leptin and Multiple-Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, neuronal loss, and permanent neurological impairments. The etiology of MS is not clearly understood, but genetics and environmental factors can affect the susceptibility of individuals. Obesity or a body mass index of (BMI) > 30 kg/m2 is associated with serious health consequences such as lipid profile abnormalities, hypertension, type 2 diabetes mellitus, reduced levels of vitamin D, and a systemic lowgrade inflammatory state. The inflammatory milieu can negatively affect the CNS and promote MS pathogenesis due in part to the increased blood-brain barrier permeability by the actions of adipose tissue-derived cytokines or adipokines. By crossing the blood-brain barrier, the pro-inflammatory adipokines such as leptin, resistin, and visfatin activate the CNS-resident immune cells, and promote the inflammatory responses; subsequently, demyelinating lesions occur in the white matter of the brain and spinal cord. Therefore, better knowledge of the adipokines' role in the induction of obesity-related chronic inflammation and subsequent events leading to the dysfunctional blood-brain barrier is essential. In this review, recent evidence regarding the possible roles of obesity and its related systemic low-grade inflammation, and the roles of adipokines and their genetic variants in the modulation of immune responses and altered blood-brain barrier permeability in MS patients, has been elucidated. Besides, the results of the current studies regarding the potential use of adipokines in predicting MS disease severity and response to treatment have been explored.

Topics: Adipokines; Adipose Tissue; Cytokines; Diabetes Mellitus, Type 2; Humans; Inflammation; Leptin; Lipids; Multiple Sclerosis; Neurodegenerative Diseases; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Vitamin D

Multiple sclerosis (MS) is a multifactorial, inflammatory, and neurodegenerative disease of the central nervous system, where environmental factors interact with genetic susceptibility. The role of diet on MS has not been comprehensively elucidated; therefore, through an extensive search of relevant literature, this review reports the most significant evidence regarding nutrition as a possible co-factor influencing the inflammatory cascade by acting on both its molecular pathways and gut microbiota. Since nutritional status and dietary habits in MS patients have not been extensively reported, the lack of a scientific-based consensus on dietary recommendation in MS could encourage many patients to experiment alternative dietetic regimens, increasing the risk of malnutrition. This work investigates the health implications of an unbalanced diet in MS, and collects recent findings on nutrients of great interest among MS patients and physicians. The aim of this review is to elucidate the role of an accurate nutritional counseling in MS to move toward a multidisciplinary management of the disease and to encourage future studies demonstrating the role of a healthy diet on the onset and course of MS.

Topics: Animals; Antioxidants; Body Composition; Complementary Therapies; Diet; Disease Models, Animal; Dysbiosis; Fatty Acids; Fatty Acids, Unsaturated; Humans; Inflammation; Leptin; Lipopolysaccharides; Malnutrition; Micronutrients; Multiple Sclerosis; Nutritional Status; Obesity; Osteoporosis; Randomized Controlled Trials as Topic; Recommended Dietary Allowances; Risk Factors; Vitamin D

The high prevalence of osteoporosis, observed in multiple sclerosis (MS) patients, has been attributed to reduced mobility and or the use of disease-modifying drugs. However, MS-impaired cardiovascular autonomic nervous system (ANS) function has the potential of reducing bone mass density (BMD) by altering the expression and/or function of the neuronal, systemic, and local mediators of bone remodeling. This review describes the complex regulation of bone homeostasis with a focus on MS, providing evidence that ANS dysfunction and low BMD are intertwined with MS inflammatory and neurodegenerative processes, and with other MS-related morbidities, including depression, fatigue, and migraine. Strategies for improving ANS function could reduce the prevalence of MS osteoporosis and slow the rate of MS progression, with a significant positive impact on patients' quality of life.

Topics: Adiponectin; Autonomic Nervous System; Bone Density; Bone Remodeling; Brain; Cardiovascular System; Depression; Endocannabinoids; Fatigue; Humans; Inflammation; Leptin; Migraine Disorders; Multiple Sclerosis; Nerve Degeneration; Neuropeptide Y; Osteocalcin; Osteopontin; Osteoporosis; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Serotonin; Vitamin D

The proportion to which genetic and environmental factors contribute to the etiology of multiple sclerosis (MS) is still incompletely understood. An interesting association between MS etiology and obesity has recently been shown although the mechanisms underlying this association are still unknown. We propose deregulated gut microbiota and increased leptin levels as possible mechanisms underlying MS etiology in obese individuals.. Alterations in the human gut microbiota and leptin levels have recently been established as immune modulators in both MS patients and obese individuals. A resemblance between pro-inflammatory bacterial profiles in MS and obese individuals was observed. Furthermore, elevated leptin levels push the immune system towards a more pro-inflammatory state and inhibit the regulatory immune response. Deregulated gut microbiota and elevated leptin levels may explain the increased risk of developing MS in obese individuals. Further research to confirm causality is warranted.

Topics: Animals; Gastrointestinal Microbiome; Humans; Leptin; Mice; Multiple Sclerosis; Obesity; Risk Factors

Leptin, synthesised by adipocytes, has been identified as a hormone that can influence inflammatory activity. Several studies have investigated leptin levels in patients with multiple sclerosis (MS), but the results are not consistent. This study aims to derive a more precise evaluation on the relationship between circulating leptin levels and MS.. A comprehensive literature searched up to July 2017 was conducted to evaluate the association of circulating leptin levels and MS. The random-effect model was applied to calculate pooled standardised mean difference (SMD) and its 95% CI.. Circulating leptin levels of patients with MS and healthy controls.. Of 2155 studies identified, 33 met eligibility criteria and 9 studies with 645 patients with MS and 586 controls were finally included in the meta-analysis. Meta-analysis revealed that, compared with the healthy control group, the MS group had significantly higher plasma/serum leptin levels, with the SMD of 0.70% and 95% CI (0.24 to 1.15). Subgroup analyses suggested that the leptin levels of patients with MS were associated with region, age, study sample size, measurement type, gender and blood sample type.. Overall, our study suggests that patients with MS have a significantly higher leptin level than in healthy controls. Further mechanism studies and longitudinal large cohort studies are still needed to further reveal the role of leptin in the pathogenesis of MS.

Topics: Biomarkers; Humans; Leptin; Multiple Sclerosis

Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Astrocytes; Autoimmune Diseases; CD8-Positive T-Lymphocytes; Complement Factor D; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Immune System; Inflammation; Interleukin-17; Leptin; Mesenchymal Stem Cells; Mice; Microglia; Multiple Sclerosis; Nicotinamide Phosphoribosyltransferase; Obesity; Oligodendroglia; Prevalence; Resistin; Risk; Th1 Cells; Th2 Cells

Clinical and experimental data, together with epidemiological studies, have suggested that the pathogenesis of multiple sclerosis (MS) might involve factors that link the immune system with metabolic status. Moreover, recent research has shown that leptin, the adipocyte-derived hormone that controls food intake and metabolism, can promote experimental autoimmune encephalomyelitis, an animal model of MS. In patients with MS, the association of leptin with disease activity has been dissected at the molecular level, providing new mechanistic explanations for the role of this hormone in MS. Here, we review the intricate relationship between leptin and other metabolic modulators within a framework that incorporates the latest advances linking the CNS, immune tolerance and metabolic status. We also consider the translational implications of these new findings for improved management of MS.

Topics: Animals; Humans; Leptin; Multiple Sclerosis; Self Tolerance

Over the last few years, a series of molecules known to play a function in metabolism has also been shown to play an important role in the regulation of the immune response. In this context, the adipocyte-derived hormone leptin has been shown to regulate the immune response in normal as well as in pathological conditions. More specifically, it has been shown that conditions of reduced leptin production (i.e., genetic leptin deficiency, anorexia nervosa, malnutrition) are associated with increased susceptibility to infections. Conversely, immune-mediated disorders such as autoimmune disorders are associated with increased secretion of leptin and production of proinflammatory, pathogenic cytokines. Leptin could represent the "missing link" among immune response, metabolic function, and nutritional status. Indeed, more recently, leptin-deficient mice have been shown to be resistant to a series of experimentally induced autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Normal wild-type mice show increased secretion of leptin in serum upon EAE induction, and brain inflammatory infiltrates stain positive for leptin. Finally, leptin neutralization with leptin antagonists improves the EAE course by profoundly altering intracellular signaling of myelin-reactive T cells and increasing the number of regulatory forkhead/winged helix transcription factor 3(+)CD4(+) T cells. These data suggest that leptin can be considered as a link among immune tolerance, metabolic state, and autoimmunity and that strategies aimed at interfering with the leptin axis could represent innovative, therapeutic tools for autoimmune disorders.

Topics: Animals; Autoimmune Diseases; Brain; CD4-Positive T-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Homeostasis; Humans; Immunity; Inflammation; Leptin; Metabolism; Multiple Sclerosis; Obesity; T-Lymphocytes, Regulatory

The function of hormones has expanded to include immunomodulation and neuroprotection in addition to their classic roles. The story of how hormones influence inflammation and neuron and glial function is being slowly unraveled. There is increasing evidence that estrogen, progesterone, and testosterone contain immune responses and influence damage repair in the nervous system. Hormones such as prolactin and vitamin D are being explored as immunomodulators and may influence diseases such as multiple sclerosis (MS) or may be used therapeutically to modulate the immune response. More recently identified hormones, such as leptin and gherlin, may also influence the course of disease. This chapter reviews some of the evidence that supports a role for hormones in MS.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Ghrelin; Gonadal Steroid Hormones; Hormones; Humans; Leptin; Male; Mice; Multiple Sclerosis; Pregnancy; Thyroid Hormones; Vitamin D

Proteomic analysis is not limited to the analysis of serum or tissues. Synovial, peritoneal, pericardial and cerebrospinal fluid represent unique proteomes for disease diagnosis and prognosis. In particular, cerebrospinal fluid serves as a rich source of putative biomarkers that are not solely limited to neurologic disorders. Peptides, proteolytic fragments and antibodies are capable of crossing the blood-brain barrier, thus providing a repository of pathologic information. Proteomic technologies such as immunoblotting, isoelectric focusing, 2D gel electrophoresis and mass spectrometry have proven useful for deciphering this unique proteome. Cerebrospinal fluid proteins are generally less abundant than their corresponding serum counterparts, necessitating the development and use of sensitive analytical techniques. This review highlights some of the promising areas of cerebrospinal fluid proteomic research and their clinical applications.

Topics: Alzheimer Disease; Biomarkers; Brain Injuries; Brain Ischemia; Cerebrospinal Fluid Proteins; Cerebrospinal Fluid Rhinorrhea; Creutzfeldt-Jakob Syndrome; Dementia; Humans; Leptin; Low Back Pain; Moyamoya Disease; Multiple Sclerosis; Neurodegenerative Diseases; Nutrition Disorders; Paraneoplastic Cerebellar Degeneration; Parkinson Disease; Polymorphism, Genetic; Proteomics; Schizophrenia; Signal Transduction

Topics: Animals; Autoimmunity; Encephalomyelitis, Autoimmune, Experimental; Estrogens; Female; Genetic Predisposition to Disease; Humans; Leptin; Male; Menstrual Cycle; Multiple Sclerosis; Progesterone; Sex Factors

Adipokines secreted by fatty tissue have inflammatory properties and are suggested biomarkers of MS disease activity. To assess this, 88 MS patients were followed with nine repeated measurements of leptin and adiponectin and 12 magnetic resonance imaging (MRI) scans for two years; six months without any immunomodulatory treatment followed by 18 months during interferon-beta (IFNB) treatment. Serum levels of leptin dropped and adiponectin increased upon initiation of IFNB-therapy, but were not associated with clinical or MRI disease activity or with treatment response. Our findings indicate that leptin and adiponectin are not useful as biomarkers of MS disease activity.

Topics: Adiponectin; Biomarkers; Cohort Studies; Disease Progression; Double-Blind Method; Female; Humans; Immunologic Factors; Interferon-beta; Leptin; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Prospective Studies; Treatment Outcome

Adipocytokines such as leptin (LEP) and adiponectin (ADIPOQ) represent a link between metabolism, nutritional status and immune responses. The present study aimed to determine the possible association between single nucleotide polymorphisms of LEP and ADIPOQ genes with multiple sclerosis (MS).. Single nucleotide polymorphisms in LEP (rs2167270 or 19G > A and rs7799039 or -2,548G > A) and ADIPOQ (rs1501299 or +276G > T and rs266729 or -11,377C > G) were genotyped in 305 patients and 255 healthy individuals using polymerase chain reaction-restriction fragment length polymorphism. Sera levels of leptin and adiponectin were measured using enzyme-linked immunosorbent assay.. The frequencies of low leptin producer rs2167270GG genotype and rs2167270G allele were significantly lower in patients with MS compared to those of controls (for GG genotype: 39.7% and 49.8%, respectively; P = 0.01; for G allele: 63.3% and 68.8%, respectively; P = 0.05). Both polymorphisms in ADIPOQ did not show any significant association with disease susceptibility, though after gender categorization the frequency of high adiponectin producer rs1501299TT genotype and rs1501299T allele were significantly higher in male controls compared to male patients (TT genotype: P = 0.006; T allele: P = 0.006). Additionally, rs1501299TT genotype in ADIPOQ was associated with susceptibility to primary progressive multiple sclerosis (PP-MS) (P = 0.02). Moreover, while the sera levels of leptin were only different between male patients and controls (P = 0.05), adiponectin levels were significantly higher in total and female healthy controls (P < 0.001, P = 0.002, respectively).. Our findings provide evidence to support the hypothesis that functional ADIPOQ and LEP gene polymorphisms are associated with susceptibility to MS and its clinical forms.

Topics: Adiponectin; Adolescent; Adult; Alleles; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Male; Middle Aged; Multiple Sclerosis; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Sex Factors

An imbalance of adipokines, hormones secreted by white adipose tissue, is suggested to play a role in the immunopathology of multiple sclerosis (MS). In people with MS (PwMS) of the same age, we aimed to determine whether the adipokines adiponectin, leptin, and resistin are associated with MS disease severity. Furthermore, we aimed to investigate whether these adipokines mediate the association between body mass index (BMI) and MS disease severity.. Adiponectin, resistin, and leptin were determined in serum using ELISA. 288 PwMS and 125 healthy controls (HC) were included from the Project Y cohort, a population-based cross-sectional study of people with MS born in the Netherlands in 1966, and age and sex-matched HC. Adipokine levels and BMI were related to demographic, clinical and disability measures, and MRI-based brain volumes.. Adiponectin levels were 1.2 fold higher in PwMS vs. HC, especially in secondary progressive MS. Furthermore, we found a sex-specific increase in adiponectin levels in primary progressive (PP) male patients compared to male controls. Leptin and resistin levels did not differ between PwMS and HC, however, leptin levels were associated with higher disability (EDSS) and resistin strongly related to brain volumes in progressive patients, especially in several grey matter regions in PPMS. Importantly, correction for BMI did not significantly change the results.. In PwMS of the same age, we found associations between adipokines (adiponectin, leptin, and resistin) and a range of clinical and radiological metrics. These associations were independent of BMI, indicating distinct mechanisms.

Topics: Adipokines; Adiponectin; Cross-Sectional Studies; Female; Humans; Leptin; Male; Multiple Sclerosis; Resistin

Research on the markers of immunoregulatory response in multiple sclerosis (MS) is still of great importance. The aim of our study was the evaluation of leptin, fibronectin, and UCHL1 concentrations as potential biomarkers of a relapsing-remitting type of MS (RRMS). Surface Plasmon Resonance Imaging (SPRI) biosensors were used for the evaluation of proteins concentrations in 100 RRMS patients and 46 healthy volunteers. Plasma leptin, fibronectin, and UCHL1 concentrations were significantly higher in RRMS patients compared to the control group (p < 0.001, respectively). UCHL1 concentration evaluation revealed the highest diagnostic sensitivity (100%) and negative predictive value (100%) in differentiating MS patients from healthy individuals. There was no significant difference in the UCHL1 concentrations depending on the patient's sex, the presence of relapse within the last 24 months, and the EDSS value (p > 0.05, respectively). In RRMS patients UCHL1 concentration positively correlated with fibronectin levels (r = 0.3928; p < 0.001). In the current cohort of patients plasma UCHL1 concentration was independent of the time of MS relapse and the severity of neurological symptoms. Thus current study may indicate that plasma UCHL1, besides leptin and fibronectin, also could be a promising high-sensitive potential biomarker of relapsing-remitting type of MS. However, these results should be validated with a larger group of patients, taking into account neuroimaging and cerebrospinal fluid analysis data, and by comparing them to patients with other neurological diseases as a control group.

Topics: Fibronectins; Health Status; Healthy Volunteers; Humans; Leptin; Multiple Sclerosis; Ubiquitin Thiolesterase

Multiple sclerosis (MS) is a chronic inflammatory and autoimmune disease affecting various inflammatory and nutritional parameters. Therefore, this study aimed to investigate the relationship between the Body Mass Index (BMI) of MS patients and the serum levels of leptin, orexin-A, and Transforming Growth Factor β (TGF-β).. This cross-sectional study included 25 patients suffering from MS and 40 healthy individuals as the case and control groups, respectively. The serum levels of leptin, orexin-A, and TGF-β were assessed in the participants using the Enzyme-Linked Immunosorbent Assay methods. Moreover, data were analyzed using the descriptive statistical indices, t-test, chi-square test, and linear regression test.. According to our results, the participants' mean age was 38.04 ± 7.53 and 40.23 ± 5.88 in the case and control groups, respectively. Also, the groups were not significantly different in gender, age, alcohol consumption, and smoking (p > 0.05). It was found that the mean serum levels of orexin-A and TGF-β were significantly lower in the MS patients compared to the control group, while the mean serum leptin levels were significantly higher (42.8 vs. 18.9 ng/ml, p < 0.001). Moreover, there was no significant relationship between the BMI of the MS patients and their serum levels of orexin-A, TGF-β, and leptin (p > 0.05).. In conclusion, we found significantly lower levels of orexin-A and TGF-β and a significantly higher level of leptin in the MS patients compared to the control group. In addition, there was no significant relationship between the BMI and the serum levels of orexin-A, TGF-β, and leptin in MS patients.

Topics: Adult; Body Mass Index; Cross-Sectional Studies; Female; Humans; Leptin; Lipids; Male; Middle Aged; Multiple Sclerosis; Orexins; Transforming Growth Factor beta

The effects of adipokines have been investigated in multiple sclerosis (MS) in the literature. Results are uncertain, and subgroups like adropin have not been previously studied. We primarily aimed to determine leptin and adropin levels in MS and their potential use as a biomarker.. This study was an experimental research. While 44 MS patients diagnosed according to McDonald criteria were included in the patient group, 40 people without MS diagnosis and risk factors took part in the control group. Demographic data, height, weight, body mass index, blood glucose, thyroid-stimulating hormone, alanine transaminase, aspartate transaminase, creatinine, low-density lipoprotein, leptin, adropin levels, presence of hypertension, diabetes mellitus, coronary artery disease were recorded. Expanded disability status scale and disease duration were also evaluated in the patient group. Our data were presented as mean ± standard deviations.. The mean blood leptin value of the patient group (6.12 ± 5.34 ng/mL) was significantly lower than the value of the control group (13.02 ± 8.25 ng/mL) (P < .001). The patient group had a mean adropin level of 504.12 ± 311.17 ng/mL, which was significantly lower than that of the control group (747.0 ± 309.42 ng/mL) (P < .001). Statistically insignificant differences were found between their body mass index, glucose, alanine transaminase, aspartate transaminase, thyroid-stimulating hormone, low-density lipoprotein levels (P > .001).. This is the first study that has evaluated adropin levels in patients with MS. The relationship between MS and leptin levels is still unclear. Therefore, our study might be helpful to elucidate MS pathogenesis and provide supportive criteria for diagnosis.

Topics: Adult; Body Mass Index; Cross-Sectional Studies; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Multiple Sclerosis; Turkey

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

Topics: Genome-Wide Association Study; Humans; Leptin; Mendelian Randomization Analysis; Multiple Sclerosis; Polymorphism, Single Nucleotide

Topics: Genome-Wide Association Study; Humans; Leptin; Mendelian Randomization Analysis; Multiple Sclerosis; Polymorphism, Single Nucleotide

Leptin (LEP), leptin receptor (LEPR) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1A) are involved in the pathogenesis of multiple sclerosis (MS) by affecting the inflammatory response and reactive oxygen species production. LEP rs7799039 and LEPR rs1137101 genetic variants modify the serum LEP levels and PGC1A rs8192678 alters the PGC1A activity. The study objective was to explore the associations of these variants with susceptibility to MS, disease course/clinical parameters and also with peripheral blood mononuclear cell expression of the target genes and plasma LEP concentrations, in the study subjects.. The study groups included 528 patients with MS and 429 controls. TaqMan® assays were used for genotyping and gene expression quantification. The Chi-square, parametric and nonparametric tests and simple/multiple logistic regression were performed for the statistical analysis of data.. The current findings implicate an impact of investigated genetic variants on the pathogenesis of MS.

Topics: Adult; Case-Control Studies; Female; Gene Expression; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Leptin; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis; Patient Acuity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polymorphism, Single Nucleotide; Real-Time Polymerase Chain Reaction; Receptors, Leptin

Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear.. To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS.. We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators.. Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09-1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60-0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%-31.0%).. This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

Topics: Adiponectin; Body Mass Index; Genome-Wide Association Study; Humans; Leptin; Mediation Analysis; Mendelian Randomization Analysis; Multiple Sclerosis; Obesity; Polymorphism, Single Nucleotide; Risk Factors; Vitamin D

Multiple sclerosis (MS) is the most common non-traumatic neurological cause of disability in young adults. Physical activity, particularly exercise training, is an evidence-based approach to managing symptoms, restoring function, and improving overall wellness in people with MS. As well, the use of probiotics can be effective in reducing the damage from inflammation in MS patients.. The study aimed to address changes in leptin, serotonin, and cortisol following eight weeks of aerobic exercise along with probiotic intake in a cuprizone-induced demyelination mouse model of MS.. Mice were exposed to cuprizone for 12 weeks. After 5 weeks, beam and performance tests were performed on them. The mice (n = 5 per group) were randomly divided into five groups: control (C), MS, MS with exercise (MS + Exe), MS with probiotic (MS + Prob), and MS with probiotic and exercise (MS + Prob + Exe). Exercise groups performed aerobic exercises 5 days a week, 10 min in the first week, 20 min in the second week, and 30 min daily in the third week until the eighth week. In the probiotic groups, the mice received probiotic by gavage. They were sacrificed after 3 months. Biochemical and molecular biology analyses were performed.. The results showed that leptin gene expression values in the MS + Prob + Exe, MS + Prob, and MS + Exe groups showed a decrease compared to the MS group, but the reduction was not significant (p > 0.05). Also, the leptin Elisa test in these intervention groups showed a significant decrease (P < 0.05). The serotonin gene expression values in the MS + Prob + Exe, MS + Prob, and MS + Exe groups were increased compared to the MS group, but the increase was not significant (p > 0.05). Furthermore, the serotonin Elisa test in these intervention groups showed a significant increase (P < 0.05). The cortisol Elisa test values in the MS + Exe and MS + Prob groups exhibited a decrease compared to the MS group, but the reduction was not significant (p > 0.05).. Overall, these results suggest that lifestyle interventions can be effective in improving pathological factors in patients with MS.

Topics: Animals; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Female; Hydrocortisone; Inflammation; Leptin; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Physical Conditioning, Animal; Probiotics; Serotonin

Obesity during adolescence confers an increased risk of multiple sclerosis (MS) in both adults and children. However, obesity-mediated inflammatory mechanisms require elucidation. In models of MS, leptin and fatty acid binding protein-4 (FABP-4) have been identified as proinflammatory adipokines, while adiponectin has anti-inflammatory effects.. Morning serum samples from 32 pediatric MS (POMS) patients (22 females;10 males) and 67 pediatric healthy controls (PHC) (47 females; 20 males) followed at Massachusetts General Hospital were studied. Levels of leptin, FABP-4 and adiponectin were compared between POMS and PHC groups, adjusting for sex, age and vitamin D3 levels. Associations between each marker and the time to next relapse was assessed using a Cox proportional hazards model. The association between each marker and EDSS was assessed using linear regression.. Pediatric MS patients had significantly higher levels of leptin and FABP4 and significantly lower adiponectin than healthy controls. Higher levels of adiponectin were associated with a lower hazard of relapse. Similar differences were observed between POMS and PHC males for both leptin and adiponectin, and within females for FABP4. In females with MS, there was a trend for a positive association between higher leptin levels and higher disability scores. In males with MS, paradoxically, higher leptin levels were associated with longer time to next relapse. All these results remained significant after adjusting for Vitamin D.. FABP4 and leptin levels are higher, while adiponectin levels are lower in pediatric MS compared to controls in sex-specific patterns. These adipokines could serve as biomarkers and therapeutic targets of disease risk and course in early forms of MS.

Topics: Adiponectin; Adolescent; Adult; Biomarkers; Child; Fatty Acid-Binding Proteins; Female; Humans; Leptin; Male; Multiple Sclerosis; Risk; Severity of Illness Index; Sex Factors; Young Adult

Leptin association with Multiple sclerosis (MS) pathogenesis and MS related clinical characteristics is inconsistent. Here, we investigated whether two common variants in leptin (LEP) and leptin receptor (LEPR) genes influence MS risk and leptin levels in MS patients.. In a case-control study including 169 MS patients and 100 controls we examined the association of leptin in MS. Blood samples were used for DNA extraction and plasma retrieval. Taqman genotyping assays were used for LEP rs7799039 and LEPR rs1137101 genotyping, and enzyme-linked immunosorbent assay for plasma leptin level.. Leptin levels were significantly lower in MS patients compared to controls (β = 0.157, 95%CI: 0.033-0.26, p = 0.012). LEP rs7799039AA associated with MS risk (OR: 2.52; 95%CI: 1.35-4.67, p = 0.003). None of the assessed markers associated with MS disability, severity or response to treatment.. LEP rs7799039AA is a risk factor for MS in our Kuwaiti population, and leptin levels are lower in MS patients compared to healthy controls. Our findings suggest future studies must consider all factors influencing leptin levels to resolve its controversial involvement in MS pathogenesis or progression.

Topics: Adult; Female; Humans; Kuwait; Leptin; Male; Middle Aged; Multiple Sclerosis; Receptors, Leptin; Risk; Young Adult

Multiple sclerosis is associated with immune system dysfunction and chronic inflammation; however, possible relations between immunologic and metabolic factors and some psychological indexes such as fatigue and quality of life, especially in relation to exercise training, have not yet been investigated. The present study was designed to investigate the effect of aerobic interval training on interleukin-10/tumor necrosis factor ratio and adipokine (leptin and adiponectin) concentrations in women with multiple sclerosis. Furthermore, the relationship between these factors with fatigue and quality of life were assessed.. Forty women with multiple sclerosis (Expanded Disability Status Scale ≤3) were randomized into either a non-exercising control or training group. The training group performed 8-weeks of upper and lower limb aerobic interval training. Serum concentrations of tumor necrosis factorα, interleukin-10, leptin, and adiponectin were measured before and after the 8-week intervention. Moreover, antropometric measures and measures for fatigue and quality of life were determined at the onset of and after exercise training.. The results revealed that leptin and tumor necrosis factorα levels significantly decreased subsequent to the aerobic interval training. Although blood adiponectin levels considerably increased in the training group, interleukin-10 and interleukin-10/tumor necrosis factorα ratio underwent no substantial change after the exercise training. In addition, the aerobic interval training was associated with improvement in fatigue, quality of life, and maximal oxygen consumption.. Our findings suggested that aerobic interval training can be an effective strategy for managing the immune system at least by its significant impact on inflammatory cytokines and adipokines levels in women with multiple sclerosis. Additionally, this positive impact improved fatigue and adipose tissue indicators.

Topics: Adipokines; Adult; Anaerobic Threshold; Anthropometry; Exercise; Exercise Therapy; Fatigue; Female; Humans; Interleukin-10; Leptin; Multiple Sclerosis; Oxygen Consumption; Quality of Life; Tumor Necrosis Factor-alpha

Environmental risk factors have a dominant role in the pathogenesis of multiple sclerosis (MS). Unhealthy lifestyle can predispose people to autoimmune diseases. MS was a rare disease in Kerala, but now, we notice frequent cases of MS at the city neurology clinic. Changing lifestyle and associated changes in the level of proinflammatory biomolecules like: leptin, soluble leptin receptor (SLR) and free fatty acids (FA) could be contributing to rise in MS incidence.. To identify variations in the levels of bio-molecules: leptin, SLR and FA, between MS patients and matched healthy control.. Leptin and SLR levels in the blood serum, were estimated using ELISA, while total FA levels, were estimated using an enzyme based calorimetric assay.. Mean serum FA levels in MS patients (31.39 ± 4.83 nmole/100 μl) were 2.7 fold higher than controls (11.54 ± 2.66 nmoles/100 μl) at more than 99% CI. The differences in mean leptin and SLR levels were not statistically significant.. MS patients had high level of total FA in their blood. High FA in blood may have a role in MS pathogenesis. More in-depth study is required to understand the precise mechanism by which FA rise in MS blood sample can contribute to pathogenesis.

Topics: Adult; Fatty Acids, Nonesterified; Female; Humans; India; Leptin; Middle Aged; Multiple Sclerosis; Receptors, Leptin; Young Adult

Metabolic syndrome (MetS) is thought to influence several autoimmune diseases, including multiple sclerosis (MS). Anti-inflammatory effects of treatments used for MetS, such as metformin hydrochloride and pioglitazone hydrochloride, have been demonstrated, although clinical evidence supporting use of these treatments in MS is lacking.. To determine whether metformin and/or pioglitazone are associated with a reduction in disease activity as measured by brain magnetic resonance imaging in patients with MS and MetS and to evaluate the potential mechanisms underlying this anti-inflammatory effect.. A prospective cohort study was conducted from March 1, 2012, to December 30, 2014, at a private MS referral center among 50 obese patients with MS who also developed MetS. Twenty patients received metformin hydrochloride, 850 to 1500 mg/d, and 10 patients received pioglitazone hydrochloride, 15 to 30 mg/d; 20 untreated patients served as controls. Groups were comparable in terms of sex, age, body mass index, Expanded Disability Status Scale score, disease duration, annual relapse rate, and treatment status. Patients were followed up for a mean (SD) of 26.7 (2.7) months (range, 24-33 months).. Magnetic resonance imaging of the brain was performed at 6-month intervals, and the presence of new or enlarging T2 lesions or gadolinium-enhancing lesions was registered. Serum leptin and adiponectin levels were measured. The production of cytokines by peripheral blood mononuclear cells was assayed, as were regulatory T-cell numbers and function.. Of 50 patients, after 6 months of treatment, 20 patients with MS who were treated with metformin and 10 who received pioglitazone showed a significant decrease in the number of new or enlarging T2 lesions (metformin, 2.5 at study entry to 0.5 at month 24; pioglitazone, 2.3 at study entry to 0.6 at month 24), as well as of gadolinium-enhancing lesions (metformin, 1.8 at study entry to 0.1 at month 24; pioglitazone, 2.2 at study entry to 0.3 at month 24). Compared with controls, both treatments led to a decrease in mean (SD) leptin levels (metformin, 5.5 [2.4] vs 10.5 [3.4] ng/mL, P < .001; pioglitazone, 4.1 [0.8] vs 11.0 [2.6] ng/mL, P < .001) and increase in mean (SD) adiponectin serum levels (metformin, 15.4 [5.5] vs 4.5 [2.4] μg/mL, P < .001; pioglitazone, 12.6 [3.6] vs 4.8 [0.6] μg/mL, P < .001). Mean (SD) number of myelin basic protein peptide-specific cells secreting interferon γ and interleukin (IL)-17 were significantly reduced in patients receiving metformin compared with controls (interferon γ, 30.3 [11.5] vs 82.8 [18.8], P < .001; IL-17, 212.4 [85.5] vs 553.8 [125.9], P < .001). Patients treated with pioglitazone showed significant decreases in the mean (SD) number of myelin basic protein peptide-specific cells secreting IL-6 and tumor necrosis factor compared with controls (IL-6, 361.6 [80.5] vs 1130.7 [149.21], P < .001; tumor necrosis factor, 189.9 [53.4] vs 341.0 [106.0], P < .001). Both metformin and pioglitazone resulted in a significant increase in the number and regulatory functions of CD4+CD25+FoxP3+ regulatory T cells compared with controls (metformin, 6.7 [1.5] vs 2.1 [1.0], P = .001; pioglitazone, 6.9 [0.8] vs 3.0 [0.8], P = .001).. Treatment with metformin and pioglitazone has beneficial anti-inflammatory effects in patients with MS and MetS and should be further explored.

Topics: Adipokines; Anti-Inflammatory Agents; Brain; Cohort Studies; Cytokines; Disability Evaluation; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Humans; Image Processing, Computer-Assisted; Leptin; Magnetic Resonance Imaging; Male; Metformin; Multiple Sclerosis; Obesity; Pioglitazone; PPAR gamma; RNA, Messenger; Statistics, Nonparametric; T-Lymphocytes, Regulatory; Thiazolidinediones; Time Factors

Leptin, the product of the ob gene, can modulate the immune responses and also seems to regulate Th1/Th2 balance by promoting a shift from the Th2 to the Th1 inflammatory cytokine pathway. Therefore, in this study, we aimed to investigate the association between polymorphisms of leptin gene (LEP) and leptin receptor gene (LEPR) and susceptibility to multiple sclerosis (MS). In addition, we investigated the influence of these two common polymorphisms on plasma levels of leptin.. This case-control study was conducted on 232 MS patients and 204 control subjects. Serum level measurement of leptin was performed using enzyme-linked immunosorbent assay (ELISA). G-2548-A LEP polymorphism and 223A/G polymorphism of the LEPR were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).. There was a significant difference in allele/genotype frequencies of LEP gene among MS patients and control subjects (p<0.01). The genotype frequencies of LEPR polymorphism were also significantly different between control subjects and MS patients (p=0.02). The mean serum level of leptin was significantly higher in MS patients as compared with the controls (p<0.01).. Our study implicates a significant role of LEP and LEPR polymorphisms and also leptin levels in the risk of MS and its severity. Furthermore, our findings suggest LEP and LEPR polymorphisms as important predictors for increased serum leptin in Iranian MS patients. Although this study provides new clinically relevant information regarding genetic determinants modulating risk of MS, further investigations are necessary to understand better the mechanistic implications of these observations in the development of MS.

Topics: Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Iran; Leptin; Male; Multiple Sclerosis; Polymorphism, Single Nucleotide; Receptors, Leptin; Risk Factors; Th1 Cells; Th2 Cells

Adipocytokines may be involved in multiple sclerosis (MS) as well as other autoimmune and inflammatory-related diseases. This study aims to compare levels of resistin, visfatin and leptin in three subgroups of MS patients with healthy subjects and also to study their relationship with Foxp3 expression and levels of several pro-inflammatory mediators such as interleukine-1 β(IL-1 β),tumor necrosis factor-α (TNF-α) and human sensitive C-reactive protein (hs-CRP).. A total of 391 subjects including 200 healthy controls and 191 MS patients were recruited for this case-control study. Circulating adipocytokines and inflammatory mediators were measured using immunoassay methods. Foxp3 gene expression in peripheral blood mononuclear cells (PBMC) was determined by quantitative real-time PCR. Fat tissue mass was evaluated by using dual energy X-ray absorptiometery (DEXA).. A significant difference was observed in levels of inflammatory mediators, adipocytokines, Foxp3 gene expression and adipose tissue mass between MS patients and healthy controls. All adipocytokines were positively correlated with levels of inflammatory mediators and negatively correlated with Foxp3 expression in MS patients. In controls, there were positive correlations between circulating leptin and resistin with TNF-α and IL-1β in subgroup analysis, the highest levels of TNF-α, IL-1β, hs-CRP, resistin and leptin were observed in primary progressive-MS (PP-MS) patients. Also, expression of Foxp3 and levels of visfatin in relapsing remitting-MS(RR-MS) patients were higher compared with the other subgroups.. Our findings suggest the potential role of adipocytokines in pathogenesis and severity of MS. Notably, the relationship of adipocytokines levels with inflammatory cytokines as well as clinical features of MS could be considerable in translational medicine and biomarker studies.

Topics: Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Cytokines; Disease Progression; Disease Susceptibility; Female; Forkhead Transcription Factors; Gene Expression; Humans; Interleukin-1beta; Leptin; Male; Middle Aged; Multiple Sclerosis; Nicotinamide Phosphoribosyltransferase; Resistin; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the levels of three adipocytokines: leptin, adiponectin and adipsin, in serum and cerebrospinal fluid (CSF) of twins discordant for multiple sclerosis (MS). Adipose tissue is an important component connecting immune system and several tissues and organs including CNS. Fat cells produce adipocytokines, which seem to have a role in various autoimmune disorders including MS.. Plasma samples were collected from twelve twins and CSF samples from four twins discordant for MS. The concentrations of interleukine (IL)-6, adiponectin, adipsin and leptin in plasma and CSF samples were determined by enzyme immuno assay.. A significant difference was seen in the adipocytokine levels in CSF samples. Twins with MS had higher concentrations of adiponectin (P = 0.039) and adipsin (P = 0.039), than their asymptomatic co-twins.. As adiponectin and adipsin levels in CSF did not correlate with their levels in plasma, it seems that there could be a secondary intrathecal synthesis of these adipocytokines in MS.

Topics: Adiponectin; Adult; Complement Factor D; Diseases in Twins; Female; Finland; Humans; Immunoenzyme Techniques; Interleukin-6; Leptin; Male; Middle Aged; Multiple Sclerosis; Twins, Dizygotic; Twins, Monozygotic

Chronic inflammation can associate with autoreactive immune responses, including CD4(+) T cell responses to self-Ags. In this paper, we show that the adipocyte-derived proinflammatory hormone leptin can affect the survival and proliferation of autoreactive CD4(+) T cells in experimental autoimmune encephalomyelitis, an animal model of human multiple sclerosis. We found that myelin olygodendrocyte glycoprotein peptide 35-55 (MOG(35-55))-specific CD4(+) T cells from C57BL/6J wild-type mice could not transfer experimental autoimmune encephalomyelitis into leptin-deficient ob/ob mice. Such a finding was associated with a reduced proliferation of the transferred MOG(35-55)-reactive CD4(+) T cells, which had a reduced degradation of the cyclin-dependent kinase inhibitor p27(kip1) and ERK1/2 phosphorylation. The transferred cells displayed reduced Th1/Th17 responses and reduced delayed-type hypersensitivity. Moreover, MOG(35-55)-reactive CD4(+) T cells in ob/ob mice underwent apoptosis that associated with a downmodulation of Bcl-2. Similar results were observed in transgenic AND-TCR- mice carrying a TCR specific for the pigeon cytochrome c 88-104 peptide. These molecular events reveal a reduced activity of the nutrient/energy-sensing AKT/mammalian target of rapamycin pathway, which can be restored in vivo by exogenous leptin replacement. These results may help to explain a link between chronic inflammation and autoimmune T cell reactivity.

Topics: Animals; Apoptosis; Cell Proliferation; Chronic Disease; Cyclin-Dependent Kinase Inhibitor p27; Encephalomyelitis, Autoimmune, Experimental; Energy Metabolism; Female; Glycoproteins; Humans; Inflammation; Leptin; Mice; Mice, Obese; Mice, Transgenic; Mitogen-Activated Protein Kinase 3; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Species Specificity; Th1 Cells; Th17 Cells; TOR Serine-Threonine Kinases

Disease activity in patients with multiple sclerosis (MS) is suppressed during pregnancy, whereas attack frequency increases after delivery. It is yet unclear, which immuno - endocrinological processes mediate these disease fluctuations. Leptin has been identified as a hormone that can influence inflammatory activity.. The aim of this study was to investigate whether pregnancy-induced fluctuations of serum leptin levels differed between patients with MS and controls and whether serum leptin levels correlate with periods of enhanced and diminished disease activity.. Women with MS and healthy women were prospectively followed during and after pregnancy. The MS group could be studied already at a timepoint before pregnancy. Serum leptin and soluble leptin receptor (SLR) levels were measured using enzyme-linked immunosorbent assay.. Pre-pregnancy serum leptin levels were (mean +/- SD) 22.9 +/- 12.8 ng/ml in the MS group. These levels increased in the third trimester to 28.5 +/- 15.0 ng/ml (P = 0.007). The third trimester serum leptin levels in healthy women were comparable, 29.4 +/- 19.0 ng/ml. Serum leptin levels after delivery dropped to 18.5 +/- 12.8 ng/ml in women with MS (P < 0.001) and to a lesser extend (22.0 +/- 17.5 ng/ml) in healthy women (P = 0.04). SLR levels showed the same pattern. Remarkably, women with the highest relative decrease in serum leptin levels after delivery had more often a postpartum relapse (P = 0.008).. In women with MS, leptin increased during late pregnancy. A postdelivery drop in leptin levels was observed in both the MS and control group. The postdelivery drop was associated with the occurrence of postpartum relapse.

Topics: Adult; Biomarkers; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Multiple Sclerosis; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Trimesters; Prospective Studies; Receptors, Leptin; Recurrence; Young Adult

In multiple sclerosis (MS), oligodendrocyte injury is believed to be caused by an aberrant immune response initiated by autoreactive T cells. Increasing evidence indicates that inflammatory responses in the central nervous system are not exclusively detrimental, but may also exert protective effects. Such protective effects are potentially mediated by the local secretion of neurotrophic factors by immune cells. We previously reported that T cells and monocytes in vitro and in inflammatory MS lesions produce leukaemia inhibitory factor (LIF), a member of the neuropoietic family of neurotrophins. In the present study, we report a reduced LIF production by CD4+ T cells of relapsing remitting MS patients as compared to healthy controls. Furthermore, immunomodulatory agents such as leptin, IFN-beta and simvastatin were studied for their potential to alter LIF and secretion of other cytokines by T cells and monocytes of relapsing remitting MS patients and healthy controls. Low doses of simvastatin, but not IFN-beta or leptin enhanced LIF secretion by CD4+ T cells of RR-MS patients. We further demonstrated that LIF did not influence viability, proliferation and cytokine secretion of T cells. Together these data provide new information on the regulation of LIF secretion by immune cells. Further insights into the complex regulation of neurotrophic factors such as LIF may prove useful for treatment of MS.

Topics: Adult; Aged; CD4-Positive T-Lymphocytes; Cells, Cultured; Cytokines; Cytoprotection; Down-Regulation; Female; Humans; Interferon-beta; Interleukin-6; Leptin; Leukemia Inhibitory Factor; Male; Middle Aged; Multiple Sclerosis; Neuroprotective Agents; Reference Values; Simvastatin; T-Lymphocytes; Up-Regulation

The role of leptin was investigated in relapsing-remitting multiple sclerosis (MS). Control and MS patients showed comparable baseline serum leptin levels. During the first year of IFNbeta-1a treatment, leptin significantly decreased since 2 months after starting therapy in 11 patients who had no relapses. A significant decrease in IL12/IL10 ratio was observed in this group of patients only after 1 year of treatment. An increase of leptin was observed before the first clinical exacerbation in 13 relapsing patients. Leptin may play a pathogenic role in MS and can be a useful marker of disease activity and response to therapy.

Topics: Adult; Biomarkers; Cytokines; Female; Humans; Interferon beta-1a; Interferon-beta; Leptin; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis; Reference Values; Secondary Prevention; Treatment Outcome