leptin and Neurodegenerative-Diseases

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

Recent biochemical and behavioural evidence indicates that metabolic hormones not only regulate energy intake and nutrient content, but also modulate plasticity and cognition in the central nervous system. Disruptions in metabolic hormone signalling may provide a link between metabolic syndromes like obesity and diabetes, and cognitive impairment. For example, altered metabolic homeostasis in obesity is a strong determinant of the severity of age-related cognitive decline and neurodegenerative disease. Here we review the evidence that eating behaviours and metabolic hormones-particularly ghrelin, leptin, and insulin-are key players in the delicate regulation of neural plasticity and cognition. Caloric restriction and antidiabetic therapies, both of which affect metabolic hormone levels can restore metabolic homeostasis and enhance cognitive function. Thus, metabolic hormone pathways provide a promising target for the treatment of cognitive decline.

Topics: Cognition; Energy Metabolism; Feeding Behavior; Ghrelin; Humans; Insulin; Leptin; Neurodegenerative Diseases; Obesity

Protein tyrosine phosphatases are enzymes which help in the signal transduction in diabetes, obesity, cancer, liver diseases and neurodegenerative diseases. PTP1B is the main member of this enzyme from the protein extract of human placenta. In phosphate inhibitors development, significant progress has been made over the last 10 years. In early-stage clinical trials, few compounds have reached whereas in the later stage trials or registration, yet none have progressed. Many researchers investigate different ways to improve the pharmacological properties of PTP1B inhibitors.. In the present review, authors have summarized various aspects related to the involvement of PTP1B in various types of signal transduction mechanisms and its prominent role in various diseases like cancer, liver diseases and diabetes mellitus.. There are still certain challenges for the selection of PTP1B as a drug target. Therefore, continuous future efforts are required to explore this target for the development of PTP inhibitors to treat the prevailing diseases associated with it.

Topics: Animals; Antineoplastic Agents; Diabetes Mellitus; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Female; Forecasting; Humans; Hypoglycemic Agents; Insulin; Leptin; Mice; Models, Molecular; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents; Placenta; Pregnancy; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction

Life expectancy has considerably increased over the last decades. The negative consequence of this augmented longevity has been a dramatic increase of age-related chronic neurodegenerative diseases, such as Alzheimer's, Parkinson's and multiple sclerosis. Epidemiology is telling us there exists a strong correlation between the neuronal loss characterizing these disorders and metabolic dysfunction. This review aims at presenting the evidence supporting the existence of a molecular system linking metabolism with neurodegeneration, with a specific focus on the role of two hormones with a key role in the regulatory cross talk between metabolic imbalance and the damage of nervous system: leptin and ghrelin. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Topics: Animals; Ghrelin; Humans; Leptin; Neurodegenerative Diseases

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Ghrelin; Humans; Inflammation; Inflammation Mediators; Leptin; Macrophage Activation; Microglia; Neuralgia; Neurodegenerative Diseases; Neuroglia; Neuropeptide Y; Neuropeptides; Pain; Pro-Opiomelanocortin; Tachykinins; Vasoactive Intestinal Peptide

The peripheral actions of the metabolic hormones, leptin and insulin, are well documented. However, the functions of these hormones are not restricted to the periphery because evidence is growing that both leptin and insulin can readily cross the blood-brain barrier and have widespread central actions. The hippocampus in particular expresses high levels of both insulin and leptin receptors as well as key components of their associated signaling cascades. Moreover, recent studies indicate that both hormones are potential cognitive enhancers. Indeed, it has been demonstrated that both leptin and insulin markedly influence key cellular events that underlie hippocampal learning and memory including activity-dependent synaptic plasticity and the trafficking of glutamate receptors to and away from hippocampal synapses. The hippocampal formation is also a prime site for the neurodegenerative processes that occur during Alzheimer's disease, and impairments in either leptin or insulin function have been linked to central nervous system-driven diseases like Alzheimer's disease. Thus, the capacity of the metabolic hormones, leptin and insulin, to regulate hippocampal synaptic function has significant implications for normal brain function and also central nervous system-driven disease.

Topics: Blood-Brain Barrier; Hippocampus; Humans; Insulin; Leptin; Neurodegenerative Diseases; Neuronal Plasticity; Receptors, Leptin; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synapses

Adipokines secreted by adipose tissue are recognized to be crucial for the regulation and maintenance of energy homeostasis. Leptin is the best characterized adipokine involved in energy metabolism and inflammatory status, being associated with the development of a number of diseases, including atherosclerosis, diabetes, certain cancers and immune-mediated processes. Recently leptin was found to exert neurotrophic effects and neuroprotective activity slowing down neuronal damage after acute brain injuries as well as during long-term neurodegenerative processes. Moreover there are the evidences that leptin influences receptor signalling as well as the synthesis and releasing of several neurotransmitters. The aim of this review is to discuss the role of leptin in the neuroprotection and the regulation of diverse neuronal functions in the health and disease.

Topics: Animals; Apoptosis; Humans; Leptin; Neurodegenerative Diseases; Neurons; Neuroprotective Agents

Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.

Topics: Adiponectin; Alzheimer Disease; Body Weight; Brain-Derived Neurotrophic Factor; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Leptin; Metabolic Diseases; Neurodegenerative Diseases

TOR (target of rapamycin) is a serine-threonine protein kinase that is conserved across a diverse range of species from fungi to mammals. The signaling pathway that is anchored by TOR is also conserved across species. In mammals, mTOR integrates growth factor, amino acid, nutrient and energy sensing signals, and thus plays a major role in cell growth and proliferation, protein synthesis and autophagy. As a result of the pivotal role of mTOR in signaling, the aberrant regulation of mTOR has been implicated in several disease processes, including cancer, diabetes, ocular diseases and neurodegenerative disorders, as well as in lifespan extension. More recently, rapamycin (sirolimus) analogs that antagonize the mTOR signaling pathway have been approved for the treatment of several cancers. This review describes some recent advances in the understanding of mTOR signaling, with an emphasis on the functional consequences of mTOR inhibition and therapeutic intervention strategies.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Enzyme Inhibitors; Eye Diseases; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Longevity; Neoplasms; Neurodegenerative Diseases; Protein Serine-Threonine Kinases; Signal Transduction; TOR Serine-Threonine Kinases

Leptin is a hormone produced by adipocytes that regulates satiety (food uptake) and energy homeostasis by activating receptors expressed in neurons of the hypothalamus. Leptin receptors are also found in other brain regions such as the hippocampus and cerebral cortex, and have known roles in regulating neural development and neuroendocrine functions. Recent evidence indicates that leptin could be neuroprotective, enhancing neuronal survival both in vitro and in vivo. Intriguingly, administration of leptin protects against neuronal death in animal models of cerebral ischemic injury and hemiparkisonism. Activation of the Janus kinase (JAK)-signal transducers and activator of transcription (STAT), phosphatidylinositol (PI) 3-kinase and the extracellular signal regulated kinase (ERK) pathways are known downstream events of leptin receptor signaling, all of which are pro-survival and anti-apoptotic. The relative ease of leptin's accessibility to the brain by peripheral administration makes it a potential drug candidate in the development of therapeutics for brain injuries and neurodegeneration.

Topics: Animals; Brain; Brain Injuries; Humans; Leptin; Neurodegenerative Diseases; Neuroprotective Agents

Leptin, a hormone produced by adipocytes, provides signals to specific regions of the hypothalamus to control energy homeostasis. However, the past decade of research has not only revealed that leptin receptors are widely expressed in the CNS, but has also identified numerous additional functions for this hormone in the brain. In particular, there is evidence that leptin influences neuronal excitability via the activation as well as trafficking of specific potassium channels in several brain regions. Leptin-induced alterations in neuronal excitability have been implicated in the regulation of food intake, reward behaviour and anti-convulsant effects. A number of studies have also identified a role for leptin in cognitive processes that involve activation of leptin receptors in limbic structures, such as the hippocampus. Indeed, leptin influences hippocampal-dependent learning and memory, and more recently leptin has been shown to have anti-depressant properties. Characterisation of these novel actions of leptin is providing valuable insights into the role of this hormone in the regulation of diverse neuronal functions in health and disease.

Topics: Animals; Antidepressive Agents; Cognition; Humans; Hypothalamus; Learning; Leptin; Memory; Nervous System Physiological Phenomena; Neurodegenerative Diseases; Receptors, Leptin; Reward; Signal Transduction

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

Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause inducible (i) NO synthase (NOS) synthesis, which in turn produces massive amounts of nitric oxide (NO). NO, by inactivating enzymes and leading to cell death, is toxic not only to invading viruses and bacteria, but also to host cells. Injection of LPS induces interleukin (IL)-1beta, IL-1alpha, and iNOS synthesis in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood-brain barrier. Thereafter, this induction occurs in the hypothalamic regions (such as the temperature-regulating centers), paraventricular nucleus (releasing and inhibiting hormone neurons), and the arcuate nucleus (a region containing these neurons and axons bound for the median eminence). Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone melatonin, respectively, may be caused by NO. The induction of iNOS in the temperature-regulating centers by infections may cause the decreased febrile response in the aged by loss of thermosensitive neurons. NO may play a role in the progression of Alzheimer's disease and parkinsonism. LPS similarly activates cytokine and iNOS production in the cardiovascular system leading to coronary heart disease. Fat is a major source of NO stimulated by leptin. As fat stores increase, leptin and NO release increases in parallel in a circadian rhythm with maxima at night. NO could be responsible for increased coronary heart disease as obesity supervenes. Antioxidants, such as melatonin, vitamin C, and vitamin E, probably play important roles in reducing or eliminating the oxidant damage produced by NO.

Topics: Aging; Animals; Atherosclerosis; Central Nervous System; Corticosterone; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Isoenzymes; Leptin; Lipopolysaccharides; Models, Biological; Neurodegenerative Diseases; Nitric Oxide; Nitric Oxide Synthase; Pineal Gland; Tumor Necrosis Factor-alpha

Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disease with no cure to date. Therapeutic agents used to treat ALS are very limited, although combined therapies may offer a more effective treatment strategy. Herein, we have studied the potential of nanomedicine to prepare a single platform based on mesoporous silica nanoparticles (MSNs) for the treatment of an ALS animal model with a cocktail of agents such as leptin (neuroprotective) and pioglitazone (anti-inflammatory), which have already demonstrated promising therapeutic ability in other neurodegenerative diseases. Our goal is to study the potential of functionalized mesoporous materials as therapeutic agents against ALS using MSNs as nanocarriers for the proposed drug cocktail leptin/pioglitazone (

Topics: Amyotrophic Lateral Sclerosis; Animals; DNA-Binding Proteins; Leptin; Mice; Mice, Transgenic; Nanoparticles; Neurodegenerative Diseases; Pioglitazone; Silicon Dioxide

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin's effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin's actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43

Topics: Adipokines; Amyotrophic Lateral Sclerosis; Animals; Humans; Leptin; Male; Mice; Motor Neurons; Neurodegenerative Diseases; Signal Transduction; Spinal Cord

Environmental factors such as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. Epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol (RSV) HFD + RSV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RSV groups and their offspring. Molecularly, a significant increase in DNA methylation (5-mC) levels, as well as increased gene expression of

Topics: Adenosine; Animals; Body Weight; Brain; Cognition; Diet, High-Fat; Dietary Supplements; DNA Methylation; Epigenesis, Genetic; Epigenomics; Female; Inflammation; Leptin; Male; Maternal Exposure; Maze Learning; Methylation; Mice; Neurodegenerative Diseases; Neuronal Plasticity; Obesity; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Resveratrol; Triglycerides

It has been previously demonstrated that hydrogen sulfide (H

Topics: Animals; Apoptosis; Cell Division; Cell Line; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Environmental Pollutants; Formaldehyde; Gene Expression Regulation; Genes, p16; Hippocampus; Hydrogen Sulfide; Leptin; Mice; Neurodegenerative Diseases; Neurons; Receptors, Leptin; Signal Transduction; Sulfides; Up-Regulation

Anorexia nervosa (AN) commonly arises during adolescence leading to interruptions of somatic and psychological development as well as to atrophic brain changes. It remains unclear whether these brain changes are related to the loss of neurons, glia, neuropil or merely due to fluid shifts. We determined leptin levels and two brain-derived damage markers: glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) of 43 acute AN patients and 50 healthy control woman (HCW). Peripheral GFAP and NSE concentrations of AN patients were not elevated and not different from HCW. Subjects with particularly low leptin concentration, indicating severe malnutrition, did not show abnormal values either. During weight recovery the marker proteins remained unchanged. Our preliminary results are in line with neuroimaging studies supporting the reversibility of brain changes in AN and do not substantiate hypotheses relying on the extensive damage of brain cells as an explanation for cerebral atrophy in AN.

Topics: Adaptation, Physiological; Adolescent; Adult; Anorexia Nervosa; Biomarkers; Body Mass Index; Brain; Down-Regulation; Female; Glial Fibrillary Acidic Protein; Humans; Interview, Psychological; Leptin; Malnutrition; Neurodegenerative Diseases; Neuroglia; Neurons; Personality Inventory; Phosphopyruvate Hydratase; Predictive Value of Tests; Reproducibility of Results

In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.

Topics: Animals; Behavior, Animal; Blood Glucose; Brain; Brain-Derived Neurotrophic Factor; Caspases; Cell Survival; Disease Progression; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Glucose; Huntingtin Protein; Immunoblotting; Insulin; Leptin; Male; Mice; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Neurodegenerative Diseases; Nuclear Proteins; Time Factors; Up-Regulation