leptin and Encephalitis

Global levels of obesity are reaching epidemic proportions, leading to a dramatic increase in incidence of secondary diseases and the significant economic burden associated with their treatment. These comorbidities include diabetes, cardiovascular disease, and some psychopathologies, which have been linked to a low-grade inflammatory state. Obese individuals exhibit an increase in circulating inflammatory mediators implicated as the underlying cause of these comorbidities. A number of these molecules are also manufactured and released by white adipose tissue (WAT), in direct proportion to tissue mass and are collectively known as adipokines. In the current review we focused on the role of two of the better-studied members of this family namely, leptin and adiponectin, with particular emphasis on their role in neuro-immune interactions, neuroinflammation and subsequent brain diseases. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.

Topics: Adipokines; Adiponectin; Animals; Encephalitis; Humans; Inflammation; Leptin; Obesity

Dysfunction of specific hypothalamic neurons is regarded as an important mechanism predisposing to the development of obesity. Recent studies have revealed that the consumption of fat-rich foods can activate an inflammatory response in the hypothalamus, which disturbs the anorexigenic and thermogenic signals generated by the hormones leptin and insulin, leading in turn to anomalous body mass control. Depending on diet composition, cytokines are expressed in the hypothalamus, contributing to the activation of intracellular inflammatory signal transduction. At least 4 distinct signaling pathways have been identified and the molecular mechanisms leading to the impairment of the leptin and insulin actions have been determined. Here, we present the mechanisms involved in diet-induced resistance to leptin and insulin action in the hypothalamus and discuss some of the potential applications of this knowledge in the therapeutics of obesity.

Topics: Animals; Body Weight; Cytokines; Dietary Fats; Encephalitis; Humans; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Obesity; Signal Transduction

Acute hypoxia is experienced by a variety of individuals (neonates to the elderly) and in an assortment of conditions and diseases (terrorist bomb attack to decompensated heart failure). Increasingly, elaboration of inflammatory cytokines appears key to the brain-based response to hypoxia, as evidenced by the biobehaviors of malaise, fatigue, lethargy, and loss of interest in the physical and social environment. These sickness symptoms implicate hypoxia-dependent activation of the neuroimmune system as a key component of acute hypoxia. Type 2 diabetes (T2D) is associated with increased incidence, severity, and delayed recovery from hypoxic events. Why T2D negatively affects acute hypoxia is not well understood. Recent work, however, reveals that anti-inflammatory pathways tied to the interleukin (IL)-1beta arm of the neuroimmune system may be critical. In this review, the authors examine the link between acute hypoxia, T2D, and neuroimmunity.

Topics: Animals; Autoimmune Diseases of the Nervous System; Brain; Diabetes Mellitus, Type 2; Encephalitis; Humans; Hypoxia, Brain; Interleukin-1beta; Leptin; Neuroimmunomodulation; Signal Transduction

To compare the effects of a palatable cafeteria diet on serum parameters and neuroinflammatory markers of young and aged female Wistar rats.. Three-month-old (young) and 18-month-old (aged) female Wistar rats had access to a cafeteria diet (Caf-Young, Caf-Aged) or a standard chow diet (Std-Young, Std-Aged).. The Caf-Young group showed a higher food consumption, weight gain, visceral fat depot, serum insulin and leptin levels, and the insulin resistance index (HOMA-IR) than the Std-Young group. The Caf-Aged group exhibited an increase in interleukin-1 levels in the cerebral cortex and hippocampus. The number of GFAP-positive cells did not differ between the groups, but there was a diet effect in the cerebral cortex and an age effect in the hippocampus. Phospho-tau expression did not differ between the groups.. The 3- and 18-month-old rats responded differently to a cafeteria diet. Insulin and leptin levels are elevated in young animals fed a cafeteria diet, whereas aged animals are prone to neuroinflammation (indicated by an increase in interleukin-1β levels). A combination of hypercaloric diet and senescence have detrimental effects on the inflammatory response in the brain, which may predispose to neurological diseases.

Topics: Aging; Animals; Blood Glucose; Brain; Cerebral Cortex; Diet, High-Fat; Encephalitis; Female; Hippocampus; Insulin; Insulin Resistance; Leptin; Neuroglia; Rats, Wistar; tau Proteins

A significant change in the Western diet, concurrent with the obesity epidemic, was a substitution of saturated fatty acids with polyunsaturated, specifically linoleic acid (LA). Despite increasing investigation on type as well as amount of fat, it is unclear which fatty acids are most obesogenic. The objective of this study was to determine the obesogenic potency of LA vs. saturated fatty acids and the involvement of hypothalamic inflammation. Forty-eight mice were divided into four groups: low-fat or three high-fat diets (HFDs, 45% kcals from fat) with LA comprising 1%, 15% and 22.5% of kilocalories, the balance being saturated fatty acids. Over 12 weeks, bodyweight, body composition, food intake, calorimetry, and glycemia assays were performed. Arcuate nucleus and blood were collected for mRNA and protein analysis. All HFD-fed mice were heavier and less glucose tolerant than control. The diet with 22.5% LA caused greater bodyweight gain, decreased activity, and insulin resistance compared to control and 1% LA. All HFDs elevated leptin and decreased ghrelin in plasma. Neuropeptides gene expression was higher in 22.5% HFD. The inflammatory gene Ikk was suppressed in 1% and 22.5% LA. No consistent pattern of inflammatory gene expression was observed, with suppression and augmentation of genes by one or all of the HFDs relative to control. These data indicate that, in male mice, LA induces obesity and insulin resistance and reduces activity more than saturated fat, supporting the hypothesis that increased LA intake may be a contributor to the obesity epidemic.

Topics: Animals; Carbon Dioxide; Chemokine CX3CL1; Diet, Fat-Restricted; Encephalitis; Fatty Acids; Ghrelin; Glucose; Hypothalamus; Leptin; Linoleic Acid; Male; Mice, Inbred C57BL; Weight Gain

It has been reported that obesity leads to more marked inflammatory responses in a site-specific manner. As has been seen in other animal models of obesity, ovariectomized rodents exhibit obesity and exacerbated fever and anorectic responses to the systemic injection of lipopolysaccharide (LPS). Furthermore, they also display increased pro-inflammatory cytokine expression in several central and peripheral tissues. Interestingly, the alterations observed in the hypothalamus are more marked than those seen in other peripheral tissues. In this study, the effects of ovariectomy on hypothalamic inflammatory responses were evaluated using the central LPS injection method. LPS was intracerebroventricularly (i.c.v.) injected into ovariectomized and gonadally intact female rats, and the immune responses of the two groups were compared. The ovariectomized rats exhibited heavier body weights than the gonadally intact rats. In addition, the ovariectomized rats displayed stronger febrile responses than the gonadally intact rats. After the i.c.v. injection of LPS, the hypothalamic interleukin (IL)-1β, IL-6, and cyclooxygenase 2 mRNA levels of the ovariectomized rats were significantly higher than those of the gonadally intact rats. The effects of estradiol supplementation on the rats' immune responses were also examined. However, the febrile responses and hypothalamic IL-1β, IL-6, and TNF-α mRNA levels of estradiol-supplemented ovariectomized rats and body weight matched oil-administered (control) rats did not differ after the i.c.v. injection of LPS. These results indicate that hypothalamic sensitivity to LPS is increased in ovariectomized rats and that this change is induced by the indirect effects of gonadal steroid deficiency. As is seen in other obese animal models, ovariectomy-induced obesity might play important roles in the exacerbated inflammatory responses observed in ovariectomized rats.

Topics: Adipose Tissue; Animals; Body Temperature; Cyclooxygenase 2; Cytokines; Encephalitis; Estradiol; Female; Gene Expression Regulation; Hypothalamus; Injections, Intraventricular; Leptin; Lipopolysaccharides; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Time Factors; Toll-Like Receptor 4; Ureter

The appetite suppressing hormone leptin has emerged as an important modulator of immune function and is now considered to be a critical link between energy balance and host defense responses to pathogens. These 'adaptive' responses can, in situations of severe and sustained systemic inflammation, lead to adverse effects including brain damage that is partly mediated by neutrophil recruitment into the brain. We examined the contribution of leptin to this process in leptin-deficient (ob/ob), -resistant (db/db) and wild-type (WT) mice injected intraperitoneally with a septic dose of lipopolysaccharide (LPS). This treatment induced a dramatic increase in the number of neutrophils entering the brain of WT mice, an effect that was almost totally abolished in the mutant mice and correlated with a significant reduction in the mRNA levels of interleukin-1beta, intracellular adhesion molecule-1 and neutrophil-specific chemokines. These effects were reversed with leptin replenishment in ob/ob mice leading to recovery of neutrophil recruitment into the brain. Moreover, 48 h food deprivation in WT mice, which decreased circulating leptin levels, attenuated the LPS-induced neutrophil recruitment as did a single injection of an anti-leptin antiserum 4 h before LPS treatment in WT mice. These results provide the first demonstration that leptin has a critical role in leukocyte recruitment to the brain following severe systemic inflammation with possible implications for individuals with altered leptin levels such as during obesity or starvation.

Topics: Age Factors; Animals; Brain; Cytokines; Encephalitis; Enzyme-Linked Immunosorbent Assay; Food Deprivation; Gene Expression Regulation; Leptin; Leukocytes; Lipopolysaccharides; Mice; Mice, Transgenic; Neutrophil Infiltration; RNA, Messenger; Signal Transduction; Statistics, Nonparametric

Traumatic brain injury (TBI) induces cachexia and neuroinflammation which profoundly impact patient recovery. Adipokine genes such as leptin (ob), resistin (rstn) and fasting-induced adipose factor (fiaf) are implicated in energy metabolism and body weight control and are also associated with chronic low grade inflammation. Since central rstn and fiaf expression was increased following hypoxic/ischemic brain injury, we hypothesized that these genes would also be induced in the rat brain following TBI. Realtime RT-PCR detected a 2-2.5-fold increase in ob mRNA in the ipsilateral cortex and thalamus 12h following lateral fluid percussion (FP)-induced brain injury. Fiaf mRNA was elevated 5-7.5-fold in cortex, hippocampus and thalamus, and modest increases were also detectable in the contralateral brain. Remarkably, rstn mRNA was elevated in ipsilateral (150-fold) and in contralateral (50-fold) hippocampus. To test whether these changes were part of an inflammatory response to TBI we also examined the effects of an intracerebral injection of lipopolysaccharide (LPS). We determined that central injection of LPS produced some, but not all, of the changes seen after TBI. For example, in contrast to the stimulatory influence of TBI, LPS had no effect on ob expression in any brain region, though fiaf and rstn mRNA levels were significantly elevated in both ipsi- and contralateral cortex.. (a) brain-derived adipokines could be involved in the acute pathology of traumatic brain injury partly through modulation of central inflammatory responses, but also via leptin-mediated neuroprotective effects and (b) TBI-induced brain adipokines may induce the metabolic changes observed following neurotrauma.

Topics: Adipokines; Angiopoietin-Like Protein 4; Angiopoietins; Animals; Brain; Brain Injuries; Cerebral Cortex; Encephalitis; Energy Metabolism; Gene Expression; Hypothalamus; Leptin; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Resistin; RNA, Messenger; Thalamus

Although epidemiological studies reveal an increased incidence of obesity and an association between obesity and the prevalence/severity of ischemic stroke, little is known about the mechanisms that link obesity to ischemic stroke. This study tested the hypothesis that obesity exacerbates the cerebrovascular dysfunction and tissue injury induced by brain ischemia and reperfusion.. The adhesion of leukocytes and platelets in cerebral venules, blood-brain barrier permeability, brain water content, and infarct volume were measured in wild-type, obese (ob/ob), and leptin-reconstituted ob/ob mice subjected to 30 minutes middle cerebral artery occlusion and reperfusion. Tissue and plasma cytokine levels were determined by cytometric bead array, and a role for monocyte chemoattractant protein-1 and interleukin-6 was assessed using blocking antibodies.. Compared with wild-type mice, ob/ob exhibited larger increases in leukocyte and platelet adhesion, blood-brain barrier permeability, water content, and infarct volume after middle cerebral artery occlusion-reperfusion. Reconstitution of leptin in ob/ob mice tended to further enhance all reperfusion-induced responses. Ob/ob mice also exhibited higher plasma levels of monocyte chemoattractant protein-1 and interleukin-6 than wild-type mice. Immunoneutralization of monocyte chemoattractant protein-1, but not interleukin-6, reduced infarct volume in ob/ob mice.. Obesity worsens the inflammatory and injury responses to middle cerebral artery occlusion and reperfusion by a mechanism independent of leptin deficiency. monocyte chemoattractant protein-1 appears to contribute to the exaggerated responses to ischemic stroke in obese mice.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Capillary Permeability; Cell Adhesion; Cerebral Infarction; Cerebrovascular Circulation; Chemokine CCL2; Encephalitis; Infarction, Middle Cerebral Artery; Interleukin-6; Leptin; Leukocytes; Male; Mice; Mice, Obese; Obesity; Platelet Adhesiveness; Reperfusion Injury; Stroke

Leptin regulates energy balance by suppressing appetite and increasing energy expenditure through actions in the hypothalamus. Recently we demonstrated that the effects of leptin are, at least in part, mediated by the release of interleukin (IL)-1beta in the brain. Microglia constitute the major source of IL-1beta in the brain but it is not known whether these cells express leptin receptors, or respond to leptin to produce IL-1beta. Using RT-PCR and immunocytochemistry, we demonstrate that primary rat microglial cells express the short (non-signalling) and long (signalling) isoforms of the leptin receptors (Ob-R)s. Immunoassays performed on cell medium collected 24 h after leptin treatment (0.01-10 microg/mL) demonstrated a dose-dependent production and release of IL-1beta and its endogenously occurring receptor antagonist IL-1RA. In addition leptin-induced IL-1beta release occurs via a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. Western blot analysis demonstrated that leptin induced the synthesis of pro-IL-1beta in microglial cells and the release of mature 17 kDa isoform into the culture medium. Leptin-induced IL-1beta release was neither inhibited by the pan-caspase inhibitor BOC-D-FMK, nor by the caspase 1 inhibitor Ac-YVAD-CHO indicating that IL-1 cleavage is independent of caspase activity. These results confirm our earlier observations in vivo and demonstrate that microglia are an important source of IL-1beta in the brain in response to leptin.

Topics: Animals; Animals, Newborn; Brain; Caspase 1; Caspase Inhibitors; Cells, Cultured; Coculture Techniques; Encephalitis; Enzyme Inhibitors; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Leptin; Lipopolysaccharides; Microglia; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor

Leptin is known to be an important circulating signal for regulation of food intake and body weight. Recent evidence has suggested that leptin is involved in infection and inflammation. The afferent vagus nerve is known to be an important component for transmitting peripheral immune signals to the brain, such as interleukin (IL)-1beta expression in the brain, anorexia, and fever responses. In the present study, we investigated whether intravenous leptin-induced IL-1beta expression in the hypothalamus is mediated via afferent vagus nerve. IL-1beta transcripts in the hypothalamus were significantly increased on RT-PCR assessment 1 h after the administration of leptin (1 mg/kg iv) to mice. Subdiaphragmatic vagotomy did not significantly modify intravenous leptin-induced IL-1beta expression in the hypothalamus compared with that in sham-treated mice. These data suggest that circulating leptin directly acts in the brain independently of afferent vagus nerve input originating from the subdiaphragmatic organs.

Topics: Animals; Diaphragm; Encephalitis; Gene Expression; Hypothalamus; Injections, Intravenous; Interleukin-1; Leptin; Mice; Mice, Inbred C57BL; Neuroimmunomodulation; Neurons, Afferent; RNA, Messenger; Transcription, Genetic; Vagotomy; Vagus Nerve