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Leptin and Relatives: Molecules at the Crossroad of Inflammation and Immunometabolism

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2019) | Viewed by 44105

Special Issue Editor

Servizo Galego de Saude and Institute of Biomedical Research (SERGAS-IDIS), The NEIRID LAB, Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases, Santiago University Clinical Hospital, 15706 Santiago de Compostela, A Coruña, Spain
Interests: leptin; adipokines; inflammation; arthritis; cartilage pathophysiology; immunometabolism; natural drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Next year, in 2019, we will celebrate the 25th anniversary of the discovery of leptin, the first member of the novel, recognized superfamily of molecules, collectively named adipokines. A quarter of a century, characterized by a plethora of studies that have led to the appreciation of the remarkable potency, range of biological effects and pleiotropism of leptin, as well as of many other adipokines. Leptin research in the last 25 years has significantly increased our understanding of the cellular and molecular mechanisms linking obesity and adipose tissue dysfunction to metabolic/immune/inflammatory disorders, a picture that is still incomplete. Research on leptin and relatives has permeated almost all biomedical disciplines, from endocrinology to rheumatology, just to simply cite a few. We invite authors to present original research articles, as well as review articles, that will stimulate the continue efforts in defining the molecular and cellular mechanisms of leptin and other adipokines in pathophysiology and clinics. Papers describing compelling mechanistic evidence linking the effects of leptin, and other adipokines, to the pathogenesis of immune–inflammatory–metabolic diseases are very welcome. Manuscripts reporting clinical applications of approved or investigational-adipokines research-based drugs with an emphasis on the cellular and molecular effects related to the efficacy, toxicity, response assessment, multimodality treatment, prognostic factors and predictive markers are also very welcome.

Dr. Oreste Gualillo
Guest Editor

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Keywords

  • leptin
  • adipokines
  • inflammation
  • immunity
  • immunometabolism
  • metabolic diseases
  • obesity
  • diabetes
  • stress response

Published Papers (7 papers)

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Research

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15 pages, 1994 KiB  
Article
Avian Expression Patterns and Genomic Mapping Implicate Leptin in Digestion and TNF in Immunity, Suggesting That Their Interacting Adipokine Role Has Been Acquired Only in Mammals
by Eyal Seroussi, Martin Knytl, Frédérique Pitel, Daniel Elleder, Vladimir Krylov, Sophie Leroux, Mireille Morisson, Sara Yosefi, Shoval Miyara, Saibaba Ganesan, Mark Ruzal, Leif Andersson and Miriam Friedman-Einat
Int. J. Mol. Sci. 2019, 20(18), 4489; https://doi.org/10.3390/ijms20184489 - 11 Sep 2019
Cited by 24 | Viewed by 4803
Abstract
In mammals, leptin and tumor-necrosis factor (TNF) are prominent interacting adipokines mediating appetite control and insulin sensitivity. While TNF pleiotropically functions in immune defense and cell survival, leptin is largely confined to signaling energy stores in adipocytes. Knowledge about the function of avian [...] Read more.
In mammals, leptin and tumor-necrosis factor (TNF) are prominent interacting adipokines mediating appetite control and insulin sensitivity. While TNF pleiotropically functions in immune defense and cell survival, leptin is largely confined to signaling energy stores in adipocytes. Knowledge about the function of avian leptin and TNF is limited and they are absent or lowly expressed in adipose, respectively. Employing radiation-hybrid mapping and FISH-TSA, we mapped TNF and its syntenic genes to chicken chromosome 16 within the major histocompatibility complex (MHC) region. This mapping position suggests that avian TNF has a role in regulating immune response. To test its possible interaction with leptin within the immune system and beyond, we compared the transcription patterns of TNF, leptin and their cognate receptors obtained by meta-analysis of GenBank RNA-seq data. While expression of leptin and its receptor (LEPR) were detected in the brain and digestive tract, TNF and its receptor mRNAs were primarily found in viral-infected and LPS-treated leukocytes. We confirmed leptin expression in the duodenum by immunohistochemistry staining. Altogether, we suggest that whereas leptin and TNF interact as adipokines in mammals, in birds, they have distinct roles. Thus, the interaction between leptin and TNF may be unique to mammals. Full article
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Review

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15 pages, 692 KiB  
Review
Leptin and Associated Mediators of Immunometabolic Signaling: Novel Molecular Outcome Measures for Neurostimulation to Treat Chronic Pain
by Thomas M. Kinfe, Michael Buchfelder, Shafqat R. Chaudhry, Krishnan V. Chakravarthy, Timothy R. Deer, Marc Russo, Peter Georgius, Rene Hurlemann, Muhammad Rasheed, Sajjad Muhammad and Thomas L. Yearwood
Int. J. Mol. Sci. 2019, 20(19), 4737; https://doi.org/10.3390/ijms20194737 - 24 Sep 2019
Cited by 10 | Viewed by 3946
Abstract
Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including [...] Read more.
Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including failed back surgery, neuropathic pain, and migraine. A literature review (PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles) was performed using the following search terms: chronic pain disorders, systemic inflammation, immunometabolism, prediction, biomarkers, metabolic disorders, and neuromodulation for chronic pain. Experimental studies indicate a relationship between the development and maintenance of chronic pain conditions and a deteriorated immunometabolic state mediated by circulating cytokines, chemokines, and cellular components. A few uncontrolled in-human studies found increased levels of pro-inflammatory cytokines known to drive metabolic disorders in chronic pain patients undergoing neurostimulation therapies. In this narrative review, we summarize the current knowledge and possible relationships of available neurostimulation therapies for chronic pain with mediators of central and peripheral neuroinflammation and immunometabolism on a molecular level. However, to address the needs for predictive factors and biomarkers, large-scale databank driven clinical trials are needed to determine the clinical value of molecular profiling. Full article
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14 pages, 457 KiB  
Review
Leptin-induced Trafficking of KATP Channels: A Mechanism to Regulate Pancreatic β-cell Excitability and Insulin Secretion
by Veronica Cochrane and Show-Ling Shyng
Int. J. Mol. Sci. 2019, 20(11), 2660; https://doi.org/10.3390/ijms20112660 - 30 May 2019
Cited by 13 | Viewed by 3864
Abstract
The adipocyte hormone leptin was first recognized for its actions in the central nervous system to regulate energy homeostasis but has since been shown to have direct actions on peripheral tissues. In pancreatic β-cells leptin suppresses insulin secretion by increasing KATP channel [...] Read more.
The adipocyte hormone leptin was first recognized for its actions in the central nervous system to regulate energy homeostasis but has since been shown to have direct actions on peripheral tissues. In pancreatic β-cells leptin suppresses insulin secretion by increasing KATP channel conductance, which causes membrane hyperpolarization and renders β-cells electrically silent. However, the mechanism by which leptin increases KATP channel conductance had remained unresolved for many years following the initial observation. Recent studies have revealed that leptin increases surface abundance of KATP channels by promoting channel trafficking to the β-cell membrane. Thus, KATP channel trafficking regulation has emerged as a mechanism by which leptin increases KATP channel conductance to regulate β-cell electrical activity and insulin secretion. This review will discuss the leptin signaling pathway that underlies KATP channel trafficking regulation in β-cells. Full article
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15 pages, 881 KiB  
Review
Gastric Leptin and Tumorigenesis: Beyond Obesity
by Kyoko Inagaki-Ohara
Int. J. Mol. Sci. 2019, 20(11), 2622; https://doi.org/10.3390/ijms20112622 - 28 May 2019
Cited by 16 | Viewed by 12968
Abstract
Leptin, an adipocyte-derived hormone and its receptor (ObR) expressed in the hypothalamus are well known as an essential regulator of appetite and energy expenditure. Obesity induces abundant leptin production, however, reduced sensitivity to leptin leads to the development of metabolic disorders, so called [...] Read more.
Leptin, an adipocyte-derived hormone and its receptor (ObR) expressed in the hypothalamus are well known as an essential regulator of appetite and energy expenditure. Obesity induces abundant leptin production, however, reduced sensitivity to leptin leads to the development of metabolic disorders, so called leptin resistance. The stomach has been identified as an organ that simultaneously expresses leptin and ObR. Accumulating evidence has shown gastric leptin to perform diverse functions, such as those in nutrient absorption and carcinogenesis in the gastrointestinal system, independent of its well-known role in appetite regulation and obesity. Overexpression of leptin and phosphorylated ObR is implicated in gastric cancer in humans and in murine model, and diet-induced obesity causes precancerous lesions in the stomach in mice. While the underlying pathomechanisms remain unclear, leptin signaling can affect gastric mucosal milieu. In this review, we focus on the significant role of the gastric leptin signaling in neoplasia and tumorigenesis in stomach in the context of hereditary and diet-induced obesity. Full article
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19 pages, 1369 KiB  
Review
Leptin and Immunological Profile in Obesity and Its Associated Diseases in Dogs
by Laura Cortese, Giuseppe Terrazzano and Alessandra Pelagalli
Int. J. Mol. Sci. 2019, 20(10), 2392; https://doi.org/10.3390/ijms20102392 - 14 May 2019
Cited by 22 | Viewed by 5519
Abstract
Growing scientific evidence has unveiled increased incidences of obesity in domestic animals and its influence on a plethora of associated disorders. Leptin, an adipokine regulating body fat mass, represents a key molecule in obesity, able to modulate immune responses and foster chronic inflammatory [...] Read more.
Growing scientific evidence has unveiled increased incidences of obesity in domestic animals and its influence on a plethora of associated disorders. Leptin, an adipokine regulating body fat mass, represents a key molecule in obesity, able to modulate immune responses and foster chronic inflammatory response in peripheral tissues. High levels of cytokines and inflammatory markers suggest an association between inflammatory state and obesity in dogs, highlighting the parallelism with humans. Canine obesity is a relevant disease always accompanied with several health conditions such as inflammation, immune-dysregulation, insulin resistance, pancreatitis, orthopaedic disorders, cardiovascular disease, and neoplasia. However, leptin involvement in many disease processes in veterinary medicine is poorly understood. Moreover, hyperleptinemia as well as leptin resistance occur with cardiac dysfunction as a consequence of altered cardiac mitochondrial metabolism in obese dogs. Similarly, leptin dysregulation seems to be involved in the pancreatitis pathophysiology. This review aims to examine literature concerning leptin and immunological status in obese dogs, in particular for the aspects related to obesity-associated diseases. Full article
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17 pages, 2259 KiB  
Review
Molecular Relationships among Obesity, Inflammation and Intervertebral Disc Degeneration: Are Adipokines the Common Link?
by Clara Ruiz-Fernández, Vera Francisco, Jesus Pino, Antonio Mera, Miguel Angel González-Gay, Rodolfo Gómez, Francisca Lago and Oreste Gualillo
Int. J. Mol. Sci. 2019, 20(8), 2030; https://doi.org/10.3390/ijms20082030 - 25 Apr 2019
Cited by 79 | Viewed by 8940
Abstract
Intervertebral disc degeneration (IVDD) is a chronic, expensive, and high-incidence musculoskeletal disorder largely responsible for back/neck and radicular-related pain. It is characterized by progressive degenerative damage of intervertebral tissues along with metabolic alterations of all other vertebral tissues. Despite the high socio-economic impact [...] Read more.
Intervertebral disc degeneration (IVDD) is a chronic, expensive, and high-incidence musculoskeletal disorder largely responsible for back/neck and radicular-related pain. It is characterized by progressive degenerative damage of intervertebral tissues along with metabolic alterations of all other vertebral tissues. Despite the high socio-economic impact of IVDD, little is known about its etiology and pathogenesis, and currently, no cure or specific treatments are available. Recent evidence indicates that besides abnormal and excessive mechanical loading, inflammation may be a crucial player in IVDD. Furthermore, obese adipose tissue is characterized by a persistent and low-grade production of systemic pro-inflammatory factors. In this context, chronic low-grade inflammation associated with obesity has been hypothesized as an important contributor to IVDD through different, but still unknown, mechanisms. Adipokines, such as leptin, produced prevalently by white adipose tissues, but also by other cells of mesenchymal origin, particularly cartilage and bone, are cytokine-like hormones involved in important physiologic and pathophysiological processes. Although initially restricted to metabolic functions, adipokines are now viewed as key players of the innate and adaptative immune system and active modulators of the acute and chronic inflammatory response. The goal of this review is to summarize the most recent findings regarding the interrelationships among inflammation, obesity and the pathogenic mechanisms involved in the IVDD, with particular emphasis on the contribution of adipokines and their potential as future therapeutic targets. Full article
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Other

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8 pages, 1271 KiB  
Brief Report
Oxytocin Administration Alleviates Acute but Not Chronic Leptin Resistance of Diet-Induced Obese Mice
by Mehdi Labyb, Chloé Chrétien, Aurélie Caillon, Françoise Rohner-Jeanrenaud and Jordi Altirriba
Int. J. Mol. Sci. 2019, 20(1), 88; https://doi.org/10.3390/ijms20010088 - 26 Dec 2018
Cited by 16 | Viewed by 3473
Abstract
Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and [...] Read more.
Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and humans, we investigated the effects of oxytocin and leptin cotreatment. First, lean and diet-induced obese (DIO) mice were treated with oxytocin for 2 weeks and we measured the acute leptin response. Second, DIO mice were treated for 2 weeks with saline, oxytocin (50 μg/day), leptin (20 or 40 µg/day) or oxytocin plus leptin. Oxytocin pre-treatment restored a normal acute leptin response, decreasing food intake and body weight gain. Chronic continuous administration of oxytocin or leptin at 40 µg/day decreased body weight in the presence (leptin) or in the absence (oxytocin) of cumulative differences in food intake. Saline or leptin treatment at 20 µg/day had no impact on body weight. Oxytocin and leptin cotreatments had no additional effects compared with single treatments. These results point to the fact that chronic oxytocin treatment improves the acute, but not the chronic leptin response, suggesting that this treatment could be used to improve the short-term satiety effect of leptin. Full article
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