Novel Superactive Leptin Antagonists and their Potential Therapeutic Applications

Gertler, Arieh; Elinav, Eran

doi:10.2174/13816128113199990014

Cited by 14 publications

(9 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To understand this biphasic effect, we assessed the potential loss of selectivity for the leptin receptor. Thus, myometrial cells were treated with leptin either at 6.25 or 50 ng·mL −1 alone or in the presence of the leptin receptor antagonist SHLA (Shpilman et al, 2011;Gertler and Elinav, 2014). First, we determined by use of the interference biolayer (Octet) that SHLA has a three-fold higher affinity for the leptin receptor than leptin (KDSHLA = 0.04 nM < KDLeptin = 0.12 nM for the leptin receptor; Figure 1D).…”

Section: Leptin Receptor Stimulation Induces Primary Human Myometrialmentioning

confidence: 99%

EXPRESSION OF CONCERN: Dose‐dependent biphasic leptin‐induced proliferation is caused by non‐specific IL‐6/NF‐κB pathway activation in human myometrial cells

Barrichon

Hadi

Wendremaire

et al. 2015

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSELeptin, an adipokine synthesized by the placenta during pregnancy, has been proposed for the management of preterm labour (PTL), as it is able to prevent in vitro uterine contractility and remodelling associated with labour onset. Another common feature of labour onset is the phenotypic switch of myometrial smooth muscle cells from a proliferative to a hypertrophic state. As proliferative effects have been demonstrated for leptin in other tissues, we aimed to investigate its ability to induce myometrial proliferation and thus to maintain uterine quiescence. EXPERIMENTAL APPROACHWe stimulated human primary myometrial smooth muscle cells with leptin in the presence or absence of receptor antagonists or signalling pathway inhibitors. KEY RESULTSLeptin induced myometrial cell proliferation in a biphasic manner. At 6.25 ng·mL , leptin induced direct non-specific stimulation of the IL-6 receptor, leading to NF-κB activation, and exerted anti-proliferative effects. However, at 50 ng·mL, leptin re-induces proliferation via IL-6 receptor stimulation that requires STAT3 and delayed ERK1/2 activation. CONCLUSIONS AND IMPLICATIONSThese data bring new insights into leptin signalling-induced myometrial proliferation and its interrelationship with the IL-6/IL-6 receptor axis. In the light of our previous work, the present study emphasizes the potential value of leptin in the pharmacological management of PTL and it also strengthens the hypothesis that leptin might be a contributory factor in the parturition-related disorders observed in obese women.

show abstract

Section: Leptin Receptor Stimulation Induces Primary Human Myometrialmentioning

confidence: 99%

EXPRESSION OF CONCERN: Dose‐dependent biphasic leptin‐induced proliferation is caused by non‐specific IL‐6/NF‐κB pathway activation in human myometrial cells

Barrichon

Hadi

Wendremaire

et al. 2015

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Our findings also reveal a potential new role for leptin antagonists in modulating tissue-specific IGF-1 levels with aging. These molecules have recently been studied for their effects on cancer, muscle wasting (cachexia), and metabolic syndrome (Gertler and Elinav, 2014). Our data indicate that the leptin receptor antagonist Allo-aca can suppress IGF-1 levels in both liver and skeletal muscle independent of GH alterations.…”

Section: Discussionmentioning

confidence: 99%

The adipokine leptin mediates muscle- and liver-derived IGF-1 in aged mice

Hamrick

Dukes

Arounleut

et al. 2015

Experimental Gerontology

View full text Add to dashboard Cite

Muscle- and liver-derived IGF-1 play important roles in muscle anabolism throughout growth and aging. Yet, prolonged food restriction is thought to increase longevity in part by lowering levels of IGF-1, which in turn reduces the risk for developing various cancers. The dietary factors that modulate IGF-1 levels are, however, poorly understood. We tested the hypothesis that the adipokine leptin, which is elevated with food intake and suppressed during fasting, is a key mediator of IGF-1 levels with aging and food restriction. First, leptin levels in peripheral tissues were measured in young mice fed ad libitum, aged mice fed ad libitum, and aged calorie-restricted (CR) mice. A group of aged CR mice were also treated with recombinant leptin for 10 days. Later, aged mice fed ad libitum were treated with saline (VEH) or with a novel leptin receptor antagonist peptide (Allo-aca) and tissue-specific levels of IGF-1 were determined. On one hand, recombinant leptin induced a three-fold increase in liver-derived IGF-1 and a two-fold increase in muscle-derived IGF-1 in aged, CR mice. Leptin also significantly increased serum growth hormone levels in the aged, CR mice. On the other, the leptin receptor antagonist Allo-aca did not alter body weight or muscle mass in treated mice compared to VEH mice. Allo-aca did, however, produce a significant (20%) decline in liver-derived IGF-1 as well as an even more pronounced (>50%) decrease in muscle-derived IGF-1 compared to VEH-treated mice. The reduced IGF-1 levels in Allo-aca treated mice were not accompanied by any significant change in growth hormone levels compared to VEH mice. These findings suggest that leptin receptor antagonists may represent novel therapeutic agents for attenuating IGF-1 signaling associated with aging, and could potentially mimic some of the positive effects of calorie restriction on longevity.

show abstract

“…Presently, antagonists of leptin have been developed to treat metabolic disorders. It should be tested if they could also have anti-inflammatory activities in vivo [118–120]. Interestingly, a monoclonal antibody against the leptin receptor was shown to block human TNF production by monocytes acting as an antagonist [121].…”

Section: Adipocytokines As Future Possible Therapeutic Targetsmentioning

confidence: 99%

Adipocytokines in Rheumatoid Arthritis: The Hidden Link between Inflammation and Cardiometabolic Comorbidities

Ruscitti

Benedetto

Berardicurti

et al. 2018

Journal of Immunology Research

View full text Add to dashboard Cite

Rheumatoid arthritis is a chronic autoimmune disease affecting typically synovial joints and leading to progressive articular damage, disability, and reduced quality of life. Despite better recent therapeutic strategies improving long-term outcomes, RA is associated with a high rate of comorbidities, infections, malignancies, and cardiovascular disease (CVD). Remarkably, some well-known pathogenic proinflammatory mediators in RA, such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF), may play a pivotal role in the development of CVD. Interestingly, different preclinical and clinical studies have suggested that biologic agents commonly used to treat RA patients may be effective in improving CVD. In this context, the contribution of adipocytokines has been suggested. Adipocytokines are pleiotropic molecules, mainly released by white adipose tissue and immune cells. Adipocytokines modulate the function of different tissues and cells, and in addition to energy homeostasis and metabolism, amplify inflammation, immune response, and tissue damage. Adipocytokines may contribute to the proinflammatory state in RA patients and development of bone damage. Furthermore, they could be associated with the occurrence of CVD. In this study, we reviewed available evidence about adipocytokines in RA, because of their involvement in disease activity, associated CVD, and possible biomarkers of prognosis and treatment outcome and because of their potential as a possible new therapeutic target.

show abstract

Novel Superactive Leptin Antagonists and their Potential Therapeutic Applications

Cited by 14 publications

References 95 publications

EXPRESSION OF CONCERN: Dose‐dependent biphasic leptin‐induced proliferation is caused by non‐specific IL‐6/NF‐κB pathway activation in human myometrial cells

EXPRESSION OF CONCERN: Dose‐dependent biphasic leptin‐induced proliferation is caused by non‐specific IL‐6/NF‐κB pathway activation in human myometrial cells

The adipokine leptin mediates muscle- and liver-derived IGF-1 in aged mice

Adipocytokines in Rheumatoid Arthritis: The Hidden Link between Inflammation and Cardiometabolic Comorbidities

Contact Info

Product

Resources

About