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.

Cerebrospinal fluid levels of insulin, leptin, and agouti-related protein in relation to BMI in pregnant women.

OBJECTIVE: During pregnancy, metabolic interactions must be adapted, though neuroendocrine mechanisms for increased food intake are poorly understood. The objective of this study was to characterize differences in insulin, leptin, and agouti-related protein (AgRP) levels in serum and cerebrospinal fluid (CSF) in pregnant women with normal weight (NW) and pregnant women with overweight (OW) or obesity (OB). Placenta as a source for increased peripheral AgRP levels during pregnancy was also investigated. METHODS: Women were recruited at admission for elective cesarean section. Insulin, AgRP, and leptin were measured in serum and CSF from 30 NW, 25 OW, and 21 OB at term. Serum during pregnancy and placenta at term were collected for further AgRP analysis. RESULTS: Immunohistology showed placental production of AgRP and serum AgRP levels increased throughout pregnancy. CSF AgRP, leptin, and insulin levels were higher in OW and OB than NW. Serum leptin and insulin levels were higher and AgRP lower in OB than NW. CONCLUSIONS: High serum AgRP levels might protect from the suppressive effects of leptin during pregnancy. Pregnant women with OB and OW might further be protected from the suppressive effect of leptin by high CSF AgRP levels. Evidence was found, for the first time, of human placental AgRP production mirrored by levels in the circulation.

Proopiomelanocortin, agouti-related protein, and leptin in human cerebrospinal fluid: correlations with body weight and adiposity.

Leptin and its neuronal targets, which produce proopiomelanocortin (POMC) and agouti-related protein (AgRP), regulate energy balance. This study characterized leptin, POMC, and AgRP in the cerebrospinal fluid (CSF) of 47 healthy human subjects, 23 lean and 24 overweight/obese (OW/OB), as related to BMI, adiposity, plasma leptin, soluble leptin receptor (s-OB-R), and insulin. POMC was measured since the POMC prohormone is the predominant POMC peptide in CSF and correlates with hypothalamic POMC in rodents. Plasma AgRP was similarly characterized. CSF leptin was 83-fold lower than in plasma and correlated strongly with BMI, body fat, and insulin. The relative amount of leptin transported into CSF declined with increasing BMI, ranging from 4.5 to 0.52%, consistent with a saturable transport mechanism. CSF sOB-R was 78-fold lower than in plasma and correlated negatively with plasma and CSF leptin. CSF POMC was higher in lean vs. OW/OB subjects (P < 0.001) and correlated negatively with CSF leptin (r = -0.60, P < 0.001) and with plasma leptin, insulin, BMI, and adiposity. CSF AgRP was not different in lean vs. OW/OB; however, plasma AgRP was higher in lean subjects (P = 0.001) and correlated negatively with BMI, adiposity, leptin, insulin, and HOMA (P < 0.005). Thus, CSF measurements may provide useful biomarkers for brain leptin and POMC activity. The striking negative correlation between CSF leptin and POMC could be secondary to leptin resistance and/or neuronal changes associated with obesity but may also indicate that POMC plays a primary role in regulating body weight and adiposity. The role of plasma AgRP as a neuroendocrine biomarker deserves further study.

Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women.

BACKGROUND: Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000 th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose → sorbitol → fructose) contributes to brain exposure to fructose. METHODS: In this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF), maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM) undergoing spinal anesthesia and elective cesarean section. RESULTS: As expected, CSF glucose was ~ 60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001), and CSF sorbitol was ~ 9-times higher than plasma levels (p < 0.001). Moreover, CSF fructose correlated positively with CSF glucose (ρ 0.45, p = 0.02) and sorbitol levels (ρ 0.75, p < 0.001). Cord blood sorbitol was also ~ 7-fold higher than maternal plasma sorbitol levels (p = 0.001). There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups. CONCLUSIONS: These data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption.

Elevated CSF serotonin and dopamine metabolite levels in overweight subjects.

OBJECTIVE: Neurotransmitter systems participate in the regulation of food intake, and their activities are expected to influence eating behavior. DESIGN AND METHODS: We investigated possible associations between body mass index (BMI) and central noradrenaline, serotonin, and dopamine activities, as reflected by the cerebrospinal fluid levels of their main metabolites methoxyhydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), respectively. We studied 192 subjects (111 males, 81 females) admitted to neurologic clinic for diagnostic investigations that included CSF analysis, and were found not to suffer from any major neurological disease. Subjects were categorized in three groups, namely in lower, in the two middle, and in upper BMI quartiles, the limits calculated separately for males and females. RESULTS: No differences were found in MHPG levels between groups, while subjects in the upper BMI quartile showed significantly elevated levels of 5-HIAA and HVA compared to the levels of subjects in lower and middle quartiles. CONCLUSIONS: The results provide evidence that in overweight subjects there are enhanced demands in serotoninergic and dopaminergic signaling for their reward system that may lead to increased motivation for food consumption. The implication of reward centers in eating behavior supports the hypothesis of common mechanisms in obesity and drug addiction.

Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid: relationship with plasma FGF21 and body adiposity.

OBJECTIVE: Reports of increased circulating fibroblast growth factor 21 (FGF21) levels in obesity indicate that FGF21 may be implicated in body weight homeostasis. We sought to investigate the existence of FGF21 in human cerebrospinal fluid (CSF) and, if present, the relationship between CSF FGF21 with body adiposity and metabolic parameters. RESEARCH DESIGN AND METHODS: CSF and corresponding plasma FGF21 were measured by an enzyme-linked immunosorbent assay (18 men and 20 women, aged 19-80 years, and BMI 16.2-38.1 kg/m(2)) and correlated to body adiposity and metabolic parameters. RESULTS: CSF and plasma FGF21 increased in particular with rising BMI and fat mass. In CSF, FGF21 was detectable at concentrations ~40% that of plasma levels. CSF and plasma FGF21 levels were significantly positively correlated with BMI and fat mass, body weight, plasma insulin, and homeostasis model assessment of insulin resistance. Plasma FGF21 levels were significantly negatively correlated with plasma adiponectin. When subjected to multiple regression analysis, only fat mass was predictive of plasma FGF21 (ß = 0.758; P = 0.004) and CSF FGF21 (ß = 0.767; P = 0.007). The CSF-to-plasma FGF21 ratio was significantly negatively correlated with BMI, fat mass, and plasma FGF21. Subjects in the highest plasma FGF21 quintile had a lower CSF-to-plasma FGF21 ratio (12.7% [9.7-14.9%]) compared with those in the lowest plasma FGF21 quintile (94.7% [37.3-99.8%]) (P < 0.01). CONCLUSIONS: Our observations have important implications with respect to the potential central actions of FGF21. Future research should seek to clarify whether FGF21 would be beneficial in the management of obesity and its metabolic complications.

Mid-life adiposity factors relate to blood-brain barrier integrity in late life.

OBJECTIVE: We explored the relationship between adiposity factors measured during mid-life and blood-brain barrier (BBB) integrity measured via the cerebrospinal fluid/serum (CSF/S) albumin ratio in late life. Adiposity factors included body mass index and blood levels of sex hormone binding globulin (SHBG) and leptin. Design. Retrospective analyses over 24 years within a longitudinal study. SETTING: Population-based sample. Subjects. Eighty-one women. MAIN OUTCOME MEASURES: CSF/S albumin ratio. RESULTS: The CSF/S albumin ratio measured at age 70-84 years was higher amongst women who were overweight or obese (6.50 +/- 2.79 vs. 5.23 +/- 1.61, age-adjusted P = 0.012), and was inversely correlated with SHBG (age-adjusted r = -0.321, P < 0.005) at age 46-60 years. In stepwise regression models, SHBG predicted the CSF/S albumin ratio (beta = -0.017, R2 = 0.107, P = 0.007). The best model (R2 = 0.187) predicting CSF/S albumin ratio included SHBG, age group (age 46 years versus >46), overweight or obesity, and an age group by SHBG interaction. CONCLUSIONS: Lower levels of SHBG in mid-life were related to worse BBB integrity in women after 24 years in late life, even considering other adiposity factors. SHBG may be important for understanding sex hormone-mediated mechanisms in brain health or as an independent marker of adipose tissue, the largest endocrine organ.