Cerebrospinal Fluid Leptin Concentrations Research Articles

Effects of Exogenous Glucocorticoid Infusion on Appetitic Center Development in Postnatal Dairy Bull Calves.

The objective of this study was to determine the effects of exogenous glucocorticoid administration on leptin concentrations and brain development markers, such as protein and hypothalamic gene expression, in dairy bull calves. Within 4 h of parturition, Holstein bulls were intravenously infused with either a low cortisol dose (LC; n = 9, 3.5 µg/kg of body weight (BW)), high cortisol dose (HC; n = 9, 7.0 µg/kg BW), or control (CON; n = 9, saline) dose, with a 2nd infusion 24 h postpartum. Jugular blood was collected prior to infusion and daily until the calves were euthanized (day 5). Cerebrospinal fluid (CSF) from the third ventricle and adipose (omental, perirenal, and mesenteric) and hypothalamic tissue were collected. The blood and CSF samples were analyzed for leptin concentrations. The data were analyzed using SAS. Serum (p = 0.013) and CSF (p = 0.005) leptin concentrations in HC- and LC-treated calves were decreased compared with CON-treated calves. Leptin protein expression was decreased (p < 0.044) in perirenal and omental adipose tissue of LC-treated calves compared with CON-treated calves. Gene abundance of brain-derived neurotrophic factor and fibroblast growth factors 1 and 2 were decreased (p < 0.006) in HC- and LC-treated calves compared with CON-treated calves. In summary, cortisol administered to dairy bull calves reduced leptin concentrations, decreased leptin protein expression in perirenal and omental adipose tissue, and altered gene expression in hypothalamic tissue.

Differential impact of body mass index and leptin on baseline and longitudinal positron emission tomography measurements of the cerebral metabolic rate for glucose in amnestic mild cognitive impairment.

Several studies have suggested that greater adiposity in older adults is associated with a lower risk of Alzheimer's disease (AD) related cognitive decline, some investigators have postulated that this association may be due to the protective effects of the adipose tissue-derived hormone leptin. In this study we sought to demonstrate that higher body mass indices (BMIs) are associated with greater baseline FDG PET measurements of the regional cerebral metabolic rate for glucose (rCMRgl), a marker of local neuronal activity, slower rCMRgl declines in research participants with amnestic mild cognitive impairment (aMCI). We then sought to clarify the extent to which those relationships are attributable to cerebrospinal fluid (CSF) or plasma leptin concentrations. We used baseline PET images from 716 73 ± 8 years-old aMCI participants from the AD Neuroimaging Initiative (ADNI) of whom 453 had follow up images (≥6 months; mean follow up time 3.3 years). For the leptin analyses, we used baseline CSF samples from 81 of the participants and plasma samples from 212 of the participants. As predicted, higher baseline BMI was associated with greater baseline CMRgl measurements and slower declines within brain regions preferentially affected by AD. In contrast and independently of BMI, CSF, and plasma leptin concentrations were mainly related to less baseline CMRgl within mesocorticolimbic brain regions implicated in energy homeostasis. While higher BMIs are associated with greater baseline CMRgl and slower declines in persons with aMCI, these associations appear not to be primarily attributable to leptin concentrations.

Leptin’s effect on accelerated fracture healing after traumatic brain injury

Objective: To investigate mechanisms behind the faster rehabilitation of limb fractures when associated with traumatic brain injury (TBI).Methods: New Zealand rabbits were divided into TBI group and sham-operation group for four studies as follows: (1) blood and cerebrospinal fluid (CSF) were drawn on days 1, 3, and 7 to demonstrate changes in serum leptin, growth hormone (GH), insulin-like growth factor 1 (IGF-1), and CSF leptin; (2) bone defection was created by drilling in the tibial bone and either leptin or normal saline was injected into rabbit’s cerebellomedullary cistern. X-ray was taken at 1 days, 2 weeks, and 5 weeks and evaluated by criteria to determine rate of bone healing; (3) FITC-labeled rabbit leptin was injected into TBI and sham-operation groups, and frozen sections of rabbit brain were observed to identify differences in central nervous system (CNS) leptin by fluorescence; (4) polymerase chain reaction (PCR) was used to evaluate the expression of leptin production by brain tissue.Results: Serum and CSF leptin, GH, and IGF-1 concentrations were found to be higher in the TBI group than the sham-operation group at days 1, 3, and 7 (P<0·05). CSF leptin of the TBI group was positively correlated with serum leptin on day 1 (P<0·05), and positively correlated with GH and IGF-1 on days 3 and 7 (P<0·05). X-ray criteria demonstrated that leptin administration caused significantly faster healing calluses at 3 and 5 weeks as compared to control animals (P<0·05). FITC-labeled leptin study demonstrated that TBI animals had stronger expression of leptin in the brain than sham-operated animals. However, PCR of brain tissue leptin showed no significant differences between TBI and sham-operated animals in the expression of leptin.Conclusions: Our study suggests that increased CSF leptin, likely from blood–brain barrier breakdown, combined with elevated serum GH and IGF-1 after TBI, leads to accelerated fracture healing.

Cerebrospinal Fluid Hypocretin 1 Deficiency, Overweight, and Metabolic Dysregulation in Patients with Narcolepsy

The possible relationship between cerebrospinal fluid (CSF) hypocretin and leptin levels, overweight, and association to risk factors for diabetes 2 in narcolepsy with cataplexy were compared to patients with idiopathic hypersomnia and controls. 26 patients with narcolepsy, cataplexy, and hypocretin deficiency; 23 patients with narcolepsy, cataplexy, and normal hypocretin values; 11 patients with idiopathic hypersomnia; and 43 controls. Body mass index (BMI), serum leptin, and HbA1C were measured in patients and controls; and CSF hypocretin 1 and leptin measured in all patients. Female and male patients with narcolepsy and hypocretin deficiency had the highest mean BMI (27.8 and 26.2, respectively), not statistically different from patients with narcolepsy and normal hypocretin or controls, but statistically higher than the patients with idiopathic hypersomnia (p < 0.001 and 0.011, respectively). The number of obese patients (BMI > 30) was increased in both narcolepsy groups. Serum and CSF leptin levels correlated positively to BMI in patients and controls, but not to CSF hypocretin concentrations. HbA1C was within normal levels and similar in all groups. The study confirms a moderate tendency to obesity (BMI > 30) and overweight in patients with narcolepsy and cataplexy. Obesity was not correlated to hypocretin deficiency or reduced serum or CSF leptin concentrations. We suggest that overweight and possible metabolic changes previously reported in narcolepsy, may be caused by other mechanisms.

Correlation between Body Weight (Epididymal Fat) and Permeation Rate of Serum Leptin through the Blood-Brain Barrier (BBB) in Male Rats Aged 8 Months

In this study, in order to clarify the kinetics of leptin, we focused on the ratio of leptin concentrations in cerebrospinal fluid and serum in aged male rats, and examined the weight of epididymal fat, and the passage rate of leptin through the blood-brain barrier. In the lighter animals, the epididymal fat weight was low, while leptin concentrations in the serum and cerebrospinal fluid were also low. Conversely, in the heavier animals, the weight of epididymal fat and leptin concentrations in the serum and cerebrospinal fluid were higher. With regard to the ratio of leptin in the cerebrospinal fluid and serum, the passage rate of leptin through the blood-brain barrier was lower in the heavier animals than in the lighter animals.

Nutritional Influences on Reproductive Neuroendocrine Output: Insulin, Leptin, and Orexigenic Neuropeptide Signaling in the Ovine Hypothalamus

This study investigated how changing nutritional status may alter reproductive neuroendocrine (LH) output via circulating leptin and insulin signaling through orexigenic hypothalamic pathways. Thin sheep were given an increasing nutritional plane (INP), sheep with intermediate adiposity a static nutritional plane (SNP), and fat sheep a decreasing nutritional plane (DNP) for 6 wk. Mean group adiposities converged by wk 6, LH output increased in INP, remained unchanged in SNP, and decreased in DNP sheep. Plasma and cerebrospinal fluid (CSF) insulin and plasma leptin concentrations increased in INP but did not change in the SNP and DNP groups. In INP sheep, LH output correlated positively with adiposity and plasma and CSF insulin concentrations and negatively with orexigenic neuropeptide Y gene expression in the hypothalamic arcuate nucleus (ARC). In DNP sheep, LH output correlated positively with adiposity, CSF leptin concentrations, and ARC proopiomelanocortin gene expression and negatively with leptin receptor (OB-Rb) and agouti-related peptide gene expression in the ARC. These data are consistent with the feedback response to an increasing nutritional plane being mediated by increasing circulating insulin entering the brain and stimulating LH via inhibition of hypothalamic neuropeptide Y and the response to a decreasing nutritional plane being mediated by altered hypothalamic leptin signaling brought about by increased OB-Rb expression and decreased melanocortin signaling. Because end point adiposity was similar yet LH output was different, the hypothalamus apparently retains a nutritional memory, based on changes in orexigenic neuropeptide expression, that influences contemporary neuroendocrine responses.

Blood-Brain Leptin Transport and Appetite and Reproductive Neuroendocrine Responses to Intracerebroventricular Leptin Injection in Sheep: Influence of Photoperiod

Impaired anorectic actions of leptin may be due to intrahypothalamic insensitivity and/or reduced blood-brain transport. The influence of photoperiod on leptin responses and leptin transport from blood into cerebrospinal fluid (CSF) was examined in sheep. Sheep kept on ad libitum food for 15 wk in long days (LD) had higher voluntary food intake and lower GnRH/LH output than in short days (SD). Food intake was decreased approximately 30% after intracerebroventricular (icv) (and not iv) leptin injection, but only in SD. GnRH/LH secretion was decreased after icv (but not iv) leptin in both photoperiods. Leptin concentrations in CSF were higher in LD than SD but correlated with plasma leptin only in LD. Amounts of leptin entering CSF after iv leptin injection were greater in LD than SD. In a separate experiment, plasma (but not CSF) leptin was higher in fat than thin sheep in natural summer LD and after 5 wk in SD. CSF leptin correlated with plasma leptin in LD but not SD. CSF leptin after iv leptin injection was higher in thin than fat sheep but only in LD. Endogenous CSF to plasma concentration ratios correlated negatively with plasma concentrations, indicating decreased blood-brain transport with increased leptinemia. Therefore, icv (and not iv) leptin inhibited appetite only in SD and decreased GnRH/LH output in both photoperiods, and the proportion of circulating leptin entering CSF was higher in LD and thinner animals. Photoperiod apparently modulates intrahypothalamic leptin sensitivity of appetite, but not reproductive, regulatory pathways, whereas photoperiod and leptinemia influence leptin blood-brain transport.

Cerebrospinal fluid leptin levels in preeclampsia: relation to maternal serum leptin levels.

To determine whether cerebrospinal fluid (CSF) and circulating levels of leptin differ between women with preeclampsia and women who had an uncomplicated pregnancy. Maternal serum and CSF leptin concentrations obtained in the third trimester of the gestation were compared in 16 women with mild preeclampsia and 23 normotensive pregnant women who underwent cesarean section. Before administering local anesthetic for spinal anesthesia, 2 mL CSF and 4 mL venous blood sample were taken and were stored at -30 degrees C until serum and CSF leptin levels were measured by enzyme-linked immunosorbent assay (ELISA). Mean CSF leptin concentrations were not significantly different between the two groups (preeclampsia 9.7 +/- 4.2 ng/mL, normotensive 13.6 +/- 4.3 ng/mL, p = 0.952). Similarly, mean serum leptin concentrations were similar between the two groups (mild preeclampsia 21.7 +/- 7.1 ng/mL, normotensive 18.3 +/- 6.7 ng/mL, p = 0.698). CSF leptin levels are inversely related to the serum leptin concentrations in preeclamptic patients (r = -0.87, p = 0.000). An inverse relationship was also detected between CSF and serum leptin levels in normotensive pregnant subjects (r = -0.66, p = 0.000). CSF and serum leptin levels were similar in patients with preeclampsia and normotensive pregnant women. However, the CSF leptin was negatively correlated with the serum leptin concentrations in preeclamptic and normotensive control subjects, suggesting that leptin enters the brain by a saturable transport system. Further work is needed to confirm our findings.

Diurnal rhythm of cerebrospinal fluid and plasma leptin levels related to feeding in non-lactating and lactating rats

Leptin suppresses food intake and increases energy expenditure in the hypothalamus. Rats consume most of their daily food intake during the dark phase of the diurnal cycle. Lactating rats have increased food intake, but the involvement of leptin in the regulation of food intake in this physiological condition is not well understood. The present experiment was carried out to determine the circadian pattern of leptin concentrations in plasma and cerebrospinal fluid (CSF) in relation to the feeding behavior of non-lactating and lactating rats. Female rats were maintained on a controlled lighting schedule (lights on between 0600 and 1800 h) and the food intake of lactating rats was two- or threefold higher than that of non-lactating rats. In both groups, food intake was three times greater in the dark phase (P<0.01) compared with the light phase. The plasma concentrations of leptin were lower (P<0.01) in lactating rats than non-lactating rats in both light and dark phases, but there were no differences in plasma leptin levels between light and dark phases. In contrast, and in both groups, the leptin concentrations in CSF were lower (P<0.01) in the dark phase than in the light phase. Leptin levels in CSF were lower (P<0.01) in lactating rats than in non-lactating rats. We conclude that a diurnal pattern of leptin levels within the brain (but not in plasma) reflects characteristics of feeding behavior in lactating and non-lactating rats.

The anorectic effect of oestradiol does not involve changes in plasma and cerebrospinal fluid leptin concentrations in the rat.

Oestradiol is a potent anorectic agent that reduces both food intake and body weight. Since leptin is known to reduce food intake, we first analysed if the anorectic effect of oestradiol is driven by an increased leptin concentration in either cerebrospinal fluid or plasma. Oestradiol also reduces body weight and fat mass. Accordingly, a decrease in plasma leptin concentration can also be expected after an oestradiol-driven reduction in fat mass. To test this hypothesis was the second aim of this study. Female Wistar rats received oestradiol chronically during 14 days. During the first week of treatment there was a reduction in food intake, body weight and fat mass that returned to initial values during the second week, but no changes in ob mRNA levels were found in white adipose tissue depots. There was no effect of treatment or time on plasma and cerebrospinal fluid leptin concentrations. Therefore, the anorectic effect of oestradiol is not driven by an increase in leptin concentration either in plasma or in cerebrospinal fluid, and the reduction in fat mass that oestradiol produces is not followed by a reduction leptin concentration.

Plasma and cerebrospinal fluid leptin levels are maintained despite enhanced food intake in progesterone-treated rats.

For adipostatic control, increases in food intake are followed by increased leptin levels that in turn reduce food intake. However, progesterone administration increases both food intake and body weight. The aim of this study was to analyze changes in the white adipose tissue-leptin system in rats with enhanced plasma levels of progesterone. Female Wistar rats received progesterone chronically by means of subcutaneous implants over 30 days. They showed an increased food intake followed by increased body weight and heavier fat depots. An enhanced ob-mRNA level was detected in inguinal white adipose tissue depot on day 2 of treatment but the increase was transient, disappearing on day 6 of treatment. No changes in ob-mRNA levels were found in parametrial and retroperitoneal white adipose tissue depots. Plasma and cerebrospinal fluid leptin levels were unchanged either during the treatment or between corresponding treated and control rats. Leptin concentrations in cerebrospinal fluid were ten times lower than in plasma (0.2--0.3 ng/ml versus 2--3 ng/ml respectively). These results indicated that progesterone favours a positive energy balance not only by enhancing food intake but also by inhibiting the concurrent enhancement in plasma and cerebrospinal fluid leptin levels expected from the increased fat mass.

Development of obesity in transgenic rats with low circulating growth hormone levels: involvement of leptin resistance.

Human growth hormone (hGH) transgenic (TG) rats have been produced in our laboratory. These TG rats are characterized by low circulating hGH levels, virtually no endogenous rGH secretion, and massive obesity. To elucidate how energy balance and leptin sensitivity contributed to the establishment of this obesity. Food intake, locomotor activity and leptin concentrations in serum and cerebrospinal fluid were measured in TG rats and their non-transgenic littermates (control). The effect of intraperitoneal and intracerebroventricular injection of leptin on food intake and body weight gain was also examined. An increase in food intake and a decrease in locomotor activity were observed from 4 and 7 weeks of age, respectively, in the transgenic rats compared with control. Serum leptin concentrations of the transgenic rats were more than twice as high as those of control rats and were associated with an increased white adipose tissue mass and ob gene expression. Intraperitoneal injection of leptin significantly decreased food intake and body weight gain in control rats, but not in transgenic rats. Leptin concentration in the cerebrospinal fluid of transgenic rats was not different from that of control rats, and intracerebroventricular injection of leptin was similarly effective in reducing food intake and body weight gain as it was in control rats. These results suggest that the transgenic rats, whose GH secretion is suppressed, develop obesity due to early onset of an increase in food intake and a decrease in locomotor activity with leptin resistance resulting from deteriorating leptin transport from peripheral blood to cerebrospinal fluid.

Single intracerebroventricular bolus injection of a recombinant adenovirus expressing leptin results in reduction of food intake and body weight in both lean and obese Zucker fa/ fa rats

Leptin acts as a satiety factor within the central nervous system by binding to its receptor located in the hypothalamus. A missense mutation of the leptin receptor induces hyperphagia and obesity in the obese Zucker fa/ fa rat. Since the CNS is an important target of leptin action, we hypothesized that leptin gene transfer into the lateral cerebral ventricle could efficiently lead to inhibition of food intake and reduction of body weight in obese fa/ fa rats as well as in lean animals. A single intracerebroventricular injection of an adenoviral vector containing a cDNA encoding leptin resulted in the expression of leptin in the ependymal cells lining the ventricle and the secretion of leptin into the cerebrospinal fluid (CSF). During the first week after injection, when high concentrations of leptin were produced in the CSF, the reducing effects of leptin on food intake and body weight were comparable in lean and in obese fa/ fa rats. The subsequent decline in CSF leptin levels, that was similar in lean and obese fa/fa rats, resulted in the faster resumption of food intake and body weight gain in obese than in lean animals, confirming a reduced sensitivity to leptin in the obese group. The results of this study show that leptin gene delivery into the cerebral ventricles allows for the production of elevated leptin concentrations in CSF, and they support the hypothesis that the impaired sensitivity to leptin may be overcome in obese fa/ fa rats.

Leptin in Cerebrospinal Fluid from Children: Correlation with Plasma Leptin, Sexual Dimorphism, and Lack of Protein Binding

Previous studies in adults have established that leptin is present at very low concentrations in cerebrospinal fluid (CSF), but few data exist concerning CSF leptin in children. Current evidence suggests that CSF leptin concentrations interact with hypothalamic centers controlling food intake. Serum leptin concentrations manifest a sexual dimorphism that arises during puberty. Leptin concentrations were determined in CSF from 42 pre- and postpubertal children who had been objectively classified into non-neurological disease or aseptic meningitis groups. Multivariate analysis of the dependence of CSF leptin on gender, pubertal state, body mass index (BMI), presence of aseptic meningitis, and CSF protein concentration was performed. CSF leptin concentrations correlated with log-transformed plasma leptin concentrations in concomitantly collected samples (r = 0.582; P = 0.029). BMI and gender were significant determinants of CSF leptin in postpubertal children, but only BMI was significant in prepubertal children. Analysis with HPLC to separate protein-bound and free forms of leptin found only free leptin in CSF. CSF leptin concentrations in children reflect plasma leptin concentrations, including the advent of sexual dimorphism at puberty. Only free leptin is detectable in CSF, suggesting that it is the biologically active form.

Cerebrospinal fluid and plasma leptin measurements: covariability with dopamine and cortisol in fasting humans.

Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites, beta-lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.

Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans

The adipocyte hormone, leptin (OB protein), is proposed to be an "adiposity signal" that acts in the brain to lower food intake and adiposity. As plasma leptin levels are elevated in most overweight individuals, obesity may be associated with leptin resistance. To investigate the mechanisms underlying brain leptin uptake and to determine whether reduced uptake may contribute to leptin resistance, we measured immunoreactive leptin levels in plasma and cerebrospinal fluid (CSF) of 53 human subjects. Leptin concentrations in CSF were strongly correlated to the plasma level in a nonlinear manner (r = 0.92; p = 0.0001). Like levels in plasma, CSF leptin levels were correlated to body mass index (r = 0.43; p = 0.001), demonstrating that plasma leptin enters human cerebrospinal fluid in proportion to body adiposity. However, the efficiency of this uptake (measured as the CSF:plasma leptin ratio) was lower among those in the highest as compared with the lowest plasma leptin quintile (5.4-fold difference). We hypothesize that a saturable mechanism mediates CSF leptin transport, and that reduced efficiency of brain leptin delivery among obese individuals with high plasma leptin levels results in apparent leptin resistance.