 ± 5.6 to 58.1 ± 5.4 pg/mL) and perindopril (74.1 ± 4.7 to 64.7 ± 5.3 pg/mL) groups at 8 weeks, but returned toward the baseline in the perindopril group (67.9 ± 4.1 pg/mL) at 24 weeks. Plasma glycated hemoglobin levels or urine albumin did not change significantly after the treatment in either group. Telmisartan seemed to be more effective at suppressing aldosterone and raising adiponectin levels than perindopril; however, improvements in insulin sensitivity and albuminuria were not detected. These results are consistent with the idea that the use of an ARB with PPAR γ stimulating activity is equivalent to ACE-I for the treatment of hypertension.