International Journal of Molecular Sciences

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Open AccessEditorial

Mechanisms of Adiponectin Action

by Tania Fiaschi

Int. J. Mol. Sci. 2019, 20(12), 2894; https://doi.org/10.3390/ijms20122894 - 13 Jun 2019

Cited by 16 | Viewed by 3133

Abstract

Adiponectin, the most abundant secreted adipokine, has received great attention from the scientific community since its discovery [...] Full article

(This article belongs to the Special Issue Mechanisms of Adiponectin Action)

Research

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10 pages, 5439 KiB

Open AccessArticle

Kojyl Cinnamate Ester Derivatives Increase Adiponectin Expression and Stimulate Adiponectin-Induced Hair Growth Factors in Human Dermal Papilla Cells

by Phil June Park and Eun-Gyung Cho

Int. J. Mol. Sci. 2019, 20(8), 1859; https://doi.org/10.3390/ijms20081859 - 15 Apr 2019

Cited by 10 | Viewed by 4169

Abstract

Adiponectin (APN), released mainly from adipose tissue, is a well-known homeostatic factor for regulating glucose levels, lipid metabolism, and insulin sensitivity. A recent study showed that human hair follicles express APN receptors and the presence of APN-mediated hair growth signaling, thereby suggesting that [...] Read more.

Adiponectin (APN), released mainly from adipose tissue, is a well-known homeostatic factor for regulating glucose levels, lipid metabolism, and insulin sensitivity. A recent study showed that human hair follicles express APN receptors and the presence of APN-mediated hair growth signaling, thereby suggesting that APN is a potent hair growth-promoting adipokine. Previously, kojyl cinnamate ester derivatives (KCEDs) were synthesized in our institute as new anti-aging or adiponectin-/adipogenesis-inducing compounds. Here, we tested the activity of these derivatives to induce endogenous APN secretion. Among the derivatives, KCED-1 and KCED-2 showed improved activity in inducing APN mRNA expression, secretion of APN protein, and adipogenesis in human subcutaneous fat cells (hSCFs) when compared with the effects of Seletinoid G, a verified APN inducer. When human follicular dermal papilla cells were treated with the culture supernatant of KCED-1- or KCED-2-treated hSCFs, the mRNA expression of APN-induced hair growth factors such as insulin-like growth factor, hepatocyte growth factor, and vascular endothelial growth factor was upregulated compared with that in the control. Taken together, our study shows that among kojyl cinnamate ester derivatives, KCED-1, KCED-2, as well as Seletinoid G are effective inducers of endogenous APN production in subcutaneous fat tissues, which may in turn contribute to the promotion of hair growth in the human scalp. Full article

(This article belongs to the Special Issue Mechanisms of Adiponectin Action)

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11 pages, 822 KiB

Open AccessArticle

Interaction of Nerve Growth Factor β with Adiponectin and SPARC Oppositely Modulates its Biological Activity

by Yuu Okura, Takeshi Imao, Seisuke Murashima, Haruki Shibata, Akihiro Kamikavwa, Yuko Okamatsu-Ogura, Masayuki Saito and Kazuhiro Kimura

Int. J. Mol. Sci. 2019, 20(7), 1541; https://doi.org/10.3390/ijms20071541 - 27 Mar 2019

Cited by 7 | Viewed by 3349

Abstract

Both adiponectin and secreted protein, acidic and rich in cysteine (SPARC) inhibit platelet-derived growth factor-BB (PDGF-BB)-induced and basic fibroblast growth factor (FGF2)-induced angiogenic activities through direct and indirect interactions. Although SPARC enhances nerve growth factor (NGF)-dependent neurogenesis, the physical interaction of NGFβ with [...] Read more.

Both adiponectin and secreted protein, acidic and rich in cysteine (SPARC) inhibit platelet-derived growth factor-BB (PDGF-BB)-induced and basic fibroblast growth factor (FGF2)-induced angiogenic activities through direct and indirect interactions. Although SPARC enhances nerve growth factor (NGF)-dependent neurogenesis, the physical interaction of NGFβ with adiponectin and SPARC remains obscure. Therefore, we first examined their intermolecular interaction by surface plasmon resonance method. NGFβ bound to immobilized SPARC with the binding constant of 59.4 nM, comparable with that of PDGF-BB (24.5 nM) but far less than that of FGF2 (14.4 µM). NGFβ bound to immobilized full length adiponectin with the binding constant of 103 nM, slightly higher than those of PDGF-BB (24.3 nM) and FGF2 (80.2 nM), respectively. Treatment of PC12 cells with SPARC did not cause mitogen-activated protein kinase (MAPK) activation and neurite outgrowth. However, simultaneous addition of SPARC with NGFβ enhanced NGFβ-induced MAPK phosphorylation and neurite outgrowth. Treatment of the cells with adiponectin increased AMP-activated protein kinase (AMPK) phosphorylation but failed to induce neurite outgrowth. Simultaneous treatment with NGFβ and adiponectin significantly reduced cell size and the number of cells with neurite, even after silencing the adiponectin receptors by their siRNA. These results indicate that NGFβ directly interacts with adiponectin and SPARC, whereas these interactions oppositely regulate NGFβ functions. Full article

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21 pages, 1228 KiB

Open AccessArticle

Transcriptomic Analysis of Porcine Endometrium during Implantation after In Vitro Stimulation by Adiponectin

by Nina Smolinska, Karol Szeszko, Kamil Dobrzyn, Marta Kiezun, Edyta Rytelewska, Katarzyna Kisielewska, Marlena Gudelska, Kinga Bors, Joanna Wyrebek, Grzegorz Kopij, Barbara Kaminska and Tadeusz Kaminski

Int. J. Mol. Sci. 2019, 20(6), 1335; https://doi.org/10.3390/ijms20061335 - 16 Mar 2019

Cited by 16 | Viewed by 3751

Abstract

Comprehensive understanding of the regulatory mechanism of the implantation process in pigs is crucial for reproductive success. The endometrium plays an important role in regulating the establishment and maintenance of gestation. The goal of the current study was to determine the effect of [...] Read more.

Comprehensive understanding of the regulatory mechanism of the implantation process in pigs is crucial for reproductive success. The endometrium plays an important role in regulating the establishment and maintenance of gestation. The goal of the current study was to determine the effect of adiponectin on the global expression pattern of genes and relationships among differentially expressed genes (DE-genes) in the porcine endometrium during implantation using microarrays. Diverse transcriptome analyses including gene ontology (GO), biological pathway, networks, and DE-gene analyses were performed. Adiponectin altered the expression of 1286 genes with fold-change (FC) values greater than 1.2 (p < 0.05). The expression of 560 genes were upregulated and 726 downregulated in the endometrium treated with adiponectin. Thirteen genes were selected for real-time PCR validation of differential expression based on a known role in metabolism, steroid and prostaglandin synthesis, interleukin and growth factor action, and embryo implantation. Functional analysis of the relationship between DE-genes indicated that adiponectin interacts with genes that are involved in the processes of cell proliferation, programmed cell death, steroid and prostaglandin synthesis/metabolism, cytokine production, and cell adhesion that are critical for reproductive success. The presented results suggest that adiponectin signalling may play a key role in the implantation of pig. Full article

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Review

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21 pages, 751 KiB

Open AccessReview

Adipose Tissue, Obesity and Adiponectin: Role in Endocrine Cancer Risk

by Andrea Tumminia, Federica Vinciguerra, Miriam Parisi, Marco Graziano, Laura Sciacca, Roberto Baratta and Lucia Frittitta

Int. J. Mol. Sci. 2019, 20(12), 2863; https://doi.org/10.3390/ijms20122863 - 12 Jun 2019

Cited by 96 | Viewed by 7430

Abstract

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many [...] Read more.

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies. Full article

(This article belongs to the Special Issue Mechanisms of Adiponectin Action)

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27 pages, 1284 KiB

Open AccessReview

Adiponectin, Obesity, and Cancer: Clash of the Bigwigs in Health and Disease

by Sheetal Parida, Sumit Siddharth and Dipali Sharma

Int. J. Mol. Sci. 2019, 20(10), 2519; https://doi.org/10.3390/ijms20102519 - 22 May 2019

Cited by 181 | Viewed by 15782

Abstract

Adiponectin is one of the most important adipocytokines secreted by adipocytes and is called a “guardian angel adipocytokine” owing to its unique biological functions. Adiponectin inversely correlates with body fat mass and visceral adiposity. Identified independently by four different research groups, adiponectin has [...] Read more.

Adiponectin is one of the most important adipocytokines secreted by adipocytes and is called a “guardian angel adipocytokine” owing to its unique biological functions. Adiponectin inversely correlates with body fat mass and visceral adiposity. Identified independently by four different research groups, adiponectin has multiple names; Acrp30, apM1, GBP28, and AdipoQ. Adiponectin mediates its biological functions via three known receptors, AdipoR1, AdipoR2, and T-cadherin, which are distributed throughout the body. Biological functions of adiponectin are multifold ranging from anti-diabetic, anti-atherogenic, anti-inflammatory to anti-cancer. Lower adiponectin levels have been associated with metabolic syndrome, type 2 diabetes, insulin resistance, cardiovascular diseases, and hypertension. A plethora of experimental evidence supports the role of obesity and increased adiposity in multiple cancers including breast, liver, pancreatic, prostrate, ovarian, and colorectal cancers. Obesity mediates its effect on cancer progression via dysregulation of adipocytokines including increased production of oncogenic adipokine leptin along with decreased production of adiponectin. Multiple studies have shown the protective role of adiponectin in obesity-associated diseases and cancer. Adiponectin modulates multiple signaling pathways to exert its physiological and protective functions. Many studies over the years have shown the beneficial effect of adiponectin in cancer regression and put forth various innovative ways to increase adiponectin levels. Full article

(This article belongs to the Special Issue Mechanisms of Adiponectin Action)

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19 pages, 1327 KiB

Open AccessReview

The Emerging Role of Adiponectin in Female Malignancies

by Luca Gelsomino, Giuseppina Daniela Naimo, Stefania Catalano, Loredana Mauro and Sebastiano Andò

Int. J. Mol. Sci. 2019, 20(9), 2127; https://doi.org/10.3390/ijms20092127 - 30 Apr 2019

Cited by 44 | Viewed by 5883

Abstract

Obesity, characterized by excess body weight, is now accepted as a hazardous health condition and an oncogenic factor. In different epidemiological studies obesity has been described as a risk factor in several malignancies. Some biological mechanisms that orchestrate obesity–cancer interaction have been discovered, [...] Read more.

Obesity, characterized by excess body weight, is now accepted as a hazardous health condition and an oncogenic factor. In different epidemiological studies obesity has been described as a risk factor in several malignancies. Some biological mechanisms that orchestrate obesity–cancer interaction have been discovered, although others are still not completely understood. The unbalanced secretion of biomolecules, called “adipokines”, released by adipocytes strongly influences obesity-related cancer development. Among these adipokines, adiponectin exerts a critical role. Physiologically adiponectin governs glucose levels and lipid metabolism and is fundamental in the reproductive system. Low adiponectin circulating levels have been found in obese patients, in which its protective effects were lost. In this review, we summarize the epidemiological, in vivo and in vitro data in order to highlight how adiponectin may affect obesity-associated female cancers. Full article

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12 pages, 531 KiB

Open AccessReview

Mechanisms of Adiponectin Action: Implication of Adiponectin Receptor Agonism in Diabetic Kidney Disease

by Yaeni Kim and Cheol Whee Park

Int. J. Mol. Sci. 2019, 20(7), 1782; https://doi.org/10.3390/ijms20071782 - 10 Apr 2019

Cited by 80 | Viewed by 9458

Abstract

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression [...] Read more.

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here. Full article

(This article belongs to the Special Issue Mechanisms of Adiponectin Action)

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10 pages, 485 KiB

Open AccessReview

Adiponectin in Myopathies

by Tania Gamberi, Francesca Magherini and Tania Fiaschi

Int. J. Mol. Sci. 2019, 20(7), 1544; https://doi.org/10.3390/ijms20071544 - 27 Mar 2019

Cited by 12 | Viewed by 4803

Abstract

In skeletal muscle, adiponectin has varied and pleiotropic functions, ranging from metabolic, anti-inflammatory, insulin-sensitizing to regenerative roles. Despite the important functions exerted by adiponectin, the study of the hormone in myopathies is still marginal. Myopathies include inherited and non-inherited/acquired neuromuscular pathologies characterized by [...] Read more.

In skeletal muscle, adiponectin has varied and pleiotropic functions, ranging from metabolic, anti-inflammatory, insulin-sensitizing to regenerative roles. Despite the important functions exerted by adiponectin, the study of the hormone in myopathies is still marginal. Myopathies include inherited and non-inherited/acquired neuromuscular pathologies characterized by muscular degeneration and weakness. This review reports current knowledge about adiponectin in myopathies, regarding in particular the role of adiponectin in some hereditary myopathies (as Duchenne muscular dystrophy) and non-inherited/acquired myopathies (such as idiopathic inflammatory myopathies and fibromyalgia). These studies show that some myopathies are characterized by decreased concentration of plasma adiponectin and that hormone replenishment induces beneficial effects in the diseased muscles. Overall, these findings suggest that adiponectin could constitute a future new therapeutic approach for the improvement of the abnormalities caused by myopathies. Full article

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17 pages, 868 KiB

Open AccessReview

Adiponectin—Consideration for its Role in Skeletal Muscle Health

by Matthew P. Krause, Kevin J. Milne and Thomas J. Hawke

Int. J. Mol. Sci. 2019, 20(7), 1528; https://doi.org/10.3390/ijms20071528 - 27 Mar 2019

Cited by 88 | Viewed by 7338

Abstract

Adiponectin regulates metabolism through blood glucose control and fatty acid oxidation, partly mediated by downstream effects of adiponectin signaling in skeletal muscle. More recently, skeletal muscle has been identified as a source of adiponectin expression, fueling interest in the role of adiponectin as [...] Read more.

Adiponectin regulates metabolism through blood glucose control and fatty acid oxidation, partly mediated by downstream effects of adiponectin signaling in skeletal muscle. More recently, skeletal muscle has been identified as a source of adiponectin expression, fueling interest in the role of adiponectin as both a circulating adipokine and a locally expressed paracrine/autocrine factor. In addition to being metabolically responsive, skeletal muscle functional capacity, calcium handling, growth and maintenance, regenerative capacity, and susceptibility to chronic inflammation are all strongly influenced by adiponectin stimulation. Furthermore, physical exercise has clear links to adiponectin expression and circulating concentrations in healthy and diseased populations. Greater physical activity is generally related to higher adiponectin expression while lower adiponectin levels are found in inactive obese, pre-diabetic, and diabetic populations. Exercise training typically restores plasma adiponectin and is associated with improved insulin sensitivity. Thus, the role of adiponectin signaling in skeletal muscle has expanded beyond that of a metabolic regulator to include several aspects of skeletal muscle function and maintenance critical to muscle health, many of which are responsive to, and mediated by, physical exercise. Full article

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37 pages, 3461 KiB

Open AccessReview

Mechanisms of Adiponectin Action in Fertility: An Overview from Gametogenesis to Gestation in Humans and Animal Models in Normal and Pathological Conditions

by Alix Barbe, Alice Bongrani, Namya Mellouk, Anthony Estienne, Patrycja Kurowska, Jérémy Grandhaye, Yaelle Elfassy, Rachel Levy, Agnieszka Rak, Pascal Froment and Joëlle Dupont

Int. J. Mol. Sci. 2019, 20(7), 1526; https://doi.org/10.3390/ijms20071526 - 27 Mar 2019

Cited by 89 | Viewed by 9344

Abstract

Adiponectin is the most abundant plasma adipokine. It mainly derives from white adipose tissue and plays a key role in the control of energy metabolism thanks to its insulin-sensitising, anti-inflammatory, and antiatherogenic properties. In vitro and in vivo evidence shows that adiponectin could [...] Read more.

Adiponectin is the most abundant plasma adipokine. It mainly derives from white adipose tissue and plays a key role in the control of energy metabolism thanks to its insulin-sensitising, anti-inflammatory, and antiatherogenic properties. In vitro and in vivo evidence shows that adiponectin could also be one of the hormones controlling the interaction between energy balance and fertility in several species, including humans. Indeed, its two receptors—AdipoR1 and AdipoR2—are expressed in hypothalamic–pituitary–gonadal axis and their activation regulates Kiss, GnRH and gonadotropin expression and/or secretion. In male gonads, adiponectin modulates several functions of both somatic and germ cells, such as steroidogenesis, proliferation, apoptosis, and oxidative stress. In females, it controls steroidogenesis of ovarian granulosa and theca cells, oocyte maturation, and embryo development. Adiponectin receptors were also found in placental and endometrial cells, suggesting that this adipokine might play a crucial role in embryo implantation, trophoblast invasion and foetal growth. The aim of this review is to characterise adiponectin expression and its mechanism of action in male and female reproductive tract. Further, since features of metabolic syndrome are associated with some reproductive diseases, such as polycystic ovary syndrome, gestational diabetes mellitus, preeclampsia, endometriosis, foetal growth restriction and ovarian and endometrial cancers, evidence regarding the emerging role of adiponectin in these disorders is also discussed. Full article

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25 pages, 1686 KiB

Open AccessReview

Beneficial Effects of Adiponectin on Glucose and Lipid Metabolism and Atherosclerotic Progression: Mechanisms and Perspectives

by Hidekatsu Yanai and Hiroshi Yoshida

Int. J. Mol. Sci. 2019, 20(5), 1190; https://doi.org/10.3390/ijms20051190 - 8 Mar 2019

Cited by 327 | Viewed by 24091

Abstract

Circulating adiponectin concentrations are reduced in obese individuals, and this reduction has been proposed to have a crucial role in the pathogenesis of atherosclerosis and cardiovascular diseases associated with obesity and the metabolic syndrome. We focus on the effects of adiponectin on glucose [...] Read more.

Circulating adiponectin concentrations are reduced in obese individuals, and this reduction has been proposed to have a crucial role in the pathogenesis of atherosclerosis and cardiovascular diseases associated with obesity and the metabolic syndrome. We focus on the effects of adiponectin on glucose and lipid metabolism and on the molecular anti-atherosclerotic properties of adiponectin and also discuss the factors that increase the circulating levels of adiponectin. Adiponectin reduces inflammatory cytokines and oxidative stress, which leads to an improvement of insulin resistance. Adiponectin-induced improvement of insulin resistance and adiponectin itself reduce hepatic glucose production and increase the utilization of glucose and fatty acids by skeletal muscles, lowering blood glucose levels. Adiponectin has also β cell protective effects and may prevent the development of diabetes. Adiponectin concentration has been found to be correlated with lipoprotein metabolism; especially, it is associated with the metabolism of high-density lipoprotein (HDL) and triglyceride (TG). Adiponectin appears to increase HDL and decrease TG. Adiponectin increases ATP-binding cassette transporter A1 and lipoprotein lipase (LPL) and decreases hepatic lipase, which may elevate HDL. Increased LPL mass/activity and very low density lipoprotein (VLDL) receptor and reduced apo-CIII may increase VLDL catabolism and result in the reduction of serum TG. Further, adiponectin has various molecular anti-atherosclerotic properties, such as reduction of scavenger receptors in macrophages and increase of cholesterol efflux. These findings suggest that high levels of circulating adiponectin can protect against atherosclerosis. Weight loss, exercise, nutritional factors, anti-diabetic drugs, lipid-lowering drugs, and anti-hypertensive drugs have been associated with an increase of serum adiponectin level. Full article

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