Neutral endopeptidase activity in serum and cerebrospinal fluid.
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We measured neutral endopeptidase (NEP) activity in serum from non-smoking healthy Japanese and in cerebrospinal fluid (CSF) from patients without neurological or inflammatory diseases. The serum NEP activity (sNEP) of 25 males and 25 females, aged 20 to 65 years, ranged from 0.003 to 1.62 pmole/min/microliter. There was no significant difference in sNEP activity between the sexes (male: 0.40 +/- 0.34 pmol/min/microliter vs female: 0.37 +/- 0.30, mean +/- S.D.). There was a significant positive correlation (p < 0.05) between sNEP and age. The NEP activity in the CSF (cNEP) ranged from 0.07 to 0.63 pmole/min/microliter. Male patients with benign prostate hypertrophy (BPH) showed cNEP activity of 0.21 +/- 0.11 pmol/min/microliter (n = 13), and female patients with myoma uteri (MU) or dysplasia of the uterus mucosa (DUM) showed activity of 0.32 +/- 0.20 (n = 5). There was no significant difference in cNEP activity between the sexes. Three patients with severe body pain showed cNEP activity of 0.21, 0.15, and 0.16 pmole/min/microliter, and these values were dissimilar from those of the BPH, MU, or DUM patients.Cite
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.
Anorectic
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OBJECTIVES: 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. METHODS: Female Wistar rats received progesterone chronically by means of subcutaneous implants over 30 days. RESULTS: 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). CONCLUSIONS: 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.
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beta-Endorphin
Gonadal hormones
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In mature male sheep, the level of nutrition acutely influences the secretion of reproductive hormones. The mechanism involved is not fully understood but findings in humans and laboratory rodents would suggest a major role for leptin that is secreted from adipose tissue and then travels via the circulation to the central nervous system. Before we can begin to test this hypothesis, we need to be able to measure leptin concentrations in blood plasma and cerebrospinal fluid. We have therefore developed a radioimmunoassay using antibodies raised against biologically active recombinant bovine-ovine leptin. Using this assay, we found that plasma concentrations of leptin were highly correlated to back-fat thickness and to the ratio of back-fat thickness to liveweight, in female and castrated male sheep. Plasma concentrations of leptin were higher in female sheep than in castrated or intact male sheep. Serial samples (every 5 min) suggested that the secretion of leptin in male sheep is episodic but it does not appear to show clear pulsatility, increases post-prandially, or a diurnal rhythm. Leptin concentrations in both plasma and cerebrospinal fluid increased within 5 days in male sheep fed a diet with a high content of energy and protein that also stimulates the secretion of LH pulses. These data suggest that in sheep, as in other species, leptin production is correlated with the mass of adipose tissue and that the hormone passes from the circulation to the cerebrospinal fluid and then to hypothalamic sites. There, it may affect appetite and perhaps GnRH secretion. The role of leptin in the link between nutrition and reproduction needs further investigation.
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Regulation of proopiomelanocortin (POMC) is an important means of controlling the central melanocortin system. It has never been established whether the spectrum of POMC-derived peptides synthesized and secreted from the hypothalamus is altered in response to changes in energy homeostasis in vivo. To monitor secretion, we analyzed peptide content of rat cerebrospinal fluid. Strikingly, both the POMC precursor and ACTH were readily detected. Moreover, levels of both were lower in samples from obese Zucker rats (fa/fa) vs. lean Zucker rats (+/+, fa/+) and from fasted vs. fed rats, whereas alpha MSH could not be detected. POMC levels were also decreased in hypothalamic extracts from obese and fasted animals. In contrast, despite being the most predominant peptide in extracts, alpha MSH levels were not significantly changed in any of the rat models. The ratio of precursor to derived peptides in cerebrospinal fluid was significantly higher in obese vs. lean and fed vs. fasted rats, indicating that secretion of POMC-derived peptides is differentially down-regulated during negative energy balance. In contrast to peptide analysis, we found that POMC gene expression was not significantly decreased in fasted rat hypothalami. We conclude that regulation of peptide secretion is an important mechanism by which the POMC system is controlled.
Proopiomelanocortin
Energy homeostasis
Melanocortins
Homeostasis
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Basal (medicine)
Serum concentration
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TRH and somatostatin (SRIF) are present in high concentrations in the hypothalamus (where they function as regulators of pituitary TSH and GH secretion) and also in the extrahypothalamic brain (where they may act as peptidergic neuromodulators). Both peptides are present in the cerebrospinal fluid (CSF), though their source is not known. Since there are diurnal variations in the CSF concentrations of other neurotransmitters, in pituitary hormone secretion, and in the behavioral responses to TRH and SRIF administration, it was of interest to study the diurnal variation of CSF TRH and SRIF in CSF. CSF was continuously withdrawn from chair-restrained rhesus monkeys, and 2-h fractions were assayed for SRIF and TRH. CSF did not exhibit nonspecific RIA effects, and peptide recoveries through the collection procedure were 70–100%. TRHlike and SRIF-like immunoreactivities in CSF eluted as single peaks on reverse phase high pressure liquid chromatography with retention times similar to those of synthetic TRH and SRIF. TRH-like immunoreactivity (mean, 34 ± 2 pg/ml; n = 159) in CSF showed a significant overall diurnal variation (P < 0.005), with maximal concentrations occurring in the afternoon (1613 h). SRIF-like immunoreactivity (mean, 82 ± 3 pg/ml; n = 362) in CSF also showed a significant overall diurnal variation (P < 0.005), with maximal concentrations occurring at night (0049 h). In individual monkeys, the pattern was less readily demonstrated, with nocturnal elevations present in four monkeys, a reversed pattern in one, and a biphasic pattern ifi another. Fluctuations of TRH and SRIF in CSF may reflect hypothalamic secretion, since they parallel variations reported in serum TSH and GH, or they may reflect changes in TRH and SRIF in the extrahypothalamic brain. Further study of these rhythms may be useful in differentiating the roles of TRH and SRIF in various brain localizations.
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Immunoreactive insulin (IRI) concentrations were measured in plasma and cerebrospinal fluid (CSF) of four-month old genetically obese Zucker rats, their heterozygote lean littermates, and age-matched normal-weight Wistar rats. Basal plasma IRI was 201 + 35 microU/ml (means +/- SEM) in the obese animals and was significantly elevated compared to both lean Zucker rats (18 +/- 2.4 microU/ml, P less than 0.001) and Wistar rats (12 +/- 2.4 microU/ml, P less than 0.001). The mean CSF IRI concentration of fasted obese Zucker rats was 1.59 +/- 0.19 microU/ml; this was significantly higher than the CSF IRI level of either fasted Zucker lean rats (0.31 +/- 0.08 microU/ml, P less than 0.001) or Wistar rats (0.34 +/- 0.12 microU/ml, P less than 0.001). Plasma and CSF IRI concentrations were increased in free-feeding as compared with fasted animals. These data provide evidence that endogenous CSF insulin is derived from circulating plasma insulin in the rat and suggest that the hyperphagia and obesity of the Zucker fatty rat are not due to an inability of circulating insulin to gain access to the CSF.
Basal (medicine)
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