Requirement for Leptin in the Induction and Progression of Autoimmune Encephalomyelitis

Matarese, Giuseppe; Giacomo, Antonio Di; Sanna, Veronica; Lord, Graham M.; Howard, Jane K.; Tuoro, Antonino Di; Bloom, Stephen R.; Lechler, Robert I.; Zappacosta, Serafino; Fontana, Silvia

doi:10.4049/jimmunol.166.10.5909

Cited by 316 publications

(252 citation statements)

References 25 publications

Supporting

Mentioning

233

Contrasting

Unclassified

Order By: Relevance

“…Obesity is associated with a change in adipokine profiles including an increase in leptin which plays a proinflammatory role, and lowered ghrelin which is anti‐inflammatory. These adipokines play varied role in thymic maturation, T‐cell proliferation, development of memory cells and cytokine production,17, 28, 29, 30, 31 all mechanisms which are purported to play a role in pediatric‐onset MS 32, 33, 34, 35…”

Section: Discussionmentioning

confidence: 99%

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

Chitnis

Graves

Weinstock‐Guttman

et al. 2016

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveThe aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS.MethodsCase–control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex‐ and age‐stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex‐stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity.ResultsOnly 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms (P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS (P < 0.001).InterpretationHigher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

Chitnis

Graves

Weinstock‐Guttman

et al. 2016

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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

show abstract

“…5,81 The onset of EAE in wild-type mice is preceded by an increase in circulating leptin and is delayed by acute starvation. 5,82 During the active phase of EAE, leptin is secreted by both macrophages and T cells that have infiltrated the central nervous system, and leptin secretion by activated T cells appears to constitute an autocrine loop, sustaining their proliferation.…”

Section: Leptin and Multiple Sclerosis (Ms)mentioning

confidence: 99%

Leptin in immuno-rheumatological diseases

et al. 2011

View full text Add to dashboard Cite

Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

show abstract

Requirement for Leptin in the Induction and Progression of Autoimmune Encephalomyelitis

Cited by 316 publications

References 25 publications

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

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

Leptin in immuno-rheumatological diseases

Contact Info

Product

Resources

About