leptin and Parkinson-Disease

Leptin is a hormone that regulates appetite by acting on receptors in the hypothalamus, where it modifies food intake to maintain equilibrium with the body energy resources. Leptin and its receptors are widely distributed in the central nervous system, suggesting that they may give neuronal survival signals. The potential of leptin to decrease/increase neuronal damage and neuronal plasticity in Parkinson's diseases (PD) is the subject of this review, which outlines our current knowledge of how leptin acts in the brain. Although leptin-mediated neuroprotective signalling results in neuronal death prevention, it can affect neuroinflammatory cascades and also neuronal plasticity which contribute to PD pathology. Other neuroprotective molecules, such as insulin and erythropoietin, share leptin-related signalling cascades, and therefore constitute a component of the neurotrophic effects mediated by endogenous hormones. With the evidence that leptin dysregulation causes increased neuronal vulnerability to damage in PD, using leptin as a target for therapeutic modification is an appealing and realistic option.

Topics: Adipose Tissue; Humans; Hypothalamus; Insulin; Leptin; Parkinson Disease

The exact mechanism of Parkinson's disease (PD) is not fully understood yet, but it is suggested that inflammation is one of its contributing factors. Among several inflammatory factors, adipokines, especially leptin may have a great role in this mechanism; since it is not only causing inflammation, but it can also play other roles in the body that may contribute to the symptoms described for PD. Regarding the contradictions in the association of serum leptin levels with Parkinson's disease, a systematic review and meta-analysis was performed to have a more accurate estimation of this relationship.. Published literature was obtained by searching PubMed, Embase, Cochrane Library, Scopus, Ovid, ProQuest and Google Scholar. Random-effect model analysis was used to calculate pooled standard mean difference (SMD) with 95% confidence interval (CI). Heterogeneity was tested with the heterogeneity statistic Q and quantified using I. Six studies including a total number of 198 PD patients and 182 controls were finally included in the meta-analysis. Serum leptin levels in PD patients were non-significantly lower than those in control group (SMD = -0.40 ng/ml, 95% CI -2.33-1.53). Subgroup analyses revealed that serum leptin levels of PD patients and controls in either females or males didn't show any significant difference.. This meta-analysis revealed that leptin level doesn't show any significant difference between PD patients and healthy controls, even when taking the participants' gender into consideration.

Topics: Female; Humans; Inflammation; Leptin; Male; Parkinson Disease

Leptin is involved in the regulation of blood pressure; however, no studies have evaluated the role of leptin in blood pressure changes during orthostatic stress in PD patients. The aim of this study was to determine whether plasma leptin levels influence orthostatic blood pressure changes in PD patients.. We enrolled 55 patients and 25 age-matched healthy controls in this study. Associations between head-up tilt test measurements and leptin levels were evaluated.. Systolic blood pressure changes during the head-up tilt tests were strongly correlated with leptin levels at baseline and at a 60-degree head-up tilt in PD patients, but not in control subjects. Multiple regression analysis also demonstrated that leptin levels were associated with orthostatic blood pressure changes.. These observations suggest that low leptin levels may be associated with orthostatic hypotension during the head-up tilt test in patients with PD. © 2016 International Parkinson and Movement Disorder Society.

Topics: Aged; Aged, 80 and over; Blood Pressure; Female; Humans; Hypotension, Orthostatic; Leptin; Male; Middle Aged; Parkinson Disease

As the population of the world ages, the prevalence of neurodegenerative disease continues to rise, accompanied by increases in disease burden related to obesity and metabolic disorders. Thus, it will be essential to develop tools for preventing and slowing the progression of these major disease entities. Epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. Experimentally, the fat-derived hormone leptin has been shown to act as a neuroprotective agent in various animal models of dementia, toxic insults, ischemia/reperfusion, and other neurodegenerative processes. Specifically, leptin minimizes neuronal damage induced by neurotoxins and pro-apoptotic conditions. Leptin has also demonstrated considerable promise in animal models of obesity and metabolic disorders via modulation of glucose homeostasis and energy intake. However, since obesity is known to induce leptin resistance, we hypothesize that resistance to the neuroprotective effects of leptin contributes to the pathogenesis of obesity-associated neurodegenerative diseases. This review aims to explore the literature pertinent to the role of leptin in the protection of neurons from the toxic effects of aging, obesity and metabolic disorders, to investigate the physiological state of leptin resistance and its causes, and to consider how leptin might be employed therapeutically in the prevention and treatment of neurodegenerative disease.

Topics: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Humans; Hypothalamus; Leptin; Mice; Neurons; Neuroprotective Agents; Obesity; Parkinson Disease; Rats

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

Recent studies demonstrate major effects of adrenal medullary and catecholaminergic pathways on a wide variety of normal physiologic and regulatory events. Alterations in these pathways, involving changes in catecholamines or in proteins and peptides costored and coreleased with catecholamines, may lead to profound changes in autonomic, cardiovascular, neuroendocrine, metabolic, nociceptive, and immune function. These findings have important implications for a variety of human disease states. In addition, molecules associated with catecholaminergic function may provide novel diagnostic and therapeutic strategies for human disease and suggest specific genetic loci as important and fruitful targets for further genetic and pharmacogenetic studies.

Topics: Catecholamines; Chromaffin Cells; Chromogranin A; Chromogranins; Dopamine beta-Hydroxylase; Humans; Hypertension; Leptin; Mutation; Nervous System Diseases; Parkinson Disease; Pheochromocytoma

Heap-up of α-synuclein (α-Syn) and its association with tau protein are esteemed to trigger the onset of Parkinson's disease (PD). The purpose of this study was to develop multi-functional liposomes incorporated with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, 1,2-dimyristoyl-sn-glycero-3-phosphocholine and phosphatidylserine (PS) to load astragaloside IV (AS-IV) and nestifin-1 (NF-1), followed by grafting with wheat germ agglutinin (WGA) and leptin (Lep) (WGA-Lep-AS-IV-NF-1-PS-liposomes) to protect dopaminergic neurons from apoptosis. Experimental results showed that increasing the mole percentage of DSPC and PS enhanced the particle size, particle stability and entrapment efficiency of AS-IV and NF-1, and reduced the drug releasing rate. Strong affinity of NF-1 to PS was evidenced by nuclear magnetic resonance spectroscopy. WGA-Lep-AS-IV-NF-1-PS-liposomes diminished transendothelial electrical resistance and improved the capacity of propidium iodide, AS-IV and NF-1 to penetrate the blood-brain barrier (BBB). Immunocytochemical staining exhibited the ability of functionalized liposomes to target Lep receptor and α-Syn in MPP

Topics: Dopaminergic Neurons; Humans; Leptin; Liposomes; Parkinson Disease; Phosphatidylserines; Saponins; tau Proteins; Triterpenes; Wheat Germ Agglutinins

Topics: Apoptosis; Catechin; Dopaminergic Neurons; Humans; Leptin; Liposomes; Parkinson Disease; Phosphatidic Acids; Resveratrol

There is some evidence that Parkinson's Disease (PD) patients have lower body weight and lower fat mass when compared to healthy subjects and that lower body weight and fat mass influence disease risk and progression. It remains unclear, however, if weight loss of fat mass loss occurs only in a subgroup of patients and whether fat distribution is altered during PD. The aim of this study was to prospectively investigate adipose tissue content and distribution in PD patients.. The body fat composition of PD patients (N = 54) was compared with age matched healthy controls (N = 55) using a magnetic resonance imaging (MRI)-based method. A longitudinal MRI scan was acquired in 25 PD patients after a mean follow up period of 12 months.. The volume of total body fat as well as of visceral fat showed no difference between PD patients and healthy controls at baseline or at follow up. However, PD patients displayed decreased subcutaneous fat tissue (p = 0.01) and a higher visceral to subcutaneous fat ratio as compared to controls (p = 0.004). After follow up, 16 PD patients did not lose weight, while 9 PD patients lost between 0.5 and 10 kg.. Fat distribution is altered in PD patients, with an increased ratio of visceral to subcutaneous fat.

Topics: Adipose Tissue; Body Fat Distribution; Body Mass Index; Body Weight; Case-Control Studies; Female; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Leptin; Magnetic Resonance Imaging; Male; Parkinson Disease; Statistics as Topic; Statistics, Nonparametric

Parkinson's disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared with both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD, whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, magnetic resonance imaging analysis revealed that WT mice had significantly greater total and visceral body fat compared with SNCA mice (p < 0.007). At the age of 24 weeks SNCA mice displayed significantly increased hunger compared with WT (p < 0.03). At the age of 36 weeks, SNCA mice displayed significant hypoleptinemia compared with WT, both on a normal diet and a HCD (p < 0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared with WT, as measured in a Comprehensive Laboratory Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such metabolic abnormalities and providing an animal model for discovery of the underlying mechanisms and potential therapeutic interventions.

Topics: Adipose Tissue; alpha-Synuclein; Animals; Disease Models, Animal; Energy Intake; Energy Metabolism; Insulin Resistance; Leptin; Male; Mice; Mutation; Parkinson Disease

Patients with multiple system atrophy (MSA) frequently exhibit orthostatic hypotension (OH). Leptin, an adipose-derived hormone, contributes to the sympathetic control of blood pressure (BP), and loss of leptin may cause OH. We aimed to clarify the relationship between leptin and OH in MSA. Serum leptin levels were measured in 36 patients with MSA, 25 patients with other atypical parkinsonian disorders (APDs), including progressive supranuclear palsy-Richardson syndrome and corticobasal syndrome, and 26 control subjects. Blood samples were obtained after fasting for 12h. In MSA patients, baseline BP was measured in the recumbent position after a 3-min rest, and orthostatic changes in BP were evaluated after 0-3 min of standing. Serum leptin levels did not differ significantly between MSA patients (5.9 ± 0.8 ng/ml), other APD patients (5.2 ± 0.8 ng/ml), and controls (6.1 ± 1.3 ng/ml; P=0.8). In MSA patients, serum leptin levels correlated significantly with body mass index (P=0.01), but not baseline BPs (systolic BP, P=0.20; diastolic BP, P=0.44) or orthostatic drop in BP (systolic BP, P=0.13; diastolic BP, P=0.58). Our observations indicated that the circulating level of leptin was preserved, and OH occurred independent of the leptin level in MSA patients.

Topics: Aged; Autonomic Nervous System Diseases; Blood Pressure; Female; Humans; Hypotension, Orthostatic; Leptin; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Supranuclear Palsy, Progressive

The exact mechanism of weight gain (WG) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with idiopathic Parkinson's disease remains unknown.. To investigate a possible involvement of ghrelin, neuropeptide Y (NPY) and leptin in WG after DBS.. Twenty-three Parkinson patients were submitted for body composition measurements and blood sampling 3 days before, and 3 and 6 months after STN DBS. Peripheral concentrations of ghrelin, NPY, and leptin were determined, as well as the L-dopa equivalent daily dose. Patients were clinically evaluated using the Unified Parkinson's Disease Rating Scale.. Three months after surgery, a significant WG was observed (3.09 ± 5.00 kg; p = 0.007) with no further increase at 6 months. Three months postoperatively, NPY circulating levels increased significantly (p = 0.05), while the increase of ghrelin levels reached statistical significance at 6 months (p = 0.001). WG was significantly associated with changes of ghrelin and leptin levels at 3 and 6 months, respectively.. STN DBS seems to temporarily dysregulate the hypothalamic secretion of NPY and ghrelin. The variation of weight may be attributed to an increased production of ghrelin and leptin. A possible neuroprotective role of DBS, exerted through the increase of ghrelin levels, should be further studied.

Topics: Aged; Body Composition; Deep Brain Stimulation; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Parkinson Disease; Subthalamic Nucleus; Treatment Outcome; Weight Gain

OBJECTIVES - Determine whether bilateral subthalamic nucleus stimulation (STN-DBS) in Parkinson's disease (PD) is associated with an increase in neuropeptide Y (NPY) and/or resistance to inhibition by leptin in relation to post-surgery weight gain. MATERIALS AND METHODS - This prospective study included 20 patients who underwent bilateral STN-DBS and 17 who refused surgery. Data were obtained at baseline, 3 and 6 months on neurological and nutritional status, including determination of body mass index (BMI) and serum NPY and leptin levels. RESULTS -  NPY and leptin levels changed over time, with a distinct pattern. The BMI increase at 6 months was greater in the surgical group (5.5 ± 6.3% vs 0.5 ± 3.5%; P = 0.035). Medical group exhibited a reduction in leptin level (-2.0 ± 4.3 ng/ml) and a consequent increase in NPY level (72.4 ± 58.7 pmol/ml). However, STN-DBS patients showed an increase in leptin (3.1 ± 5.0 ng/ml; P = 0.001 vs medical group) and also in NPY (12.1 ± 53.6 pmol/ml; P = 0.022 vs medical group) levels, which suggests resistance to inhibition by leptin. Rise in NPY level correlated with higher stimulation voltages. CONCLUSIONS -  Bilateral STN-DBS causes disruption of the melanocortin system, probably related to diffusion of the electric current to the hypothalamus. This mechanism may in part explain the weight gain of patients with PD after surgery.

Topics: Aged; Body Mass Index; Electric Stimulation Therapy; Female; Humans; Leptin; Male; Melanocortins; Middle Aged; Neuropeptide Y; Parkinson Disease; Prospective Studies; Subthalamic Nucleus; Treatment Outcome; Weight Gain

Topics: Adiponectin; Aged; Circadian Rhythm; Female; Humans; Leptin; Male; Middle Aged; Parkinson Disease; Resistin

Weight gain has been reported in patients with Parkinson's disease (PD) treated with deep brain stimulation of the subthalamic nucleus (STN-DBS). To evaluate the influence of STN-DBS on weight changes, we studied food-related hormones.. Anthropometric parameters and food-related hormones (leptin, adiponectin, resistin, ghrelin, cortisol, insulin, and thyroid stimulating hormone) were measured in 27 patients with STN-DBS during a 12 month period following electrode implantation.. Besides marked motor improvements on STN-DBS, PD patients significantly gained weight. The mean weight gain at 12 months was 5.2±(SD)5.8 kg. A significant decrease in cortisol levels compared to baseline appeared at month 2 and persisted at 12 months (p<0.01, corrected), with no significant changes in other hormones tested.. Changes in peripheral food-related hormones do not appear to cause weight gain in PD patients. Direct effects of STN-DBS on hypothalamic catabolic/anabolic peptide balance remain hypothetical and necessitate further elucidation.

Topics: Adiponectin; Adult; Aged; Deep Brain Stimulation; Eating; Female; Ghrelin; Hormones; Humans; Hydrocortisone; Hypothalamus; Insulin; Leptin; Male; Middle Aged; Parkinson Disease; Resistin; Subthalamic Nucleus; Thyrotropin; Weight Gain

To investigate the role of leptin, ghrelin, GH and IGF-1 in energy balance disturbances in Parkinson's disease (PD).. Thirty-nine patients were included: 11 PD patients with unintentional weight loss, 16 PD patients without weight loss and 12 controls. UPDRS, MMSE, MADRS, appetite scale, BMI, adipose tissue content, plasma leptin and active ghrelin concentrations and serum GH, IGF-1, TSH, T3 and T4, concentrations were evaluated.. A lower plasma leptin concentration and a higher serum IGF-1 concentration were found in PD patients with weight loss. BMI and the content of adipose tissue were positively correlated with leptin concentration in all PD patients. Paradoxically, the lower BMI was, the lower plasma active ghrelin concentration was in PD patients with the weight loss.. These findings confirm that changes of plasma leptin concentration occur in PD patients with loss of weight.

Topics: Adipose Tissue; Aged; Appetite; Body Mass Index; Energy Metabolism; Female; Ghrelin; Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Parkinson Disease; Thyroid Hormones; Thyrotropin; Weight Loss

Weight loss is a common problem in Parkinson's disease (PD), but the causative mechanisms behind this weight loss are unclear. We compared 26 PD patients with sex and age matched healthy controls. Examinations were repeated at baseline, after one and after two years. Body fat mass was measured by Dual X-ray Absorptiometry (DXA). Seventy three per cent of the PD patients lost body weight. Loss of body fat mass constituted a considerable part of the loss of body weight. In the patients who lost weight, serum leptin levels were lower than in those who did not lose weight. The relationship between low body fat mass and low leptin levels seems to be relevant, at least for female PD patients. It is reasonable to believe that low leptin levels in these patients could be secondary to the decreased body fat mass.

Topics: Absorptiometry, Photon; Adipose Tissue; Aged; Antiparkinson Agents; Female; Follow-Up Studies; Humans; Leptin; Levodopa; Male; Middle Aged; Parkinson Disease; Radioimmunoassay; Sex Factors; Statistics, Nonparametric; Weight Loss

The death of midbrain dopaminergic neurons in sporadic Parkinson disease is of unknown etiology but may involve altered growth factor signaling. The present study showed that leptin, a centrally acting hormone secreted by adipocytes, rescued dopaminergic neurons, reversed behavioral asymmetry, and restored striatal catecholamine levels in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic cell death. In vitro studies using the murine dopaminergic cell line MN9D showed that leptin attenuated 6-OHDA-induced apoptotic markers, including caspase-9 and caspase-3 activation, internucleosomal DNA fragmentation, and cytochrome c release. ERK1/2 phosphorylation (pERK1/2) was found to be critical for mediating leptin-induced neuroprotection, because inhibition of the MEK pathway blocked both the pERK1/2 response and the pro-survival effect of leptin in cultures. Knockdown of the downstream messengers JAK2 or GRB2 precluded leptin-induced pERK1/2 activation and neuroprotection. Leptin/pERK1/2 signaling involved phosphorylation and nuclear localization of CREB (pCREB), a well known survival factor for dopaminergic neurons. Leptin induced a marked MEK-dependent increase in pCREB that was essential for neuroprotection following 6-OHDA toxicity. Transfection of a dominant negative MEK protein abolished leptin-enhanced pCREB formation, whereas a dominant negative CREB or decoy oligonucleotide diminished both pCREB binding to its target DNA sequence and MN9D survival against 6-OHDA toxicity. Moreover, in the substantia nigra of mice, leptin treatment increased the levels of pERK1/2, pCREB, and the downstream gene product BDNF, which were reversed by the MEK inhibitor PD98059. Collectively, these data provide evidence that leptin prevents the degeneration of dopaminergic neurons by 6-OHDA and may prove useful in the treatment of Parkinson disease.

Topics: Adipocytes; Animals; Apoptosis; Caspase 3; Caspase 9; Catecholamines; Cell Line; Cell Survival; CREB-Binding Protein; Disease Models, Animal; DNA Fragmentation; Flavonoids; GRB2 Adaptor Protein; Humans; Janus Kinase 2; Leptin; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Phosphorylation; Substantia Nigra; Sympatholytics

Weight gain is a common adverse effect associated with the use of most typical and atypical antipsychotic. Aim of this study was to investigate serum prolactin, leptin, cholesterol, triglyceride, lipoproteins, such high density lipoprotein (HDL), and low density lipoprotein (LDL) levels in patients with Parkinson's disease (PD)-related psychosis during long-term medication with atypical antipsychotic. The study population comprised 40 patients, who were divided into 4 groups: olanzapine (n=10), risperidone (n=10), seroquel (n=10) monotherapy, a group of 10 patients receiving only antiparkinson drugs and a control group of 8 healthy persons. The patients were evaluated at baseline and at the sixth and twelfth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), and fasting serum prolactin, leptin, lipids and lipoproteins levels. Treatment of patients with olanzapine caused marked increase of serum LDL, cholesterol, triglyceride, and leptin levels (p<0,02). No changes in HDL concentrations. There was positive relationship between serum leptin, lipid levels and BMI. However, treatment of patients with seroquel did not cause changes in serum prolactin, leptin, lipids, and lipoproteins levels. Our results suggest that treatment of patients with PD-related psychosis with seroquel appears to have minimal influence on serum leptin, prolactin, lipids, lipoproteins and BMI compared with olanzapine and risperidone.

Topics: Antiparkinson Agents; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Dibenzothiazepines; Humans; Leptin; Lipids; Lipoproteins; Olanzapine; Parkinson Disease; Psychotic Disorders; Quetiapine Fumarate; Risperidone

We compared serum leptin and satiety measures in 18 Parkinson's disease (PD) patients with unintended weight loss (WL) and 18 PD patients whose weight was stable (WS). Mean serum leptin concentrations tended to be lower in WL than WS patients, but this did not reach statistical significance. Body mass index correlated with serum leptin concentrations. Ratings of hunger, satiety, fullness, and thirst did not differ between groups. However, the mean sensation of fullness before meals correlated with serum leptin in the entire cohort of patients, particularly in the WL group. The results indicate that unintended weight loss in PD patients is unlikely to be due to abnormal serum leptin concentrations.

Topics: Aged; Female; Humans; Leptin; Male; Middle Aged; Parkinson Disease; Satiety Response; Surveys and Questionnaires; Weight Loss