Role of anti-inflammatory adipokines in obesity-related diseases

doi:10.1016/j.tem.2014.03.009

Trends in Endocrinology & Metabolism

Volume 25, Issue 7, July 2014, Pages 348-355

https://doi.org/10.1016/j.tem.2014.03.009 Get rights and content

Highlights

•
Adiponectin protects against the complications of obesity by exerting anti-inflammatory effects.
•
Several CTRPs have anti-inflammatory and anti-diabetic properties.
•
Low omentin-1 levels are associated with metabolic and cardiovascular diseases.

Obesity results in many health complications. Accumulating evidence indicates that the obese state is characterized by chronic low-grade inflammation, thereby leading to the initiation and progression of obesity-related disorders such as type 2 diabetes, hypertension, cardiovascular disease, and atherosclerosis. Fat tissue releases numerous bioactive molecules, called adipokines, which affect whole-body homeostasis. Most adipokines are proinflammatory, whereas a small number of anti-inflammatory adipokines including adiponectin exert beneficial actions on obese complications. The dysregulated production of adipokines seen in obesity is linked to the pathogenesis of various disease processes. In this review we focus on the role of the anti-inflammatory adipokines that are of current interest in the setting of obesity-linked metabolic and cardiovascular diseases.

Introduction

Obesity is a pandemic social problem worldwide. Excess fat accumulation is causally linked with various metabolic risk factors including type 2 diabetes, hypertension, and dyslipidemia, finally leading to the development of cardiovascular disease 1, 2. It is well established that obesity, in particular, visceral fat accumulation causes chronic low-grade inflammation, which contributes to the initiation and progression of metabolic disorders 3, 4, 5. Adipose tissue is an active endocrine organ and secretes a variety of bioactive molecules known as adipokines 3, 6, 7. The adipokines comprise a large number of proinflammatory mediators, including tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6, that promote disease progression. By contrast, a small number of anti-inflammatory adipokines, which are downregulated by obese states, seem to protect against the development of obese complications 3, 7, 8, 9. In this review we discuss recent progress in our understanding of the action of anti-inflammatory adipokines in the context of metabolism and cardiovascular disease.

Section snippets

Adiponectin

Adiponectin, also referred to as ACRP30 (adipocyte complement-related 30 kDa protein), is an adipocyte-specific adipokine found in human plasma at concentrations ranging from 3 to 30 μg/ml 10, 11. Adiponectin contains a collagen-repeat domain and a globular domain with a sequence homology to complement factor C1q. It is well established that adiponectin levels in plasma are negatively associated with the accumulation of body fat, particularly visceral fat [12], and that plasma adiponectin levels

Omentin-1

Omentin-1, also referred to as intelectin-1, was originally identified as a soluble galactofuranose-binding lectin [61]. Human omentin-1 forms a disulfide-linked and N-glycosylated trimer [61]. It has been reported that human omentin-1 is abundantly expressed in visceral fat tissue [62]. Omentin-1 is detectable in human blood, and circulating omentin-1 levels are decreased in obese individuals [63]. By contrast, omentin-1 concentrations are increased in obese subjects after weight reduction [64]

Concluding remarks

It has been increasingly recognized that imbalance of proinflammatory and anti-inflammatory adipokines contributes to the development of obesity-linked disorders. Dysregulation of anti-inflammatory adipokines caused by fat accumulation participates in local or systemic inflammatory responses, thereby leading to the initiation or progression of metabolic and cardiovascular disorders. In this regard, resolution of the imbalance between proinflammatory and anti-inflammatory adipokines, in

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research, a Grant-in-Aid for Challenging Exploratory Research, and grants from the Takeda Science Foundation, the Uehara Memorial Foundation, the Daiichi-Sankyo Foundation of Life Science, and the SENSHIN Medical Research Foundation to N.O. R.S. was supported by a Grant-in-Aid for Young Scientists B and by the Uehara Memorial Foundation. K.O. was supported by a Grant-in-Aid for Scientific Research C and by The Cardiovascular Research

Glossary

AMP-activated protein kinase (AMPK): AMPK acts as an energy sensor in response to low AMP concentration. AMPK promotes glucose uptake, glycolysis, and fatty acid oxidation, and inhibits the synthesis of glucose and fatty acids. AMPK is also activated by various hormonal signals including adiponectin and leptin. In addition to metabolic functions, AMPK signaling exerts many protective functions against cardiovascular disorders.
Apolipoprotein E (ApoE): ApoE is a major apolipoprotein which acts as a

References (76)

K.J. Moore et al.
Macrophages in the pathogenesis of atherosclerosis
Cell
(2011)
T. Enomoto
Adipolin/C1qdc2/CTRP12 protein functions as an adipokine that improves glucose metabolism
J. Biol. Chem.
(2011)
K. Maeda
cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1)
Biochem. Biophys. Res. Commun.
(1996)
Y. Arita
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
Biochem. Biophys. Res. Commun.
(1999)
T. Yokota
Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages
Blood
(2000)
N. Yamaguchi
Adiponectin inhibits Toll-like receptor family-induced signaling
FEBS Lett.
(2005)
K. Ohashi
Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype
J. Biol. Chem.
(2010)
P. Mandal
Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin
J. Biol. Chem.
(2011)
T. Kambara
CTRP9 protein protects against myocardial injury following ischemia–reperfusion through AMP-activated protein kinase (AMPK)-dependent mechanism
J. Biol. Chem.
(2012)
T. Maeda
Molecular cloning and characterization of a novel gene, CORS26, encoding a putative secretory protein and its possible involvement in skeletal development
J. Biol. Chem.
(2001)

J.M. Peterson

C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output

J. Biol. Chem.

(2010)

J. Weigert

The adiponectin paralog CORS-26 has anti-inflammatory properties and is produced by human monocytic cells

FEBS Lett.

(2005)

M.J. Kim

C1qTNF-related protein-6 increases the expression of interleukin-10 in macrophages

Mol. Cells

(2010)

W. Lee

C1qTNF-related protein-6 mediates fatty acid oxidation via the activation of the AMP-activated protein kinase

FEBS Lett.

(2010)

Z. Wei

C1q/TNF-related protein-12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes

J. Biol. Chem.

(2012)

Z. Wei

Endopeptidase cleavage generates a functionally distinct isoform of C1q/tumor necrosis factor-related protein-12 (CTRP12) with an altered oligomeric state and signaling specificity

J. Biol. Chem.

(2012)

T. Enomoto

Regulation of adipolin/CTRP12 cleavage by obesity

Biochem. Biophys. Res. Commun.

(2012)

S. Tsuji

Human intelectin is a novel soluble lectin that recognizes galactofuranose in carbohydrate chains of bacterial cell wall

J. Biol. Chem.

(2001)

R. Shibata

Circulating omentin is associated with coronary artery disease in men

Atherosclerosis

(2011)

H. Yamawaki

Omentin, a novel adipokine, induces vasodilation in rat isolated blood vessels

Biochem. Biophys. Res. Commun.

(2010)

S. Maruyama

Fat-derived factor omentin stimulates endothelial cell function and ischemia-induced revascularization via endothelial nitric oxide synthase-dependent mechanism

J. Biol. Chem.

(2012)

H. Yamawaki

Omentin, a novel adipocytokine inhibits TNF-induced vascular inflammation in human endothelial cells

Biochem. Biophys. Res. Commun.

(2011)

X. Zhong

Omentin inhibits TNF-alpha-induced expression of adhesion molecules in endothelial cells via ERK/NF-kappaB pathway

Biochem. Biophys. Res. Commun.

(2012)

K. Kazama

Omentin plays an anti-inflammatory role through inhibition of TNF-alpha-induced superoxide production in vascular smooth muscle cells

Eur. J. Pharmacol.

(2012)

J.M. Friedman

A war on obesity, not the obese

Science

(2003)

Y. Matsuzawa

The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism

J. Atheroscler. Thromb.

(2011)

N. Ouchi

Adipokines in inflammation and metabolic disease

Nat. Rev. Immunol.

(2011)

M.Y. Donath et al.

Type 2 diabetes as an inflammatory disease

Nat. Rev. Immunol.

(2011)

N. Ouchi

Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway

Circulation

(2000)

N. Ouchi

Obesity, adiponectin and vascular inflammatory disease

Curr. Opin. Lipidol.

(2003)

N. Ouchi

Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity

Science

(2010)

M. Ryo

Adiponectin as a biomarker of the metabolic syndrome

Circ. J.

(2004)

K. Hotta

Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys

Diabetes

(2001)

Y. Iwashima

Hypoadiponectinemia is an independent risk factor for hypertension

Hypertension

(2004)

M. Kumada

Association of hypoadiponectinemia with coronary artery disease in men

Arterioscler. Thromb. Vasc. Biol.

(2003)

N. Ouchi

Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue

Circulation

(2003)

K. Esposito

Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial

J. Am. Med. Assoc.

(2003)

N. Ouchi

Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages

Circulation

(2001)

Cited by (264)

Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice
2024, iScience
Inflammation is consistently linked to dysmetabolism. In transgenic mice (Def^+/+) model the neutrophilic peptide, alpha defensin, proved atherogenic. This phenotype occurred despite favorable cholesterol and glucose levels, and lower body weight and blood pressure. In this study, integration of metabolic&behavioral phenotyping system, endocrine, biochemical and mitochondrial assessment, pathological and immunohistochemical tests, and multiple challenge tests was established to explore the metabolic impact of alpha defensin. Compared to the control group, Def^+/+ mice exhibited lower total energy expenditure and carbohydrate utilization, and higher fat oxidation. Their ACTH-cortisol and thyroid profiles were intact. Intriguingly, they had low levels of glucagon, with high ammonia, uric acid, triglyceride, and lactate. Mitochondrial evaluations were normal. Overall, defensin-induced hypoglucagonemia is associated with lipolysis, restricted glucose oxidation, and enhanced wasting. Def^+/+ mice may be a useful model for studying the category of lean, apparently metabolically healthy, and atherosclerotic phenotype, with insight into a potential inflammatory-metabolic link.
CTRP6 regulates M1 macrophage polarization via the PPAR-γ/NF-κB pathway and reprogramming glycolysis in recurrent spontaneous abortion
2023, International Immunopharmacology
Aberrant polarization and functions of decidual macrophages are closely related to recurrent spontaneous abortion (RSA). C1q/tumor necrosis factor-related protein 6 (CTRP6) is a member of the adiponectin paralog family, and plays indispensable roles in inflammation, glucose uptake and tumor metastasis. However, the regulatory effect of CTRP6 on macrophage polarization and glycolysis in RSA and the underlying mechanisms have not been fully elucidated. In the present study, we first found that CTRP6 expression was positively correlated with the M1 macrophage marker (CD86) in decidual tissues by dual immunofluorescence analysis. In vitro experiments indicated that CTRP6 could facilitate M1 macrophage activation through the PPAR-γ/NF-κB pathway and manipulate the glycolysis of macrophages. Notably, in addition to silencing CTRP6, treatment with a PPAR-γ agonist (GW1929) inhibited M1 macrophage polarization and rescued embryo absorption in vivo. Taken together, these results identify previously unrevealed functions of CTRP6 in macrophage transformation during RSA.
Structure-activity relationship, bioactivities, molecular mechanisms, and clinical application of nuciferine on inflammation-related diseases
2023, Pharmacological Research
Nuciferine aporphine alkaloid mainly exists in Nelumbo nucifera Gaertn and is a beneficial to human health, such as anti-obesity, lowering blood lipid, prevention of diabetes and cancer, closely associated with inflammation. Importantly, nuciferine may contribute to its bioactivities by exerting intense anti-inflammatory activities in multiple models. However, no review has summarized the anti-inflammatory effect of nuciferine. This review critically summarized the information regarding the structure-activity relationships of dietary nuciferine. Moreover, biological activities and clinical application on inflammation-related diseases, such as obesity, diabetes, liver, cardiovascular diseases, and cancer, as well as their potential mechanisms, involving oxidative stress, metabolic signaling, and gut microbiota has been reviewed. The current work provides a better understanding of the anti-inflammation properties of nuciferine against multiple diseases, thereby improving the utilization and application of nuciferine-containing plants across functional food and medicine.
The liver-to-spleen ratio is a risk factor predicting oxygen demand in COVID-19 patients
2023, Infectious Medicine
We aimed to investigate risk factors predicting oxygen demand in COVID-19 patients.
Patients admitted to Shizuoka General Hospital with COVID-19 from August 2020 to August 2021 were included. First, we divided patients into groups with and without oxygen demand. Then, we compared patients' clinical characteristics and laboratory and radiological findings to determine factors predicting oxygen demand.
One hundred seventy patients with COVID-19 (aged 58±15 years, 57 females) were enrolled. Common comorbidities were cardiovascular diseases (47.6%), diabetes mellitus (28.8%), and dyslipidemia (26.5%). Elder age, higher body mass index, cardiovascular diseases, diabetes mellitus, lower lymphocyte count, albumin, hepatic attenuation value, and the liver-to-spleen ratio (L/S), higher D-dimer, aspartate aminotransferase, lactate dehydrogenase, troponin-T, C-reactive protein, KL-6, chest and abdominal circumference, and visceral fat were found in patients with oxygen demand. According to the multivariate logistic regression analysis, L/S, lymphocyte count, D-dimer, and abdominal circumference under the diaphragm were independent risk factors predicting oxygen demand in COVID-19 patients.
On admission, L/S, lymphocyte count, D-dimer, and abdominal circumference were predictive factors for oxygen demand. These factors may help in the appropriate triage of COVID-19 patients in the decision to admit them to the hospital.
The molecular link between obesity and genomic instability in cancer development
2023, Cancer Letters
Obesity has been known to be a major risk factor for various types of cancers for several decades. More recently, the relationship between dysregulated adipokines and cancer development has been the focus of much research. Adipose tissue is an important endocrine organ that secretes adipokines that affect both autocrine and paracrine signaling. These adipokines modulate inflammation, induce insulin resistance, and regulate their own behavior and production.
Adipokine-production dysregulation is due to physiological changes in adipose tissue that prompt molecular modifications, including low-grade inflammation and the stimulatory production of reactive oxygen species. Additionally, studies have linked DNA damage response, genomic instability, and the innate immune response to tumorigenesis. Further investigation of adipokines and their role in the promotion of genomic instability may clarify the link between obesity and cancer, as well as elucidate potential pharmaceutical targets. In this review, we discuss the progress of recent literature, focusing on the impact of adipokines, genomic instability, and the innate immune response on increasing the risk of cancer.
Personalizing Nutrition Strategies: Bridging Research and Public Health
2024, Journal of Personalized Medicine

View all citing articles on Scopus

View full text

Trends in Endocrinology & Metabolism

ReviewRole of anti-inflammatory adipokines in obesity-related diseases

Highlights

Introduction

Section snippets

Adiponectin

Omentin-1

Concluding remarks

Acknowledgments

Glossary

Cell

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Blood

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Mol. Cells

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Atherosclerosis

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

A war on obesity, not the obese

Science

The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism

J. Atheroscler. Thromb.

Adipokines in inflammation and metabolic disease

Nat. Rev. Immunol.

Type 2 diabetes as an inflammatory disease

Nat. Rev. Immunol.

Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway

Circulation

Obesity, adiponectin and vascular inflammatory disease

Curr. Opin. Lipidol.

Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity

Science

Adiponectin as a biomarker of the metabolic syndrome

Circ. J.

Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys

Diabetes

Hypoadiponectinemia is an independent risk factor for hypertension

Hypertension

Association of hypoadiponectinemia with coronary artery disease in men

Arterioscler. Thromb. Vasc. Biol.

Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue

Circulation

Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial

J. Am. Med. Assoc.

Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages

Circulation

Review
Role of anti-inflammatory adipokines in obesity-related diseases