Recent progress in adipocytokine research

概要

100th Anniversary of Nagoya J Med Sci: Comments to the Highly Cited Articles
Nagoya J. Med. Sci. 85. 23–26, 2023
doi:10.18999/nagjms.85.1.23

Recent progress in adipocytokine research
Noriyuki Ouchi1, Koji Ohashi1 and Toyoaki Murohara2
Department of Molecular Medicine and Cardiology, Nagoya University Graduate School of Medicine,
Nagoya, Japan
2
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

1

This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
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Ouchi N, Ohashi K, Shibata R, Murohara T. Adipocytokines and obesity-linked disorders.
Nagoya J Med Sci. 2012;74(1–2):19–30.
Obesity is closely associated with an increased risk for metabolic and cardiovascular
diseases. Adipose tissue produces a number of secretory bioactive substances, also known as
adipocytokines or adipokines, which directly affect adjacent or distant organs. Most adipocytokines are pro-inflammatory, thereby promoting the obesity-linked disorders. In contrast,
there are a small number of adipocytokines that exhibit anti-inflammatory properties. It is now
recognized that dysregulated production or secretion of adipocytokines caused by adipocyte
dysfunction leads to the development of obesity-linked complications. In this review, we focus
on the functional role of several adipocytokines in metabolic and cardiovascular diseases.
Keywords: adipocytokine, adiponectin, Sfrp5, adipolin, inflammation, cardiovascular disease
Adipose tissue produces numerous secretory factors, which are referred to as adipocytokines.
Under conditions of obesity, an imbalance between anti- and pro-inflammatory adipocytokines
contributes to the pathogenesis of metabolic and cardiovascular diseases.1 This article aimed to
introduce an overview of our recent research on the significance of crucial adipocytokines that
exert beneficial actions on obesity-related diseases, including atherosclerosis and ischemic heart
disease.
Adipolin/C1q tumor necrosis factor-related protein 12
We previously performed screening of predicted adipocytokines that are regulated by obese
states, identified C1q tumor necrosis factor-related protein (CTRP) 12, CTRP12, as a novel
adipocytokine, and designated this adipocytokine as adipolin (adipose-derived insulin-sensitizing
factor) to indicate its potential function.2 Adipolin is a member of CTRPs, which are conserved
adiponectin paralogs containing a collagen-like domain and a C1q-like domain. Adipolin is
Received: October 5, 2022; accepted: November 8, 2022
Corresponding Author: Noriyuki Ouchi, MD, PhD
Department of Molecular Medicine and Cardiology, Nagoya University Graduate School of Medicine,
65 Tsurumai-cho Showa-ku, Nagoya 466-8550, Japan
Tel: +81-52-744-2427, Fax: +81-52-744-2427, E-mail: nouchi@med.nagoya-u.ac.jp
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Noriyuki Ouchi et al

mainly expressed in adipose tissue, particularly in adipocytes. Adipolin expression in adipose
tissue and plasma is decreased in mouse models of obesity. Adipolin acts as an adipocytokine,
which improves insulin resistance in obese mice.
We attempted to investigate the impact of adipolin on cardiovascular disease and generated
adipolin-knockout (KO) mice to assess the role of endogenous adipolin in cardiovascular regulation. Under physiological conditions, adipolin-KO mice are indistinguishable from wild-type (WT)
mice. Adipolin-KO mice show enhanced neointimal thickening in response to vascular injury
with accompanying increases in vascular cell proliferation and inflammatory response in injured
arteries.3 Conversely, systemic administration of adipolin to WT mice attenuates pathological
remodeling after arterial injury. Adipolin attenuates cultured vascular smooth muscle cell (VSMC)
proliferation after treatment with growth factors and reduces lipopolysaccharide-stimulated expression of pro-inflammatory mediators in cultured macrophages. Thus, adipolin exerts a vascular
protective action, at least partially, by suppressing VSMC growth and macrophage inflammation.
Furthermore, we attempted to examine the effect of adipolin on cardiac remodeling in a
mouse model of myocardial infarction. Adipolin-KO mice show decreased cardiac function
after myocardial infarction, which is accompanied by an increased inflammatory response and
cardiomyocyte apoptosis in infarct hearts.4 In contrast, systemic delivery of adipolin ameliorates
the cardiac function of WT mice in response to myocardial infarction. Adipolin attenuates the
inflammatory response and apoptotic activity in cultured cardiac myocytes. Therefore, adipolin can
improve pathological cardiac remodeling, at least partially, by reducing cardiomyocyte inflammation and apoptosis. Collectively, these data suggest that adipolin functions as an anti-inflammatory
adipocytokine that exerts beneficial actions on cardiometabolic diseases.
Omentin
Omentin, also referred to as intelectin-1, is identified as a soluble galactofuranose-binding
lectin. Omentin is abundantly expressed in human visceral fat tissues, and circulating omentin
levels are decreased in patients with obesity. Furthermore, plasma omentin levels are reduced
in patients with coronary artery disease. We attempted to investigate the effect of omentin on
cardiovascular disorders. Omentin promotes ischemia-induced revascularization in vivo through an
endothelial nitric oxide synthase (eNOS)-dependent mechanism.5 Omentin stimulates endothelial
cell survival and angiogenic response in vitro through the AMP-activated protein kinase (AMPK)/
eNOS signaling pathways. Furthermore, transgenic mice expressing omentin in fat tissue show
decreased neointimal thickening in response to vascular injury.6 Omentin attenuates the growth
of VSMCs through an AMPK-dependent mechanism. Omentin suppresses atherosclerotic lesion
formation in a mouse model of atherosclerosis through the reduction of the inflammatory response.7 More recently, we have shown that omentin reduces abdominal aortic aneurysm formation
in response to angiotensin II in vivo by suppressing the matrix metalloproteinase expression.8
Therefore, omentin acts as a vasculoprotective adipocytokine.
We have also shown that omentin attenuates myocardial infarct size and apoptosis following
ischemia-reperfusion in vivo.9 The beneficial effect of omentin on cardiac injury is mediated through two independent mechanisms involving the Akt and AMPK signaling pathways.
Moreover, omentin reduces cardiac hypertrophy and systolic dysfunction in response to pressure
overload, partially through the AMPK pathway.10 These findings suggest that omentin serves as a
cardioprotective adipocytokine. To summarize, omentin can play an important role in preventing
cardiovascular disorders.
Both adipolin and omentin exert protective actions on obesity-related cardiovascular diseases
(eg, ischemic heart disease and vascular disease). Expression of these adipocytokines in adipose
tissue is down-regulated by obesity. Thus, reduced production of these protective adipocytokines
Nagoya J. Med. Sci. 85. 23–26, 2023

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Fig. 1  Protective roles of adipolin and omentin in cardiovascular diseases
Obesity causes reduced production of adipolin and omentin in adipose tissues, thereby leading to the development
of cardiovascular diseases.

caused by obesity, particularly excess visceral fat accumulation, may lead to the development
of cardiovascular disease (Figure 1). Furthermore, the therapeutic approaches to enhancing the
synthesis and secretion of these adipocytokines can be valuable toward prevention or treatment
of obesity-associated cardiovascular complications.

ACKNOWLEDGMENTS
This work was supported by Grant-in-Aid for Scientific Research A, Grant-in-Aid for Challenging Exploratory Research, and grants from the Takeda Science Foundation.

CONFLICT OF INTEREST
The authors declare no conflict of interest regarding this manuscript.

REFERENCES
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Sci. 2012;74(1–2):19–30.
 2 Enomoto T, Ohashi K, Shibata R, et al. Adipolin/C1qdc2/CTRP12 protein functions as an adipokine that
improves glucose metabolism. J Biol Chem. 2011;286(40):34552-34558. doi:10.1074/jbc.M111.277319.
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 6 Uemura Y, Shibata R, Kanemura N, et al. Adipose-derived protein omentin prevents neointimal formation
after arterial injury. FASEB J. 2015;29(1):141–151. doi:10.1096/fj.14-258129.
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 7 Hiramatsu-Ito M, Shibata R, Ohashi K, et al. Omentin attenuates atherosclerotic lesion formation in
apolipoprotein E-deficient mice. Cardiovasc Res. 2016;110(1):107–117. doi:10.1093/cvr/cvv282.
 8 Fang L, Ohashi K, Otaka N, et al. Omentin attenuates angiotensin II-induced abdominal aortic aneurysm
formation in apolipoprotein E-knockout mice. Cardiovasc Res. 2022;118(6):1597–1610. doi:10.1093/cvr/
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protein kinase- and Akt-dependent mechanisms. ...