leptin and Multiple-Sclerosis--Relapsing-Remitting

Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection.. To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS).. In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on. A 1-unit leptin. We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals.

Topics: Adult; Case-Control Studies; Female; Humans; Leptin; Logistic Models; Male; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Risk Factors

Leptin (LEP) may contribute to the pathogenesis of multiple sclerosis (MS) by its immunomodulatory, proinflammatory and prooxidant effects. Therefore, plasma LEP levels and mRNA expression of five genes related to the LEP signaling pathway (LEP, LEP receptor (LEPR), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1A), superoxide dismutase 2, tumor necrosis factor-alpha) were investigated in relapsing-remitting MS. In patients (N = 64), compared to healthy subjects (N = 62), relative LEP mRNA levels were significantly increased (p = 0,01), while LEPR and PGC1A mRNA levels were decreased (p = 0,001 and p = 0,04, respectively). Significant positive correlation was observed between LEPR mRNA levels and clinical parameters of MS progression (EDSS, MSSS).

Topics: Adult; Female; Humans; Leptin; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Reactive Oxygen Species; Receptors, Leptin; RNA, Messenger; Tumor Necrosis Factor-alpha; Young Adult

Increased adiposity is a risk factor for multiple sclerosis (MS) and is associated with increased disability scores. Adipokines may mediate the effects of adiposity on MS disease course.. The objective of this study is to examine the association between the adipokines (leptin and fatty acid binding protein-4, FABP4) and clinical course in individuals with MS.. Subjects (18-65 years) with relapsing-remitting MS or clinically isolated syndrome and <10 year disease duration were selected from a longitudinal clinical study. Cross-sectional and longitudinal models assessed the relationship between two adipokines (leptin and FABP4) and disease severity in women and men, adjusting for age, disease duration and disease type, Vitamin D level, testosterone level, and as well by body mass index (BMI).. Mean age of subjects ( N = 163, 56% women) was 39.3 years. Higher FABP4 levels were associated with higher Expanded Disability Status Scale (EDSS) scores in women in both univariate and multivariate analyses (odds ratio: 1.30; p = 0.005). In men, higher FABP4 level was significantly associated with change in EDSS over time (estimate: 0.0062; p = 0.035). We found no association of FABP4 levels with time to next relapse or a measure of processing speed.. FABP4 levels may be associated with increased disability in both men and women with MS independent of effects of BMI and other hormones. Future studies should expand these analyses and further explore downstream mechanisms of adiposity-related effects in MS.

Topics: Adiposity; Adult; Body Mass Index; Disabled Persons; Fatty Acid-Binding Proteins; Female; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Severity of Illness Index; Sex Factors

We investigated the effect of glatiramer acetate (GA) on the modulation of immune cell subpopulations and serum levels of multiple immune/metabolic markers in patients with relapsing-remitting multiple sclerosis (RRMS) to understand whether the treatment with GA could induce a specific change in the immunometabolic asset of patients with RRMS.. We performed an extensive peripheral blood immunophenotyping and measured serum levels of several parameters involved in the pathogenesis of RRMS and also relevant in the pathogenesis of metabolic syndrome and obesity such as leptin, soluble leptin-receptor (sLep-R), myeloperoxidase (MPO), soluble CD40 ligand (sCD40-L), soluble tumor necrosis factor-receptor (sTNF-R), monocyte chemoattractant protein 1 (MCP-1), soluble Inter-Cellular Adhesion Molecule-1 (sICAM-1) and osteoprotegerin (OPG), in 20 naïve-to-treatment RRMS patients and 20 healthy controls. We repeated these analyses over time at 6 and 12 months after starting GA treatment.. Our analysis showed that naïve-to-treatment RRMS patients had a lower number of CD16(+)CD56(+) NK cells, CD19(+) B cells, CD4(+) T cells co-expressing the MHC class II activation marker HLA-DR (CD4(+)DR(+)) and naïve CD4(+)CD45RA(+) T cells in basal conditions. GA treatment induced a specific and significant decrease of circulating CD19(+) B cells. Naïve-to-treatment RRMS patients also showed a significantly higher number of CD4(+) T cells with a memory phenotype (CD4(+)CD45RO(+)) whose peripheral frequency was not affected by GA treatment. These changes over time associated with a higher serum concentration of leptin and lower levels of MPO. GA treatment also reduced significantly the circulating levels of sCD40-L and sTNF-R overtime.. Our data suggest that the clinical outcome of GA treatment is associated with changes in immune cell subpopulations and modulation of specific immunometabolic markers. These data add substantial evidence of the immune modulating effect of GA during RRMS and could be of relevance in understanding the pathogenesis of disease and its follow-up.

Topics: Adult; Biomarkers; CD4-Positive T-Lymphocytes; Female; Glatiramer Acetate; Humans; Leptin; Longitudinal Studies; Lymphocyte Count; Male; Metabolic Syndrome; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Obesity; Peptides

Experimental evidences indicate that leptin is involved in the neuroinflammatory process sustaining multiple sclerosis (MS). However, the relationship between leptin and body fat, as assessed by body mass index (BMI), in MS was not previously evaluated. It was the aim of this study to compare serum leptin levels between patients with MS and healthy controls and to evaluate the possible relationship between circulating leptin levels and disease severity.. Eighty-four MS patients and 57 sex-matched healthy volunteers were enrolled. Serum leptin levels were measured in all patients and controls. MS patients were stratified in 3 groups according to their degree of disability as assessed by the Expanded Disability Status Scale (EDSS). Patients were classified as having low (33 patients with an EDSS score <1.5), intermediate (28 patients with an EDSS score from 2 to 3) and high disability (23 patients with an EDSS score ≥3.5).. No significant differences in serum leptin levels and BMI were observed between patients and controls. In patients with MS, serum leptin levels were significantly correlated with BMI in those patients with low (R(2) = 0.363; p < 0.001) and intermediate disability (R(2) = 0.408; p < 0.001), but not in patients with a higher disability score (R(2) = 0.064; p = 0.256).. BMI, the major determinant of leptin level in physiological conditions, has a minor role in determining the serum levels of leptin in MS patients with a high EDSS score. Future longitudinal studies will be required in order to provide further insights into the regulation of leptin secretion in patients with MS.

Topics: Adolescent; Adult; Aged; Body Mass Index; Disability Evaluation; Female; Humans; Leptin; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Severity of Illness Index; Young Adult

Leptin and adipocyte-fatty acid binding protein (A-FABP) are produced by white adipose tissue and may play a role in chronic inflammation in Multiple Sclerosis (MS). To assess leptin and A-FABP in relapsing and progressive forms of MS.. Adipokine levels were measured in untreated adult relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and Healthy control (HC). Pediatric-onset MS (POMS) and pediatric healthy controls (PHC) were also assessed. Leptin and A-FABP levels were measured in serum by ELISA. Groups were compared using linear mixed-effects model.. Excluding two patients with Body Mass Index (BMI) > 50, a significant difference in leptin level was found between RRMS and HC controlling for age (p = 0.007), SPMS and HC controlling for age alone (p = 0.002), or age and BMI (p = 0.007). A-FABP levels were higher in SPMS than HC (p = 0.007), controlling for age and BMI. Differences in A-FABP levels between POMS and PHC was observed after controlling for age (p = 0.019), but not when BMI was added to the model (p = 0.081).. Leptin and A-FABP levels are highest in SPMS compared to HC, suggesting a role in pathogenesis of this disease subtype. A-FABP levels are increased in POMS patients and may play a role in the early stages of disease.

Topics: Adolescent; Adult; Case-Control Studies; Child; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting

In this study we observed higher serum leptin levels in relapsing-remitting multiple sclerosis (RRMS) patients during remission than in controls. The expression of leptin receptor (ObR) was higher in CD8+ T cells and monocytes from RRMS patients in relapse than in patients in remission and in controls. Relapsing patients showed high levels of pSTAT3 and low expression of SOCS3 and leptin administration induced an up-regulation of pSTAT3 only in monocytes from patients in relapse. Our data suggest that ObR may be involved in the development of clinical relapses in RRMS patients and suggest a rationale for potential targeting of the leptin axis during MS.

Topics: Adult; Bacterial Toxins; Case-Control Studies; CD8-Positive T-Lymphocytes; Cytokines; Female; Flow Cytometry; Gene Expression Regulation; Heat-Shock Proteins; Hemolysin Proteins; Humans; Leptin; Male; Middle Aged; Monocytes; Multiple Sclerosis, Relapsing-Remitting; Radioimmunoassay; Receptors, Leptin; Sex Factors; STAT3 Transcription Factor

We analyzed the serum and cerebrospinal fluid (CSF) leptin secretion and the interaction between serum leptin and CD4(+)CD25+ regulatory T cells (T(Regs)) in naive-to-therapy relapsing-remitting multiple sclerosis (RRMS) patients. Leptin production was significantly increased in both serum and CSF of RRMS patients and correlated with IFN-gamma secretion in the CSF. T cell lines against human myelin basic protein (hMBP) produced immunoreactive leptin and up-regulated the expression of the leptin receptor (ObR) after activation with hMBP. Treatment with either anti-leptin or anti-leptin-receptor neutralizing antibodies inhibited in vitro proliferation in response to hMBP. Interestingly, in the RRMS patients, an inverse correlation between serum leptin and percentage of circulating T(Regs) was also observed. To better analyze the finding, we enumerated T(Regs) in leptin-deficient (ob/ob) and leptin-receptor-deficient (db/db) mice and observed the significant increase in T(Regs). Moreover, treatment of WT mice with soluble ObR fusion protein (ObR:Fc) increased the percentage of T(Regs) and ameliorated the clinical course and progression of disease in proteolipid protein peptide (PLP(139-151))-induced relapsing-experimental autoimmune encephalomyelitis (R-EAE), an animal model of RRMS. These findings show an inverse relationship between leptin secretion and the frequency of T(Regs) in RRMS and may have implications for the pathogenesis of and therapy for multiple sclerosis.

Topics: Adult; Animals; Case-Control Studies; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cell Line; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; In Vitro Techniques; Interferon-gamma; Leptin; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Myelin Basic Protein; Neutralization Tests; Receptors, Cell Surface; Receptors, Interleukin-2; Receptors, Leptin; T-Lymphocyte Subsets

Leptin, a hormone synthesized mainly by adipocytes, can modulate the immune response and seems to be involved in the induction of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). However, the possible role of leptin in MS pathogenesis has not yet been elucidated. In this study we investigated the effect of leptin on cytokine production by peripheral blood mononuclear cells (PBMCs) of MS patients (either in the acute or in the stable phase of the disease) and healthy controls. We also analyzed leptin effects on cytokine production by monocytes in relapsing MS patients. Our data showed that leptin induced tumor necrosis factor-alpha, interleukin-6, and interleukin-10 production by PBMCs of patients in an acute phase of disease but not in patients in a stable phase or in healthy controls. Moreover, we found no effect of leptin in monocytes from relapsing MS patients. Therefore we conclude that leptin may modulate the MS inflammatory process during relapses.

Topics: Adolescent; Adult; Cells, Cultured; Cytokines; Female; Humans; Interleukin-10; Interleukin-6; Leptin; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Tumor Necrosis Factor-alpha

Leptin is synthesized by adipocytes to regulate appetite. Leptin has also been implicated in the pathogenesis of multiple sclerosis (MS) leading to speculation about a beneficial effect of fasting to autoimmune patients. We measured plasma leptin and its soluble receptor (OB-Rs) in 52 MS patients and 50 controls. We also cultured MS and control peripheral blood mononuclear cells (PBMC), T-cells and monocytes +/- recombinant leptin (rleptin), to assess leptin's direct effect on pro- and anti-inflammatory cytokine secretion. We found similar leptin and OB-Rs plasma levels between patients and controls. Untreated patients in the acute phase or in remission, or patients treated with methylprednisolone, had lower leptin levels than patients in the acute phase or in remission receiving IFN-beta. OB-Rs levels were low in patients refractory to IFN-beta but higher in patients receiving methylprednisolone or patients in remission receiving IFN-beta. PBMC from untreated patients in the acute phase, secreted spontaneously IFN-gamma, TNF-alpha and IL-10. IFN-gamma was contributed by T-cells, TNF-alpha and IL-10 primarily by monocytes and to a lesser extent by T-cells. The overall effect of rleptin on PBMC was a net increase in IL-10 production and a net reduction in IFN-gamma production. These results do not warrant a beneficial effect of fasting to MS patients.

Topics: Adult; Blood Cells; Body Mass Index; Case-Control Studies; Cells, Cultured; Cytokines; Female; Humans; Immunologic Factors; Interferon-gamma; Interleukin-10; Leptin; Leukocytes, Mononuclear; Male; Middle Aged; Monocytes; Multiple Sclerosis, Relapsing-Remitting; Receptors, Cell Surface; Receptors, Leptin; Solubility; T-Lymphocytes; Th1 Cells; Th2 Cells