Associations of serum kisspeptin levels with metabolic and reproductive parameters in men.

Central kisspeptin action is well known in reproductive regulation; however, its peripheral action is not well understood. This study aimed to 1) compare serum or cerebrospinal fluid (CSF) kisspeptin levels between different body mass index (BMI) groups 2) compare the levels of kisspeptin between serum and CSF, and 3) determine correlations between serum or CSF kisspeptin levels with clinical, metabolic, and reproductive parameters. There were 40 male subjects undergoing operations with lumbar puncture anesthesia. Subgroup analysis was performed to compare between the normal (n = 12), overweight (n = 10), and obese groups (n = 17). One lean subject was recruited for correlation analysis. Serum kisspeptin levels were significantly higher in the obese group when compared to the normal weight and overweight groups even after adjusting for age or diastolic blood pressure (DBP) (p < 0.05 all). Serum leptin levels were significantly higher in the obese group when compared to the normal weight and overweight groups (p < 0.05 all). CSF kisspeptin levels were below the minimum detectable concentration for the assay (<0.06 ng/mL). Serum kisspeptin was positively correlated with body weight, BMI, plasma insulin, the homeostatic model assessment for insulin resistance (HOMA-IR), and serum leptin but was negatively correlated with plasma LH (p < 0.05 all). In conclusion, serum kisspeptin was related to obesity, leptin, insulin, and insulin resistance, while CSF kisspeptin was below the limits of detection. Thus, peripheral kisspeptin might have a role in metabolic regulation.

Palmitate Is Increased in the Cerebrospinal Fluid of Humans with Obesity and Induces Memory Impairment in Mice via Pro-inflammatory TNF-α.

Obesity has been associated with cognitive decline, atrophy of brain regions related to learning and memory, and higher risk of developing dementia. However, the molecular mechanisms underlying these neurological alterations are still largely unknown. Here, we investigate the effects of palmitate, a saturated fatty acid present at high amounts in fat-rich diets, in the brain. Palmitate is increased in the cerebrospinal fluid (CSF) of overweight and obese patients with amnestic mild cognitive impairment. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Palmitate induces astroglial and microglial activation in the mouse hippocampus, and its deleterious impact is mediated by microglia-derived tumor necrosis factor alpha (TNF-α) signaling. Our results establish that obesity is associated with increases in CSF palmitate. By defining a pro-inflammatory mechanism by which abnormal levels of palmitate in the brain impair memory, the results further suggest that anti-inflammatory strategies may attenuate memory impairment in obesity.

Transnasal Delivery of the Peptide Agonist Specific to Neuromedin-U Receptor 2 to the Brain for the Treatment of Obesity.

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.

Multiple Sclerosis Risk Factors and Pathogenesis.

PURPOSE OF REVIEW: This article summarizes recent advances in the identification of genetic and environmental factors that affect the risk of developing multiple sclerosis (MS) and the pathogenic processes involved in acute relapses and relapse-independent disability progression. RECENT FINDINGS: The number of single-nucleotide polymorphisms associated with increased risk of MS has increased to more than 200 variants. The evidence for the association of Epstein-Barr virus infection, vitamin D deficiency, obesity, and smoking with increased risk of MS has further accumulated, and, in cases of obesity and vitamin D deficiency, the evidence for causal association has strengthened. Interactions between genetic and environmental factors have been studied more extensively. Dietary factors and changes in the gut microbiota are emerging as possible modulators of the disease risk. Several processes important to MS pathogenesis have been newly investigated or investigated more comprehensively, including the role of B cells, innate immune cells, meningeal inflammation, cortical and gray matter demyelination, and early axonal and neuronal loss. SUMMARY: MS is a complex disease in which the interaction between genetic and environmental factors causes a cascade of events, including activation of the adaptive and innate immune system, blood-brain barrier breakdown, central nervous system demyelination, and axonal and neuronal damage with variable degrees of repair. These events manifest as potentially reversible focal neurologic symptoms or progressive nonremitting physical and cognitive disability, or both. Advances in the understanding of the risk factors and pathogenic mechanisms of MS have resulted in improved therapeutic strategies. The results of ongoing or future studies are needed to successfully and fully translate these advances into clinical practice.

The Levels and Duration of Sensory and Motor Blockades of Spinal Anesthesia in Obese Patients That Underwent Urological Operations in the Lithotomy Position.

Obesity has a significant effect on the cephalic spread of a spinal block (SB) due to a reduction in cerebrospinal fluid (CSF). SB is controlled by the tissue blood flow in addition to the CSF. Some positions and techniques of surgery used can cause changes in hemodynamics. We investigated effects of hemodynamic changes that may occur during Transurethral prostate resection (TUR-P) and lithotomy position (LP) at the SB level in obese versus nonobese individuals. Sixty patients who had undergone TUR-P operation under spinal anesthesia were divided into a nonobese (BMI < 25 kg/m(2), Group N) or obese (BMI ≥ 30 kg/m(2), Group O) group. SB assessments were recorded afterthe LP. SB at 6 and 120 min and the peak SB level were compared between two groups. Hemodynamics were recorded after LP. Peak and 6 min SB levels were similar between the groups, while 120 min SB levels were significantly higher for Group O (P < 0.05). Blood pressure (BP) after the LP was significantly higher for Group N (P < 0.05). LP and TUR-P increased the BP in Group N when compared to Group O. The increase in hemodynamics enhances the blood flow in the spinal cord and may form similar SB levels in nonobese patients to those in obese patients. However, SB time may be longer in obese patients.

Intrathecal synthesis of oligoclonal bands in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome: new evidence supporting immunological pathogenesis.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome (ROHHADS) is a rare, but potentially lethal, pediatric disorder. To date, nearly 80 patients have been reported in the literature; however, the etiopathogenesis is still unclear and debated. Both genetic and paraneoplastic or immune-mediated causes have been supposed to be involved in this syndrome. Nonetheless, at this time, a diagnostic biomarker is not available and diagnosis is based exclusively on clinical criteria. Aiming to establish the immune-mediated pathogenesis, we report 2 children with a clinical picture consistent with ROHHADS and whose cerebrospinal fluid analysis disclosed an intrathecal synthesis of oligoclonal bands. Even if many aspects remain to be explained, this finding suggests that ROHHADS could share similar pathogenetic mechanisms with other immune-mediated central nervous system disorders, and even more important, it might pave the way to a therapeutic chance for these patients by means of immunotherapy.

Hypocretin-1 deficiency in a girl with ROHHAD syndrome.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare and complex pediatric syndrome, essentially caused by dysfunction of 3 vital systems regulating endocrine, respiratory, and autonomic nervous system functioning. The clinical spectrum of ROHHAD is broad, but sleep/wake disorders have received relatively little attention so far, although the central hypothalamic dysfunction would make the occurrence of sleep symptoms likely. In this case report, we expand the phenotype of ROHHAD with a number of striking sleep symptoms that together can be classified as a secondary form of narcolepsy. We present a 7-year-old girl with ROHHAD who displayed the classic features of narcolepsy with cataplexy: excessive daytime sleepiness with daytime naps, visual hallucinations, and partial cataplexy reflected in intermittent loss of facial muscle tone. Nocturnal polysomnography revealed sleep fragmentation and a sleep-onset REM period characteristic for narcolepsy. The diagnosis was confirmed by showing an absence of hypocretin-1 in the cerebrospinal fluid. We discuss potential pathophysiological implications as well as symptomatic treatment options.

Proteomic analysis of cerebrospinal fluid from obese women with idiopathic intracranial hypertension: a new approach for identifying new candidates in the pathogenesis of obesity.

Body weight control is tightly regulated in the hypothalamus. The inaccessibility of human brain tissue can be partially solved by using cerebrospinal fluid (CSF) as a tool for assessing the central nervous system's production of orexigen and anorexigen factors. Using proteomic analysis, the present study investigated the differentially displayed proteins in human CSF from obese and non-obese subjects. We designed a case-control study conducted in a reference hospital where eight obese (cases) and eight non-obese (controls) women with idiopathic intracranial hypertension were included. Intracranial hypertension was normalised through the placement of a ventriculo- or lumboperitoneal shunt in the 12 months before their inclusion in the study. Isotope-coded protein label (for proteins > 10 kDa) and label-free liquid chromatography (for proteins < 10 kDa) associated with mass spectrometry analysis were used. Eighteen differentially expressed proteins were identified. Many of them fall into three main groups: inflammation (osteopontin, fibrinogen γ and ß chain, α1 acid glycoprotein 2 and haptoglobin), neuroendocrine mediators (neurosecretory protein VGF, neuroendocrine protein 7B2, chromogranin-A and chromogranin B), and brain plasticity (testican-1, isoform 10 of fibronectin, galectin-3 binding protein and metalloproteinase inhibitor type 2). The differential production of osteopontin, neurosecretory protein VGF, chromogranin-A and fibrinogen γ chain was further confirmed by either enzyme-linked immunosorbent assay or western blotting. In conclusion, we have identified potential candidates that could be involved in the pathogenesis of obesity. Further studies aiming to investigating the precise role of these proteins in the pathogenesis of obesity and their potential therapeutic implications are needed.

Decreased cerebrospinal fluid/plasma ratio of the novel satiety molecule, nesfatin-1/NUCB-2, in obese humans: evidence of nesfatin-1/NUCB-2 resistance and implications for obesity treatment.

CONTEXT: The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in overweight individuals. OBJECTIVES: The aim of the study was to investigate the mechanisms underlying brain nesfatin-1/NUCB-2 uptake and to determine whether reduced uptake may contribute to nesfatin-1/NUCB-2 resistance. DESIGN: Cerebrospinal fluid (CSF) and corresponding plasma nesfatin-1/NUCB-2 were measured by ELISA [18 men and 20 women; age, 19-80 yr; body mass index (BMI), 16.2-38.1 kg/m(2)] and correlated to body adiposity and metabolic parameters. RESULTS: CSF/plasma nesfatin-1/NUCB-2 ratio was significantly negatively associated with BMI, body weight, fat mass, and CSF glucose. BMI was predictive of CSF/plasma nesfatin-1/NUCB-2 ratio (ß = -0.786; P = 0.045). CSF nesfatin-1/NUCB-2 was significantly positively associated with plasma nesfatin-1/NUCB-2 (R = 0.706; P < 0.01). There was a significant linear relation between CSF and plasma nesfatin-1/NUCB-2 in lean (BMI <25 kg/m(2); R = 0.744; P = 0.002) and obese (BMI ≥ 30 kg/m(2); R = 0.693; P = 0.026) subjects. Subjects in the highest plasma nesfatin-1/NUCB-2 quintile had lower CSF/plasma nesfatin-1/NUCB-2 ratio [26.5% (26.0-29.5%)] compared to the lowest plasma nesfatin-1/NUCB-2 quintile [38.5% (34.0-42.0%)] (P < 0.01), corresponding BMI [32.4 (31.0-35.0) vs. 23.3 (19.7-23.5) kg/m(2); P < 0.01], and fat mass [32.8 (29.5-40.6) vs. 30.7 (8.2-20.1) kg/m(2); P < 0.01]. CONCLUSIONS: Our observations have important implications with respect to the potential weight-reducing actions of nesfatin-1/NUCB-2 treatment. Future research should seek to clarify whether nesfatin-1/NUCB-2 would be beneficial in the management of obesity.

Cerebrospinal fluid corticosteroid levels and cortisol metabolism in patients with idiopathic intracranial hypertension: a link between 11beta-HSD1 and intracranial pressure regulation?

CONTEXT: The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. OBJECTIVE: The aim was to characterize 11ß-HSD1 in human cerebrospinal fluid (CSF) secretory [choroid plexus (CP)] and drainage [arachnoid granulation tissue (AGT)] structures, and to evaluate 11ß-HSD1 activity after therapeutic weight loss in IIH. DESIGN AND SETTING: We conducted in vitro analysis of CP and AGT and a prospective in vivo cohort study set in two tertiary care centers. PATIENTS OR OTHER PARTICIPANTS: Twenty-five obese adult female patients with active IIH were studied, and 22 completed the study. INTERVENTION: Fasted serum, CSF, and 24-h urine samples were collected at baseline, after 3-month observation, and after a 3-month diet. MAIN OUTCOME MEASURES: Changes in urine, serum, and CSF glucocorticoids (measured by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry) after weight loss were measured. RESULTS: 11ß-HSD1 and key elements of the glucocorticoid signaling pathway were expressed in CP and AGT. After weight loss (14.2±7.8 kg; P<0.001), global 11ß-HSD1 activity decreased (P=0.001) and correlated with reduction in intracranial pressure (r=0.504; P=0.028). CSF and serum glucocorticoids remained stable, although the change in CSF cortisone levels correlated with weight loss (r=-0.512; P=0.018). CONCLUSIONS: Therapeutic weight loss in IIH is associated with a reduction in global 11ß-HSD1 activity. Elevated 11ß-HSD1 may represent a pathogenic mechanism in IIH, potentially via manipulation of CSF dynamics at the CP and AGT. Although further clarification of the functional role of 11ß-HSD1 in IIH is needed, our results suggest that 11ß-HSD1 inhibition may have therapeutic potential in IIH.

Interleukin-6 levels in the central nervous system are negatively correlated with fat mass in overweight/obese subjects.

Recently, we demonstrated that intracerebroventricular injection of IL-6 increases energy expenditure and decreases body fat in rodents. Therefore, IL-6 may play a role in appetite and body weight control in the central nervous system. In the present study we evaluated cerebrospinal fluid (CSF) and serum IL-6 levels in humans in relation to body fat content and to CSF and serum levels of leptin. Thirty-two healthy overweight/obese male subjects with a body mass index range of 29.3-36.0 kg/m(2) were studied. Total and sc body fat were measured by dual energy x-ray absorptiometry and computed tomography, respectively. CSF IL-6 levels were in some individuals higher than serum IL-6 levels and correlated negatively with total body weight, sc and total body fat. In contrast, CSF leptin levels were 30-60 times lower than serum leptin levels and correlated positively with serum leptin, body weight, sc and total body fat. Furthermore, there was a negative correlation between CSF IL-6 and leptin. In conclusion, CSF IL-6 differs in many ways from CSF leptin. CSF IL-6 may be locally produced rather than serum derived, and body fat-regulating regions in the central nervous system may be exposed to insufficient IL-6 levels in more severe obesity.

Cerebrospinal fluid ghrelin is negatively associated with body mass index.

Ghrelin is a 28 amino acid peptide hormone, predominantly expressed in the gastric epithelium and, at a lower level, in the hypothalamus. Although several lines of evidence indicate that ghrelin has a role in appetite regulation, nevertheless the regulation and role of central ghrelin levels remain unclear. To further characterize the role of ghrelin in the regulation of body adiposity, we investigated the association between fasting cerebrospinal fluid (CSF) ghrelin levels and body mass index (BMI) in humans. We consecutively enrolled 19 adults (aged 21-76 yr, 15 females and 4 males), including 4 obese, 7 overweight and 8 lean subjects, who underwent spinal anesthesia during surgery for non-malignant conditions. We found a negative association between fasting CSF ghrelin levels and BMI (r = -0.48, p = 0.035) and a trend towards lower (by 16%) fasting CSF ghrelin levels in the obese (p = 0.06 for the difference between lean and obese subjects). In conclusion, we found a negative association between fasting CSF ghrelin levels and BMI in humans. Our data suggest that central ghrelin may have a role in the regulation of body adiposity in humans, which requires further study to be fully elucidated.

Fasting and postprandial cerebrospinal fluid glucose concentrations in healthy women and in an obese binge eater.

OBJECTIVE: We hypothesized that abnormal entry of glucose into the central nervous system (CNS) might exist in some chronic binge eaters of carbohydrates, as either a cause or consequence of binge eating. The purpose of this study was thus to determine fasting and postprandial glucose concentrations in the cerebrospinal fluid (CSF) of healthy women, and to obtain similar data in an obese, irritable woman with chronic binge eating of postpartum onset. METHOD: CSF was sampled continuously at 0.1 ml/min from 1100 hr to 1700 hr from the binge eating patient, who consumed 5,000 to 10,000 calories per day (preferentially binging on refined carbohydrates), and 4 healthy women via an indwelling, flexible spinal canal catheter. CSF aliquots were obtained at 10-min intervals for measurement of glucose concentrations. Simultaneously, blood was withdrawn at 30-min intervals to obtain serum for glucose assay. A glucose-rich mixed liquid meal was consumed by participants at 1300 hr. RESULTS: In striking contrast to the normal women, our bulimic patient showed no postprandial rise whatever in CSF glucose concentrations. Fasting CSF glucose concentrations were slightly lower whereas fasting serum glucose levels were normal in the bulimic patient, compared with the normal women. After eating, serum glucose levels increased in all participants, but less so in our patient. DISCUSSION: This is the first description of a lack of postprandial elevation in CSF glucose concentration in a patient with a binge eating disorder. Defective transport of glucose across the blood-brain barrier might account for the observed abnormality. While considering other possibilities, we conjecture that our patient's binge eating was an attempt to compensate for impaired postprandial entry of glucose into her CNS.

Cerebrospinal fluid oestrone in pseudotumour cerebri.

The concentration of oestrone in the cerebrospinal fluid (CSF) from obese young women with pseudotumour cerebri was much greater than predicted and found in normal subjects. Each woman with pseudotumour cerebri, and a high level of CSF oestrone and a CSF protein less than 0·2 g/l, had clinical improvement when treated with an 800 calorie/day diet and dexamethasone 2 mg/day.

Cerebrospinal fluid adenosine 3',5'-monophosphate, 5-hydroxyindoleacetic acid and homovanillic acid in patients with sleep apnoea syndrome.

Adenosine 3',5'-monophosphate (cyclic AMP), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in the cerebrospinal fluid of patients with respiratory disorder and hypersomnia and in control patients. Patients with the sleep apnoea syndrome confirmed polygraphically showed elevated levels of cyclic AMP and 5-HIAA. Cyclic AMP levels were inversely correlated with arterial Po(2), measured under resting conditions. The level of HVA also was raised, but the change was not statistically significant.