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Adipokines 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 47294

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Prof. Dr. Christa Büchler

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Guest Editor

Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
Interests: adipose tissue; obesity; non-alcoholic fatty liver disease; adiponectin; chemerin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue, “Adipokines 3.0”, will cover a selection of original research articles and current review articles related to the role of adipokines in health and disease. Up-to-date review articles, commentaries, and experimental papers are all welcome.

Adipokines act in an autocrine, paracrine, or endocrine manner. Although adipokine levels have emerged as promising biomarkers in various diseases, they are not used as predictive or diagnostic markers in clinical practice yet. The leptin analog “recombinant methionyl human leptin”, though, has been approved for the treatment of patients with generalized and partial lipodystrophy already.

Over the past decade, associations among adipokines and obesity, cardiovascular disease, type 2 diabetes, cancer, fertility, and many more have been identified. Further research has focused on the role of these proteins in rheumatoid arthritis, inflammatory bowel disease, kidney disease, chronic liver injury, systemic lupus erythematosus, neurological diseases, and asthma, just to mention a few. There is evidence that brown adipose tissue has its own set of secreted hormones, so-called “brown adipokines”. These factors exert autocrine and endocrine functions beyond their role in thermogenic function. Adipokine receptors are less well characterized, and analysis of their tissue distribution and biological activities awaits further investigation. Development of adipokine receptor agonists and antagonists opens up new avenues of drugs and may finally lead to new therapeutic targets and the appreciation of more adipokines in clinical practice.

Prof. Dr. Christa Büchler
Guest Editor

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Keywords

adipocyte
white adipose tissue
brown adipose tissue
obesity
inflammation
metabolic diseases
cancer
adipokine
adipokine receptor
drugs

Published Papers (10 papers)

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Research

Jump to: Review

17 pages, 2984 KiB

Open AccessArticle

Downregulation of CTRP-3 by Weight Loss In Vivo and by Bile Acids and Incretins in Adipocytes In Vitro

by Andreas Schmid, Jonas Gehl, Miriam Thomalla, Alexandra Hochberg, Anja Kreiß, Marissa Patz, Thomas Karrasch and Andreas Schäffler

Int. J. Mol. Sci. 2020, 21(21), 8168; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218168 - 31 Oct 2020

Cited by 10 | Viewed by 2004

Abstract

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (n = 179) undergoing bariatric surgery (BS). Moreover, patients (n = 131) participating in a low-calorie diet (LCD) program were studied. CTRP 3 levels were quantified by ELISA and mRNA expression was analyzed in AT and in 3T3-L1 adipocytes treated with bile acids and incretins. There was a persistent downregulation of CTRP-3 serum levels during weight loss. CTRP-3 expression was higher in subcutaneous than in visceral AT and serum levels of CTRP-3 were positively related to AT expression levels. A rapid decrease of circulating CTRP-3 was observed immediately upon BS, suggesting weight loss-independent regulatory mechanisms. Adipocytes CTRP-3 expression was inhibited by primary bile acid species and GLP 1. Adipocyte-specific CTRP-3 deficiency increased bile acid receptor expression. Circulating CTRP-3 levels are downregulated during weight loss, with a considerable decline occurring immediately upon BS. Mechanisms dependent and independent of weight loss cause the post-surgical decline of CTRP-3. The data strongly argue for regulatory interrelations of CTRP-3 with bile acids and incretin system. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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14 pages, 2069 KiB

Open AccessArticle

Chemerin-156 is the Active Isoform in Human Hepatic Stellate Cells

by Marlen Spirk, Sebastian Zimny, Maximilian Neumann, Nichole McMullen, Christopher J. Sinal and Christa Buechler

Int. J. Mol. Sci. 2020, 21(20), 7555; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207555 - 13 Oct 2020

Cited by 8 | Viewed by 2022

Abstract

The chemokine chemerin exists as C-terminally processed isoforms whose biological functions are mostly unknown. A highly active human chemerin variant (huChem-157) was protective in experimental hepatocellular carcinoma (HCC) models. Hepatic stellate cells (HSCs) are central mediators of hepatic fibrogenesis and carcinogenesis and express the chemerin receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). Here we aimed to analyse the effect of chemerin isoforms on the viability, proliferation and secretome of the human HSC cell line LX-2. Therefore, huChem-157, 156 and 155 were over-expressed in LX-2 cells, which have low endogenous chemerin levels. HuChem-157 produced in LX-2 cells activated CMKLR1 and GPR1, and huChem-156 modestly induced GPR1 signaling. HuChem-155 is an inactive chemerin variant. Chemerin isoforms had no effect on cell viability and proliferation. Cellular expression of the fibrotic proteins galectin-3 and alpha-smooth muscle actin was not regulated by any chemerin isoform. HuChem-156 increased IL-6, IL-8 and galectin-3 in cell media. HuChem-157 was ineffective, and accordingly, did not enhance levels of these proteins in media of primary human hepatic stellate cells when added exogenously. These analyses provide evidence that huChem-156 is the biologic active chemerin variant in hepatic stellate cells and acts as a pro-inflammatory factor. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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17 pages, 2258 KiB

Open AccessArticle

Chemerin Isoform-Specific Effects on Hepatocyte Migration and Immune Cell Inflammation

by Susanne Feder, Astrid Bruckmann, Nichole McMullen, Christopher J. Sinal and Christa Buechler

Int. J. Mol. Sci. 2020, 21(19), 7205; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197205 - 29 Sep 2020

Cited by 8 | Viewed by 2351

Abstract

Murine chemerin is C-terminally processed to the bioactive isoforms, muChem-156 and muChem-155, among which the longer variant protects from hepatocellular carcinoma (HCC). However, the role of muChem-155 is mostly unknown. Here, we aimed to compare the effects of these isoforms on the proliferation, migration and the secretome of the human hepatocyte cell lines HepG2 and Huh7 and the murine Hepa1-6 cell line. Therefore, huChem-157 and -156 were overexpressed in the human cells, and the respective murine variants, muChem-156 and -155, in the murine hepatocytes. Both chemerin isoforms produced by HepG2 and Hepa1-6 cells activated the chemerin receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). HuChem-157 was the active isoform in the Huh7 cell culture medium. The potencies of muChem-155 and muChem-156 to activate human GPR1 and mouse CMKLR1 were equivalent. Human CMKLR1 was most responsive to muChem-156. Chemerin variants showed no effect on cell viability and proliferation. Activation of the mitogen-activated protein kinases Erk1/2 and p38, and protein levels of the epithelial–mesenchymal transition marker, E-cadherin, were not regulated by the chemerin variants. Migration was reduced in HepG2 and Hepa1-6 cells by the longer isoform. Protective effects of chemerin in HCC include the modulation of cytokines but huChem-156 and huChem-157 overexpression did not change IL-8, CCL20 or osteopontin in the hepatocytes. The conditioned medium of the transfected hepatocytes failed to alter these soluble factors in the cell culture medium of peripheral blood mononuclear cells (PBMCs). Interestingly, the cell culture medium of Huh7 cells producing the inactive variant huChem-155 reduced CCL2 and IL-8 in PBMCs. To sum up, huChem-157 and muChem-156 inhibited hepatocyte migration and may protect from HCC metastasis. HuChem-155 was the only human isoform exerting anti-inflammatory effects on immune cells. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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7 pages, 813 KiB

Open AccessCommunication

Endogenous Chemerin from PVAT Amplifies Electrical Field-Stimulated Arterial Contraction: Use of the Chemerin Knockout Rat

by Emma D. Flood and Stephanie W. Watts

Int. J. Mol. Sci. 2020, 21(17), 6392; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176392 - 02 Sep 2020

Cited by 10 | Viewed by 1790

Abstract

Background: We previously reported that the adipokine chemerin, when added exogenously to the isolated rat mesenteric artery, amplified electrical field-stimulated (EFS) contraction. The Chemerin1 antagonist CCX832 alone inhibited EFS-induced contraction in tissues with but not without perivascular adipose tissue (PVAT). These data suggested indirectly that chemerin itself, presumably from the PVAT, facilitated EFS-induced contraction. We created the chemerin KO rat and now test the focused hypothesis that endogenous chemerin amplifies EFS-induced arterial contraction. Methods: The superior mesenteric artery +PVAT from global chemerin WT and KO female rats, with endothelium and sympathetic nerve intact, were mounted into isolated tissue baths for isometric and EFS-induced contraction. Results: CCX832 reduced EFS (2–20 Hz)-induced contraction in tissues from the WT but not KO rats. Consistent with this finding, the magnitude of EFS-induced contraction was lower in the tissues from the KO vs. WT rats, yet the maximum response to the adrenergic stimulus PE was not different among all tissues. Conclusion: These studies support that endogenous chemerin modifies sympathetic nerve-mediated contraction through Chemerin1, an important finding relative in understanding chemerin’s role in control of blood pressure. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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27 pages, 11857 KiB

Open AccessArticle

The In Vitro Effect of Prostaglandin E₂ and F_2α on the Chemerin System in the Porcine Endometrium during Gestation

by Kamil Dobrzyn, Marta Kiezun, Ewa Zaobidna, Katarzyna Kisielewska, Edyta Rytelewska, Marlena Gudelska, Grzegorz Kopij, Kinga Bors, Karolina Szymanska, Barbara Kaminska, Tadeusz Kaminski and Nina Smolinska

Int. J. Mol. Sci. 2020, 21(15), 5213; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155213 - 23 Jul 2020

Cited by 8 | Viewed by 2379

Abstract

Chemerin belongs to the group of adipocyte-derived hormones known as adipokines, which are responsible mainly for the control of energy homeostasis. Adipokine exerts its influence through three receptors: Chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C motif chemokine receptor-like 2 (CCRL2). A growing body of evidence indicates that chemerin participates in the regulation of the female reproductive system. According to the literature, the expression of chemerin and its receptors in reproductive structures depends on the local hormonal milieu. The aim of this study was to investigate the in vitro effect of prostaglandins E₂ (PGE₂) and F_2α (PGF_2α) on chemerin and chemerin receptor (chemerin system) mRNAs (qPCR) and proteins (ELISA, Western blotting) in endometrial tissue explants collected from early-pregnant gilts. Both PGE₂ and PGF_2α significantly influenced the expression of the chemerin gene, hormone secretion, and the expression of chemerin receptor genes and proteins. The influence of both prostaglandins on the expression of the chemerin system varied between different stages of gestation. This is the first study to describe the modulatory effect of PGE₂ and PGF_2α on the expression of the chemerin system in the porcine uterus during early gestation. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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Review

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20 pages, 2016 KiB

Open AccessReview

Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

by Sebastian Dommel and Matthias Blüher

Int. J. Mol. Sci. 2021, 22(3), 1500; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031500 - 02 Feb 2021

Cited by 31 | Viewed by 8706

Abstract

The mechanisms of how obesity contributes to the development of cardio-metabolic diseases are not entirely understood. Obesity is frequently associated with adipose tissue dysfunction, characterized by, e.g., adipocyte hypertrophy, ectopic fat accumulation, immune cell infiltration, and the altered secretion of adipokines. Factors secreted from adipose tissue may induce and/or maintain a local and systemic low-grade activation of the innate immune system. Attraction of macrophages into adipose tissue and altered crosstalk between macrophages, adipocytes, and other cells of adipose tissue are symptoms of metabolic inflammation. Among several secreted factors attracting immune cells to adipose tissue, chemotactic C-C motif chemokine ligand 2 (CCL2) (also described as monocyte chemoattractant protein-1 (MCP-1)) has been shown to play a crucial role in adipose tissue macrophage infiltration. In this review, we aimed to summarize and discuss the current knowledge on CCL2 with a focus on its role in linking obesity to cardio-metabolic diseases. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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32 pages, 1209 KiB

Open AccessReview

The Role of the Adipokines in the Most Common Gestational Complications

by Paweł Gutaj, Rafał Sibiak, Maurycy Jankowski, Karina Awdi, Rut Bryl, Paul Mozdziak, Bartosz Kempisty and Ewa Wender-Ozegowska

Int. J. Mol. Sci. 2020, 21(24), 9408; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249408 - 10 Dec 2020

Cited by 42 | Viewed by 4402

Abstract

Adipocytokines are hormonally active molecules that are believed to play a key role in the regulation of crucial biological processes in the human body. Numerous experimental studies established significant alterations in the adipokine secretion patterns throughout pregnancy. The exact etiology of various gestational complications, such as gestational diabetes, preeclampsia, and fetal growth abnormalities, needs to be fully elucidated. The discovery of adipokines raised questions about their potential contribution to the molecular pathophysiology of those diseases. Multiple studies analyzed their local mRNA expression and circulating protein levels. However, most studies report conflicting results. Several adipokines such as leptin, resistin, irisin, apelin, chemerin, and omentin were proposed as potential novel early markers of heterogeneous gestational complications. The inclusion of the adipokines in the standard predictive multifactorial models could improve their prognostic values. Nonetheless, their independent diagnostic value is mostly insufficient to be implemented into standard clinical practice. Routine assessments of adipokine levels during pregnancy are not recommended in the management of both normal and complicated pregnancies. Based on the animal models (e.g., apelin and its receptors in the rodent preeclampsia models), future implementation of adipokines and their receptors as new therapeutic targets appears promising but requires further validation in humans. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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29 pages, 6906 KiB

Open AccessReview

Adipokines in the Skin and in Dermatological Diseases

by Dóra Kovács, Fruzsina Fazekas, Attila Oláh and Dániel Törőcsik

Int. J. Mol. Sci. 2020, 21(23), 9048; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239048 - 28 Nov 2020

Cited by 27 | Viewed by 4898

Abstract

Adipokines are the primary mediators of adipose tissue-induced and regulated systemic inflammatory diseases; however, recent findings revealed that serum levels of various adipokines correlate also with the onset and the severity of dermatological diseases. Importantly, further data confirmed that the skin serves not only as a target for adipokine signaling, but may serve as a source too. In this review, we aim to provide a complex overview on how adipokines may integrate into the (patho) physiological conditions of the skin by introducing the cell types, such as keratinocytes, fibroblasts, and sebocytes, which are known to produce adipokines as well as the signals that target them. Moreover, we discuss data from in vivo and in vitro murine and human studies as well as genetic data on how adipokines may contribute to various aspects of the homeostasis of the skin, e.g., melanogenesis, hair growth, or wound healing, just as to the pathogenesis of dermatological diseases such as psoriasis, atopic dermatitis, acne, rosacea, and melanoma. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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34 pages, 1216 KiB

Open AccessReview

Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression

by Ming-Ling Chang, Zinger Yang and Sien-Sing Yang

Int. J. Mol. Sci. 2020, 21(21), 8308; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218308 - 05 Nov 2020

Cited by 49 | Viewed by 6578

Abstract

Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett’s esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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18 pages, 1038 KiB

Open AccessReview

Adipokines and Obesity. Potential Link to Metabolic Disorders and Chronic Complications

by Katarzyna Zorena, Olga Jachimowicz-Duda, Daniel Ślęzak, Marlena Robakowska and Małgorzata Mrugacz

Int. J. Mol. Sci. 2020, 21(10), 3570; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103570 - 18 May 2020

Cited by 189 | Viewed by 11184

Abstract

The World Health Organization (WHO) has recognized obesity as one of the top ten threats to human health. It is estimated that the number of obese and overweight people worldwide exceeds the number of those who are undernourished. Obesity is not only a state of abnormally increased adipose tissue in the body, but also of increased release of biologically active adipokines. Adipokines released into the circulating blood, due to their specific receptors on the surface of target cells, act as classic hormones affecting the metabolism of tissues and organs. What is more, adipokines and cytokines may decrease the insulin sensitivity of tissues and induce inflammation and development of chronic complications. Certainly, it can be stated that in an era of a global obesity pandemic, adipokines may gain more and more importance as regards their use in the diagnostic evaluation and treatment of diseases. An extensive search for materials on the role of white, brown and perivascular fatty tissue and obesity-related metabolic and chronic complications was conducted online using PubMed, the Cochrane database and Embase. Full article

(This article belongs to the Special Issue Adipokines 3.0)

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