Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis

Rosa, Veronica De; Procaccini, Claudio; Cava, Antonio La; Chieffi, Paolo; Nicoletti, Giovanni Francesco; Fontana, Silvia; Zappacosta, Serafino; Matarese, Giuseppe

doi:10.1172/jci26523

Cited by 120 publications

(99 citation statements)

References 29 publications

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“…Abnormalities in the immune system have been reported in db/db mice, which suggests that the immune system might be involved in the pathogenesis of diabetes [29,30]. Recent studies have shown that leptin-deficient ob/ob mice are resistant to induction of experimental autoimmune encephalomyelitis, and leptin blockade inhibits T cell autoreactivity and slows disease progression in SJL/J mice [31,32]. Thus, further studies on DC function in db/db mice may provide new insights into our understanding of whether and to what extent DC contribute to the pathogenesis of diabetes development.…”

Section: Discussionmentioning

confidence: 99%

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

et al. 2006

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Previous studies demonstrated that lymphocyte development is impaired in leptin receptor (Ob-R)-deficient db/db mice. However, it remains unclear whether or not leptin signaling plays a physiological role in dendritic cell (DC) development and function. In this study, we first detected Ob-R expression in murine DC. Using db/db mice at a pre-diabetic stage, we demonstrate that the total number of DC generated from bone marrow (BM) cultures is significantly lower than in WT controls. Similarly, selective blockade of leptin with a soluble mouse Ob-R chimera (Ob-R:Fc) inhibited DC generation in wild-type BM cultures. The reduced DC yield in db/db BM culture was attributed to significantly increased apoptosis, which was associated with dysregulated expression of Bcl-2 family genes. Moreover, db/db DC displayed markedly reduced expression of co-stimulatory molecules and a Th2-type cytokine profile, with a poor capacity to stimulate allogeneic T cell proliferation. Consistent with their impaired DC phenotype and function, db/db DC showed significantly down-regulated activities of the PI3K/Akt pathway as well as STAT-3 and IjB-a. In conclusion, our findings demonstrate the involvement of leptin signaling in DC survival and maturation.See accompanying commentary: http://dx

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Section: Discussionmentioning

confidence: 99%

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

et al. 2006

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“…Male C57BL/6j mice (5-weeks old) ( Janvier Labs, St. Berthevin, France) were divided in six groups: two control groups that were untreated and exposed to normoxia or hypoxia; two groups treated with daily intraperitoneal injections of recombinant Ob from day −2 to day 21 (3 μg·g −1 of initial body weight [18]), exposed to normoxia or hypoxia; two groups treated with daily i.p. injections of soluble [19]), exposed to normoxia or chronic hypoxia. Sprague-Dawley male rats (4-weeks old) (Charles River Laboratories, Larberesle, France) were divided into four groups: two control groups (vehicle in drinking water) exposed to normoxia or hypoxia; two groups treated with DCA from day 14 to day 21 (1 g·L −1 in drinking water) exposed to normoxia or chronic hypoxia.…”

Section: Animal Models and Haemodynamic Measurementsmentioning

confidence: 99%

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Huertas

Thuillet

et al. 2015

Eur Respir J

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Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ⩽5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH ( pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH. @ERSpublications Targeting Ob/ObR-b axis represents an important tool for anti-proliferative and antiinflammatory strategies in PH http://ow.ly/I00jh

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“…An example of the first approach is a recombinant human and mouse Ob-R/Fc chimeric glycoprotein. 171,172 Only the latter 2 approaches have been employed in cardiac-related research. In neonatal rat ventricular cardiomyocytes, rat L39A/D40A/F41A leptin mutein blocked hypertrophic effects and abolished increases in Ob-R gene expression elicited by leptin, Ang II, or ET-1.…”

Section: Leptin Antagonistsmentioning

confidence: 99%

Leptin Signaling and Obesity

Yang

Barouch

2007

Circulation Research

283

131

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Abstract-Leptin, among the best known hormone markers for obesity, exerts pleiotropic actions on multiple organ systems. In this review, we summarize major leptin signaling pathways, namely Janus-activated kinase/signal transducers and activators of transcription and mitogen-activated protein kinase, including possible mechanisms of leptin resistance in obesity. The effects of leptin on the cardiovascular system are discussed in detail, including its contributions to hypertension, atherosclerosis, depressed myocardial contractile function, fatty acid metabolism, hypertrophic remodeling, and reduction of ischemic/reperfusion injury. The overall goal is to summarize current understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease. Extensive evidence now supports the notion that maladaptation of the biological system for weight maintenance makes it extremely difficult for people to maintain weight loss. 1 Several genes have been identified to disclose a physiological system that maintains body weight within a range of about twenty pounds. 2 A key element of this system is leptin, the 16-kDa hormonal product of the obesity (ob) gene. 3 Leptin is primarily secreted by adipocytes and is a classic member of the more than 50 identified adipocytokines that participate in adipose tissue hormonal signaling. 4 Since its identification in 1994, leptin has attracted much attention as one of the most important central and peripheral signals for the maintenance of energy homeostasis. [5][6][7][8] For example, a 9-year-old girl with extreme obesity was found to lack leptin. 9 Leptin treatment reduced her weight to the normal range for her age, and the same effects were observed in her similarly affected cousin. 10 Plasma leptin is generally proportional to adipose mass. 11,12 The primary physiological role of leptin is to communicate to the central nervous system (CNS) the abundance of available energy stores and to restrain food intake and induce energy expenditure. The absence of leptin therefore leads to increased appetite and food intake that result in morbid obesity. Notably, only rare cases of severe early childhood obesity have been associated with leptin deficiency. 9,13 The remainder of the obese population typically have elevated leptin levels. 14 The failure of leptin to induce weight loss in these cases is thought to be the result of leptin resistance.Hyperleptinemia, nearly universally observed in human obesity and animal models, is accompanied by a disruption of the usual activities of the hormone, possibly at different Original received May 22, 2007; revision received July 20, 2007; accepted August 6, 2007 18 -20 Obesity is also a part of the metabolic syndrome, which is diagnosed by a set of criteria that include abdominal obesity, insulin resistance, dyslipidemia, and hypertension. This patient population faces increased risk for type 2 diabetes and cardiovascular diseases. The widely distributed Ob-Rs make the hormone an attractive candidate for a molecul...

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Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis

Cited by 120 publications

References 29 publications

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

Leptin signalling system as a target for pulmonary arterial hypertension therapy

Leptin Signaling and Obesity

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