Cryptococcosis in tree shrews (Tupaia tana and Tupaia minor) and elephant shrews (Macroscelides proboscides)

OBJECTIVE: To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS). DESIGN AND PATIENTS: Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2-hour 75-g oral glucose tolerance test (OGTT) in 85 women with PCOS (17-36 years, body mass index (BMI) 29.9 +/- 0.9 kg/m2, mean +/- SD) and 18 control women (25-47 years, BMI 25 +/- 1.7 kg/m2). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations. MEASUREMENTS: Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay. RESULTS: Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/ hip ratio, on leptin concentrations. Comparison of control subjects to a BMI-matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 +/- 1.3 vs 12.1 +/- 2.3 micrograms/l, mean +/- SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups. CONCLUSIONS: Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.     

Elevated tumour markers in patients with Balkan endemic nephropathy

OBJECTIVE: To investigate the acute effect of dexamethasone administration on serum leptin levels and the relationships between dehydroepiandrosterone (DHEAS), androstenedione, testosterone and the IGF-I/IGFBP system and leptin levels in healthy elderly humans. METHODS: In 209 healthy elderly individuals (95 men, 114 women, aged 55-80 years) measurements were made in the fasting state (0800 h) and after an overnight dexamethasone suppression test (1 mg p.o. at 2300 h. RESULTS: Mean leptin levels increased from 6.2 +/- 0.4 (SE) micrograms/l to 7.3 +/- 0.5 (SE) micrograms/l in men and from 18.9 +/- 1.4 (SE) micrograms/l to 23.9 +/- 1.8 (SE) micrograms/l in women after 1 mg dexamethasone overnight ('post treatment')(P < 0.001 for both sexes). There was a significant relationship between post-treatment leptin and dexamethasone levels (men: P = 0.002; women: P < 0.001). The increase in leptin levels after dexamethasone administration was only partially related to the increase in plasma insulin concentrations. Cortisol levels were not related to leptin. In multivariate analyses the relationship between post-treatment leptin and dexamethasone levels remained after adjustment for post-treatment insulin levels, BMI, waist:hip ratio (WHR) and age (men: P < 0.001; women: P = 0.001). Plasma (free and total) IGF-I and IGFBP-3 levels were not related to leptin levels in men or women. IGFBP-1 levels were inversely related to leptin levels (P = 0.02), but this relationship was lost after adjustment for insulin, and/or BMI. In multivariate analyses the relationship between leptin and DHEAS was inverse in women (P = 0.04) (after adjustment for BMI, WHR, insulin and glucose), while there was no relationship between leptin and DHEAS in men. CONCLUSIONS: Administration of dexamethasone acutely increased leptin levels within 9 h in this elderly population. This increase was only partly related to changes in circulating insulin concentrations, but was independent of BMI and waist:hip ratio. No relation existed between leptin and (free or total) IGF-I and IGFBP-3 in men or women. Dehydroepiandrosterone was inversely related to leptin in women. These findings suggest a contributory regulatory role for corticosteroids in modulating circulating leptin concentrations in elderly healthy individuals of both sexes, which is at least in part independent of insulin, BMI and waist:hip ratio. Dehydroepiandrosterone might play a role in the gender-specific differences in serum leptin levels.     

Widespread arterial thrombosis in association with metastatic carcinoma--a case report

Inferential studies suggest that circulating insulin concentrations positively regulate leptin secretion by adipocytes. In humans, however, insulin requires prolonged periods of time, and relatively artificial set-ups before a relationship with leptin can be observed. In the present work, serum leptin concentrations were measured in five patients with insulinoma before and one month after surgery and in five control subjects matched by sex and body mass index (BMI). The control subjects presented a mean serum leptin concentration of 6.7+/-1.5 microg/l and a BMI of 24.9+/-1.1. The mean serum leptin concentration in patients with insulinoma was 11.8+/-3.1 microg/l (P < 0.05 vs controls), with a BMI of 26.3+/-1.9. After surgery, there was a non-significant reduction in BMI (25.8+/-1.7), and a clear reduction in serum leptin concentration (5.6+/-2.4 microg/l, P < 0.05 vs pre surgical values and no difference vs control subjects). The fasting area under the curve (AUC) of insulin concentration (in mU/l per 120 min) before surgery was 14421+/-4981 and after surgery was 1306-/+171 (P < 0.05). Before surgery, serum leptin concentrations significantly correlated with BMI (r = 0.71) and AUC of insulin (r = 0.82), a correlation that was lost after surgery. In conclusion, serum leptin concentrations are significantly elevated in patients with chronically high insulin levels due to insulinoma. After surgical treatment and normalization of insulin values, leptin levels return to normal.     

Campylobacter-host cell interactions

BACKGROUND: Leptin is likely to be involved in the homeostasis of body weight. Insulin is suggested to regulate both short-term and long-term circulating leptin levels. The present study aims to assess the relation between insulin and leptin levels in obese humans. METHODS: Some 53 obese subjects (body mass index 35.1 +/- 3.9 kg m-2 (mean +/- SD)) were prescribed a hypocaloric diet and randomized to either a placebo or the intestinal lipase inhibitor orlistat for 2 years. Serum leptin and insulin levels were determined repeatedly during these 2 years (5 times in the fasting condition and twice after an oral glucose load). RESULTS: Leptin concentrations appeared to be regulated at a specific level for each individual throughout the weight-loss period. The BMI explained 39.7% of the total variance in leptin levels, the body-fat distribution 17.2%, individual characteristics 30.3%; and the fasting serum insulin concentration 1.0%. After a mean weight loss of 7.7 +/- 4.9 kg, the time-integrated insulin response to an oral glucose load was significantly lower but the leptin response remained unchanged. CONCLUSIONS: The BMI is the main determinant of the circulating leptin concentration in obese humans. Individual characteristics seem to determine the leptin level, given the BMI. In a short-term observational study in obese humans, changes of insulin levels do not appear to be correlated to changes in leptin levels.     

Human leukocyte antigens associated with hyperthyroid Graves ophthalmology in Japanese patients

PURPOSE: Leptin is a recently discovered hormone that appears as a regulator of energy balance. It is important to know whether leptin concentrations are changed under conditions of altered energy homeostasis. Consequently, we examined the effects of exercise with fasting and exercise with feeding on circulating leptin concentrations in healthy men and in type 1 diabetic patients with normal body weight and well controlled diabetes. METHODS: Leptin concentrations were determined with radioimmunoassay. RESULTS: During a 3-h cycle ergometer exercise with fasting, leptin decreased by 42% (P < 0.01) in nine healthy men and by 23% (P = 0.05) in eight male type 1 diabetic patients. Leptin fell equally by 12% (P < 0.03) both in nine healthy men and in eight male type 1 diabetic patients who were studied as a resting control group. The absolute fall in leptin in healthy men was similar in the exercise and resting control groups (0.8 +/- 0.1 microgram.L-1 vs 0.8 +/- 0.2 microgram.L-1). However, due to lower leptin concentration before the exercise, the relative decrease (42%) was greater than during the resting control study (12%, P < 0.005). This difference was not seen in the diabetic patients. Fasting leptin concentration correlated positively with BMI (r = 0.75, P < 0.001) and fasting insulin (r = 0.71, P < 0.01) in healthy men as well as with insulin level (r = 0.54, p < 0.05) in type 1 diabetic patients. When exercise was performed with feeding, and this was associated with a significant rise in serum cortisol level (marathon run, 14 healthy men and 7 type 1 diabetic patients), leptin concentration did not change significantly. CONCLUSIONS: 1) During morning hours, leptin decreases both in healthy men and in type 1 diabetic patients, reflecting a diurnal variation of leptin concentration and the effect of fasting on leptin concentration. 2) The fall in leptin during morning hours is augmented by physical exercise in healthy men. 3) If exercise is performed with feeding and associated with a rise in serum cortisol level, leptin concentration remains unchanged. These data suggest that although exercise may reduce circulating leptin levels, the effect is small and can be counterbalanced by feeding or a rise in serum cortisol concentration.     

Determinants of serum leptin levels in Cushing's syndrome

Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing's syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 +/- 2.7 yr; body mass index (BMI), 29.6 +/- 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 +/- 3.1 yr; BMI, 26.3 +/- 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing's syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing's syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.     

Local and systemic tolerance to orally administered dinitrochlorobenzene is not broken by cholera toxin

OBJECTIVE: Withdrawal of testosterone prevents the development of hyperglycaemia in male Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus (NIDDM), but the exact mechanism has not been established. The present studies were undertaken to examine a possible role of testosterone in the development of obesity in young OLETF rats who have not shown marked hyperphagia. METHODS: Body weight, food intake and circulating concentrations of metabolic factors including immunoreactive leptin (IRL) were measured at five weeks of age in young male OLETF rats and their lean controls, Long-Evans-Tokushima-Otsuka (LETO) rats. At six weeks of age, both LETO and OLETF rats were bilaterally orchiectomized (Orchx) and half of each group implanted with a silastic tube containing testosterone. After a three week observation period, all animals were killed and circulating concentrations of metabolic factors and the ob gene expression in retroperitoneal white adipose tissues were measured. RESULTS: Body weight and 24h food intake were already increased in OLETF rats at five weeks of age. Serum testosterone concentrations were significantly lower in OLETF rats than in LETO rats. Expression of the ob gene was significantly decreased in the retroperitoneal white adipose tissue of OLETF rats, and their serum IRL concentrations were lower. Food intake and body weight gain for three weeks after the operation were significantly lower in the Orchx group of OLETF rats than in the sham-operated group. Hyperglycaemia, accompanied by hyperinsulinaemia, was attenuated by orchiectomy in OLETF rats. Circulating IRL concentrations were significantly higher in OLETF rats than in LETO rats and decreased by orchiectomy. Testosterone supplement reversed all of the changes caused by orchiectomy in OLETF rats. In contrast, the changes, which were observed after orchiectomy in OLETF rats, were not obvious in LETO rats. CONCLUSION: The present data indicate that testosterone plays a role in the development of obesity and NIDDM in young OLETF rats, but that changes of leptin production in white adipose tissue may not be important in the development of obesity in young OLETF rats.     

Circulating leptin has saturable transport into intrathecal space in humans

BACKGROUND: Leptin is an adipocyte-derived hormone that is thought to provide a negative feedback signal to control body fat mass by interacting with its hypothalamic receptor. The present study was undertaken to examine the uptake of leptin in cerebrospinal fluid (CSF) space in humans and whether the transport of leptin into CSF space is an active phenomenon or due to free access through the blood-CSF barrier. METHODS: We determined serum and CSF leptin concentrations by radioimmunoassay in 17 men [42 +/- 4 years, mean +/- SE; body mass index (BMI) 27.3 +/- 1.8 kg m-2] and 22 women (40 +/- 3 years, BMI 25.1 +/- 1.0 kg m-2). The function of the blood-CSF barrier was evaluated by determining the CSF/serum albumin ratio. RESULTS: Serum leptin concentration was lower in male (5.8 +/- 1.6 microgram L-1) than in female subjects (13.1 +/- 1.7 microgram L-1, P = 0. 001), whereas the concentrations of leptin in CSF were virtually identical in male (0.34 +/- 0.03 microgram L-1) and female (0.36 +/- 0. 03 microgram L-1) subjects. Serum leptin was correlated positively with BMI both in men (r = 0.89, P < 0.01, n = 10) and in women (r = 0.61, P < 0.05, n = 14), whereas no correlation between CSF leptin concentration and BMI was found in either group. The CSF/serum leptin ratio correlated negatively with serum leptin concentration both in men (r = -0.93, P < 0.001) and in women (r = -0.77, P < 0. 001) and with BMI both in men (r = -0.75, P = 0.02, n = 10) and in women (r = -0.64, P < 0.02, n = 14). The CSF/serum albumin ratio was not correlated with the CSF/serum leptin ratio in either group. CSF leptin concentrations and the CSF/serum leptin ratio were virtually identical in subjects with impaired and normal blood-CSF barrier function. CONCLUSION: Thus, our data support the presence of a saturable and active transporter of leptin from circulation into intrathecal space.     

Leptin levels in children with central precocious puberty

Several studies have suggested that sufficient serum leptin levels may be involved in the initiation of puberty. To assess further the relationship between leptin and the onset of puberty in humans, we measured the serum leptin concentration in children with central precocious puberty (CPP). We studied 65 children with either idiopathic (IPP; n = 50 girls and 3 boys) or neurogenic central precocious puberty (NPP; n = 5 girls and 7 boys). The serum leptin levels in these patients were compared with normative data from healthy children and adolescents using SD scores that adjust for body mass index (BMI) and Tanner stage. The mean SD scores of IPP and NPP girls were +0.4 +/- 0.1 and +1.0 +/- 0.5, respectively, compared with that of age-matched prepubertal girls and +0.7 +/- 0.2 and +1.6 +/- 0.6 compared with that of girls matched for pubertal stage. The CPP girls with lower BMIs contributed larger SD scores, such that the leptin SD score was negatively correlated with BMI. A similar, modest increase in leptin levels in the CPP girls was evident when additional normative data were considered. The mean leptin SD scores of IPP and NPP boys were -0.9 +/- 0.5 and +0.7 +/- 0.3, respectively, compared with that of normal boys at Tanner stage 3-4. Serum leptin levels in the boys with CPP were not different from those in healthy boys in any of the normative studies. These data should be interpreted cautiously, but they suggest that girls with CPP have modestly elevated serum leptin concentrations compared with those in healthy children and adolescents. In addition, the negative correlation between the leptin SD score and BMI suggests that sufficient leptin levels may be associated with initiation of puberty in girls.     

Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans

The expression of leptin, an adipocyte-derived protein whose circulating levels reflect energy stores, can be induced by tumor necrosis factor (TNF)alpha in rodents, but an association between the TNF alpha system and leptin levels has not been reported in humans. To evaluate the potential association between serum leptin and the TNF alpha system, we measured the levels of soluble TNF alpha-receptor (sTNF alpha-R55), which has been validated as a sensitive indicator of activation of the TNF alpha system. We studied two groups: 1) 82 young healthy normal controls and 2) 48 patients with noninsulin dependent diabetes mellitus (NIDDM) and 24 appropriately matched controls. By simple regression analysis in controls, there was a strong positive association between leptin and 3 parameters: body mass index, sTNF alpha-R55, and insulin levels. In a multiple regression analysis model, leptin remained significantly and strongly associated with body mass index, and the association of leptin with both insulin and sTNF alpha-R55, although weakened, remained significant. Patients with NIDDM had leptin concentrations similar to controls of similar weight. Importantly, serum levels of sTNF alpha-R55 were also positively and independently associated with leptin in this group of diabetic subjects and matched controls. These data are consistent with the hypothesis that the TNF alpha system plays a role in regulating leptin levels in humans. Further elucidation of a possible role of the TNF alpha system in leptin expression and circulating levels may have important implications for our understanding of obesity and cachexia in humans.     

Recent progress in research on plant polyphenol oxidase

The study objective was to determine circulating levels of the appetite-controlling neuropeptides, neuropeptide Y (NPY), galanin, and leptin, in subjects with eating disorders. The study group consisted of 48 obese women aged 19 to 45 years, 15 women with anorexia nervosa aged 18 to 23 years, and 19 lean healthy women aged 18 to 42 years (control group). The obese women were divided into four groups: (A) body mass index (BMI) = 25 to 30 kg/m2, n = 9 (overweight); (B) BMI = 31 to 40 kg/m2, n = 23 (moderate obesity); (C) BMI greater than 40 kg/m2, n = 9 (severe obesity); and (D) BMI = 31 to 40 kg/m2, n = 7 (moderate obesity + non-insulin-dependent diabetes mellitus [NIDDM]). Plasma NPY, galanin, and leptin concentrations were measured in peripheral blood samples with radioimmunoassay methods. Plasma NPY levels in obese women (groups A, B, C, and D) were significantly higher as compared with the control group (P < .01, P < .001, P < .001, and P < .001, respectively). The highest plasma NPY concentrations were observed in obese women with NIDDM. Plasma galanin levels were significantly higher in groups B, C, and D (P < .001, P < .001, and P < .001, respectively). Plasma leptin concentrations were significantly higher in groups C and D as compared with the control group (P < .001 and P < .001, respectively). Plasma NPY and galanin concentrations in women with anorexia nervosa did not differ from the levels in the control group. However, plasma leptin concentrations were significantly lower in anorectic women than in the control group (P < .01). Our results indicate that inappropriate plasma concentrations of NPY, galanin, and leptin in obese women may be a consequence of their weight status, or could be one of many factors involved in the pathogenesis of obesity.     

Body composition and age in African-American and Caucasian women: relationship to plasma leptin levels

Leptin is a recently isolated peptide hormone released from adipocytes that has been postulated to play a role in appetite regulation and energy metabolism. Aging affects both food intake and body composition. Body composition is also affected by ethnicity. We have evaluated the relationships between serum leptin levels, age, body composition (by dual-energy x-ray absorptiometry), and hormonal parameters in a cross-sectional study of 94 women, 53 African-American (AAF) and 41 Caucasian (CF). Our hypotheses were as follows: (1) changes in body composition would be related to age in a sinusoidal pattern, (2) changes in serum leptin would parallel changes in body fat, (3) serum leptin levels would be influenced by body fat distribution, and (4) serum leptin would be related to serum concentrations of sex hormones. Serum leptin paralleled changes in body fat and body mass index (BMI) with age. In the entire group, serum leptin correlated closely with measures of body fat, including BMI and total fat mass, and there was no difference in leptin levels between the two ethnic groups. In simple regression analysis, serum leptin was related to both serum estradiol and testosterone. The relationship between serum leptin and trunk fat was linear in both groups, but significantly different in AAF and CF (P = .014). Serum leptin was associated with the trunk to lower-extremity fat ratio in CF (r = .67, P = .001) but not in AAF. Body fat was increased with advancing age until about 65 years and then declined. Measures of lean body mass declined linearly with age in the entire group, as well as both subgroups. In the entire group, total lean body mass and lean body mass corrected for BMI (lean body mass/BMI) were inversely related to age. In subjects aged less than 60 years AAF were stronger (P < .05) and had both a larger BMI and fat mass (P < .05) than CF. However, the patterns of age-related changes in fat body mass, lean body mass, and BMI were similar in both groups. In the entire group, multiple regression analysis indicated that the age, free thyroxine index (FTI), and leptin concentration were predictors of the body composition and distribution of trunk to lower-body fat. These observations indicate that there is a sinusoidal relationship between body fat and age, with a decline in body fat in extreme old age in both AAF and CF, and that serum leptin concentrations are more closely related to body fat and BMI than to age or ethnicity.     

Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year

The gene product from the ob gene, leptin, has recently been characterized in humans. The circulating level of leptin is related to body mass index (BMI) and more closely to estimates of total body fat, whereas visceral fat has been reported to be of minor importance. However, it is unknown if leptin is directly regulated by hormones that influence substrate metabolism and body composition. We studied leptin in adult growth hormone (GH)-deficient (GHD) patients substituted with GH treatment for 12 months in a parallel double-blind, placebo-controlled study. Twenty-seven GHD adults aged 44.9 +/- 1.9 years underwent anthropometric measurements for determination of regional and total body fat (BMI, waist to hip ratio [WHR], computed tomographic [CT] scan, dual-energy x-ray absorptiometry [DEXA] scan, and bioimpedance analysis [BIA]) before and after 12 months of placebo-controlled GH substitution (2 IU/m2) in a parallel design. The same measurements were performed in 42 healthy adults aged 39.1 +/- 1.7 years. The logarithm of serum leptin levels correlated positively with abdominal subcutaneous fat and total body fat (BIA and DEXA) in untreated GHD patients and healthy subjects. Fasting insulin did not correlate with leptin levels in either of the groups. After 12 months of GH administration, the body composition of GHD patients was significantly changed with respect to a marked decrease in body fat. The relations of leptin to the estimates of body fat were maintained, and leptin was furthermore related to BMI and fasting insulin. In multiple linear regression analyses, additional estimates of visceral adiposity (intraabdominal fat and maximal anterior-posterior diameter determined by CT scan) were significant determinants of leptin in the healthy subjects. The increase in fasting insulin levels during GH substitution correlated negatively with the reduction in leptin levels (r = -.823, P = .003). At baseline, leptin levels were increased in the patients compared with controls in both sexes (women, 21.8 +/- 3.3 v 11.3 +/- 1.4 ng/mL, P = .002; men, 8.1 +/- 1.2 v 4.7 +/- 0.7 ng/mL, P = .008). Leptin levels were similar in GHD patients treated for 12 months compared with healthy controls for both women and men (women, 15.9 +/- 2.3 and 11.3 +/- 1.4 ng/mL, P = .163; men, 7.1 +/- 2.8 and 4.7 +/- 0.7 ng/mL, P = .759). In healthy adults and in GHD patients, leptin levels were significantly higher in women than in men (11.3 +/- 1.4 v 4.7 +/- 0.7 ng/mL, P < .001; 21.8 +/- 3.3 v 8.1 +/- 1.2 ng/mL, P < .001). Gender remained a significant determinant of leptin levels in several models of multiple linear regression analysis also including age, estradiol levels, insulin, and estimates of body fat. We conclude that leptin is increased but not differently regulated in GHD patients compared with normal subjects, and that leptin levels are closely related to estimates of body fat. This relationship is maintained during a decrease in body fat due to GH substitution.     

X-ray structural characterization of SR 142948, a novel potent synthetic neurotensin receptor antagonist

In ob/ob mice, leptin deficiency results in hypogonadotrophic hypogonadism, impaired sexual maturation and infertility, which are all corrected by leptin administration. In humans, pubertal development and menarche are related to the attainment of a critical amount of body fat. To examine whether changes in circulating concentrations of leptin could be a hormonal signal influencing gonadotrophin secretion, we studied 98 adolescents and young adults of both sexes, aged 13-19 years, whose weight varied from normal to massively obese and whose sexual maturation was between Tanner stages 3 and 5. We measured leptin, sex steroids and circulating gonadotrophin concentrations in the basal state and in response to GnRH. In perimenarchial and young adult girls, we found that the LH and FSH responses to GnRH were negatively correlated with body mass index (BMI: r = -0.45 and -0.47 respectively, P < 0.0025) and circulating leptin (r = -0.53 and -0.49 respectively, P < 0.002). Decreased LH and FSH responses to GnRH were associated with increased adiposity and hyperleptinaemia. Our data do not establish, but are consistent with a direct neuroendocrine negative effect of excess leptin on the central reproductive system of obese girls. In boys of comparable adiposity, we found no influence of BMI or leptin on gonadotrophin concentrations, which is another aspect of the sexual dimorphism characterizing human leptin physiology.     

Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure

Leptin, secreted from fat cells, functions as a lipostat mechanism through modulation of satiety signals. The role of leptin in humans has been only partly revealed. However, obese patients have markedly elevated levels of this hormone, and in both normal-weight and obese subjects there is a direct correlation between serum leptin levels and the percentage of body fat. The aim of the present study was to investigate the role of leptin and its relation to body fat content in chronic renal failure (CRF), a disorder associated with decreased appetite. Serum leptin levels and body composition (dual-energy x-ray absorptiometry) were measured in a cohort of 59 patients with terminal CRF (creatinine clearance rate, 8 +/- 1 ml/min). Sixteen of the patients were re-evaluated after 12 mo of peritoneal dialysis treatment, and eight patients were re-evaluated after 12 mo of hemodialysis treatment. The mean serum leptin concentrations were markedly higher (mean +/- SEM) in patients with CRF than in healthy control subjects matched for gender and body mass index (25.7 +/- 5.2 ng/ml versus 8.4 +/- 0.9 ng/ml; P < 0.001). Patients with ongoing signs of inflammation (C-reactive protein > 10 mg/L) demonstrated higher serum leptin levels (41.9 +/- 13.7 ng/ml versus 18.6 +/- 4.2 ng/ml; P < 0.05) than patients with normal C-reactive protein. A strong positive correlation (rho = 0.83; P < 0.0001) was found between serum leptin concentrations and the percentage of body fat. After 12 mo of peritoneal dialysis, the amount of body fat increased markedly (19.0 +/- 1.5 to 25.1 +/- 2.2 kg; P < 0.001), and the changes in serum leptin concentrations correlated significantly (rho = 0.69; P < 0.01) to the changes in the body fat content. In contrast, no significant changes in either body fat content or serum leptin levels were recorded in the eight patients that were re-evaluated after 12 mo of hemodialysis. Serum leptin concentrations are approximately three times higher in patients with CRF compared with healthy control subjects with a similar body mass index. In this study, it is also demonstrated that serum leptin is a good marker for the body fat content in CRF patients and correlates strongly to changes in body fat during 12 mo of peritoneal dialysis. These findings suggest that serum leptin could serve as a valuable clinical marker for the body fat content in patients with CRF. Further studies are needed to verify the hypothesis that increased serum leptin concentrations may contribute to uremic anorexia.     

Inverse correlation between serum testosterone and leptin in men

Besides its role in the regulation of energy balance, leptin seems to be involved in linking energy stores to the reproductive system. A gender-dependent difference exists in plasma leptin concentration and leptin messenger ribonucleic acid expression in rodents and humans. This difference does not seem to be explained simply by differences in the amount of body fat between genders. To elucidate the relationship of endogenous testosterone and leptin, we studied the serum leptin concentrations in 269 elderly nondiabetic men. In addition, to assess whether exogenously administered testosterone could influence leptin production, we followed the serum levels of leptin in 10 healthy men during a 12-month treatment with 200 mg testosterone enanthate, i.m., weekly for contraceptive purposes. We found that the serum leptin concentration correlated inversely (r = -0.39; P < 0.001) with that of testosterone in elderly men. This inverse correlation was still present when body mass index and plasma insulin were included in the analysis. The administration of testosterone to young men suppressed serum leptin from the pretreatment level of 3.4 +/- 1.4 to 1.9 +/- 0.6 micrograms/L during the therapy. After cessation of testosterone injections, serum leptin concentration returned back to the pretreatment level. It is concluded that testosterone has a suppressive effect on leptin production, as reflected by circulating levels of this hormone.     

Novel D-ring analogues of podophyllotoxin as potent anti-cancer agents

Insulin is one of the hormonal regulators of leptin synthesis and participates in adipose tissue maintenance. The present study was undertaken to clarify the association of endogenous insulin secretion and mode of therapy with body fat and serum leptin levels in diabetic subjects. We measured the fasting serum C-peptide level, as an estimate of endogenous insulin secretion, and the serum leptin level in 176 Japanese diabetic subjects (79 men and 97 women; age, 55.9+/-14.3 years; body mass index [BMI], 23.8+/-4.1 kg/m2 [mean+/-SD]). Thirty-one subjects were treated with diet therapy alone, 66 with sulfonylurea (SU), and 79 with insulin (including 29 with type I diabetes mellitus). Body fat was analyzed by the impedance method. Serum leptin levels significantly correlated with the BMI and body fat and were higher in women, mainly because of their greater body fat. Serum C-peptide concentrations positively correlated with body fat and serum leptin in subjects treated with diet and SU. In insulin-treated type II diabetic subjects, both serum C-peptide and the daily insulin dose were weakly associated with body fat and serum leptin. In those subjects, despite a lower percent body fat and body fat mass, serum leptin concentrations (10.3+/-8.4 ng/mL) were comparable to the levels in subjects treated with diet (8.8+/-8.5 ng/mL). When compared within the same BMI and body fat groups (BMI 20 to 25 and > 25 kg/m2) including the control subjects matched for age and sex, serum leptin levels were higher in insulin-treated type II diabetic subjects versus the control subjects and diabetic patients treated with diet or SU. Stepwise regression analysis for all of the diabetic subjects showed that both the serum C-peptide level and exogenous insulin administration, as well as the BMI, gender, and age, were determinants of the serum leptin level. In conclusion, endogenous insulin secretion is closely associated with body fat and serum leptin in diabetic subjects treated with diet therapy and SU. In Japanese insulin-treated type II diabetic subjects, both endogenous and exogenous insulin are associated with body fat and serum leptin, which is maintained at levels comparable to or somewhat higher than the levels in control subjects and diabetic patients treated without insulin.     

Molecular pathology of c-kit proto-oncogene and development of gastrointestinal stromal tumors

The study evaluates faecal immunoreactive lipase (IRL) measurement in spot stool samples as an index of exocrine pancreatic function in patients with cystic fibrosis (CF). Stool samples (211) from 183 healthy volunteers (age range: 2 days-14.2 years) showed a normal log distribution of IRL values with a median concentration of 71.4 micrograms/g (range: 0.53-4160 micrograms/g). In 156 stool samples from 58 patients with proven CF, the median IRL concentration of 0.4 microgram/g (range: 0.003-107 micrograms/g) was significantly lower (P < 0.001) than that of normal controls. In healthy controls, IRL levels were age related with significantly higher levels (P < 0.001) shortly after birth compared to older children. Stimulation of the exocrine pancreas by oral milk feeding resulted in a significant (P < 0.001) increase in a faecal IRL concentration. Faecal IRL concentrations in meconium were very low and of the same magnitude as in patients with CF. CONCLUSION: Faecal IRL determination had a high diagnostic sensitivity (87%) and excellent diagnostic specificity (97%) in patients with CF. A negative test result (PVneg. 99%) virtually excluded CF under screening conditions.     

Acute infusion of naloxone, an opioid receptor antagonist, does not modify serum leptin concentrations in amenorrheic and healthy women

OBJECTIVE: To determine whether the opioidergic system is involved in the modulation of leptin secretion in healthy and amenorrheic subjects. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, University of Modena, Modena, Italy. PATIENT(S): Healthy subjects (n = 8) and patients with hypothalamic amenorrhea (n = 17) or hyperandrogenism (n = 7) and low body mass index (BMI). INTERVENTION(S): Acute infusion of naloxone (4-mg bolus) and blood sampling 15 minutes before infusion; at time of infusion; and 15, 30, 45, 60, 75, 90, and 120 minutes after infusion. MAIN OUTCOME MEASURE(S): Plasma leptin, LH, FSH, E2, and cortisol concentrations. RESULT(S): Plasma leptin concentrations were lower (P <.01) in both hypothalamic and hyperandrogenic amenorrheic subjects than in healthy controls. In all groups of subjects, no significant changes in leptin levels were observed after infusion of naloxone. A significant correlation was found between leptin concentrations and BMI when all subjects were considered together (P <.05) but was not found in the single groups. CONCLUSION(S): The present data do not support the hypothesis that opioidergic receptors are involved acutely in the modulation of leptin release in healthy and amenorrheic women.