Thyroid hormones modulate serum leptin levels: observations in thyrotoxic and hypothyroid women

Thyroid hormones and leptin are both involved in the regulation of energy metabolism. Serum leptin concentrations were measured in women with thyrotoxicosis (n = 21, mean age 45 years) or hypothyroidism (n = 14, mean age 44 years) before and 3 months after restoration of the euthyroid state. Serum leptin concentration tended to increase in both hypothyroid (14.7+/-3.5 vs 17.8+/-3.9 ng/ml, p = 0.06) and thyrotoxic (11.9+/-1.7 vs 14.4+/-2.0, p = 0.08) women after treatment (values given as mean +/- SE in the untreated and the euthyroid state respectively). Body mass index (BMI) was lower in thyrotoxic women than in hypothyroid women in the untreated state (22.1+/-0.7 vs. 26.2+/-1.9, p < 0.05). BMI was not different between both groups after treatment (24.5+/-0.7 vs. 26.3+/-2.1, p = 0.37), due to an increase of BMI in the thyrotoxic women; BMI did not change in the hypothyroid group. After controlling for BMI in a multivariate regression analysis, serum leptin concentrations were lower in hypothyroid women than in thyrotoxic women (p < 0.05), whereas posttreatment values of leptin did not differ (p = 0.44). When leptin concentrations were expressed as standard deviation scores (Z-scores) from the mean value of female controls matched for BMI and age as reported earlier, Z-scores were lower in the hypothyroid than in the thyrotoxic women (-0.63+/-0.21 vs. 0.53+/-0.18, p = 0.001). After treatment, Z-scores did not deviate from the expected values (0.05+/-0.28 vs. 0.08+/-0.16, p = 0.98). Z-scores differed before and after treatment in both hypothyroid (p = 0.01) and thyrotoxic (p = 0.02) patients. In conclusion, these data obtained in thyrotoxic and hypothyroid women indicate that thyroid states modulates serum leptin concentrations independent of BMI, with a small decrease in hypothyroidism and a small increase in thyrotoxicosis.     

Gender-dependent alterations in serum leptin in alcoholic cirrhosis

BACKGROUND & AIMS: Leptin is a peptide that decreases food intake and increases energy expenditure. It is produced in fat cells, is stimulated by cytokines, and its levels in serum are higher in females. Because anorexia, hypermetabolism, and elevated cytokine levels are frequently observed in cirrhosis, we hypothesized that the serum leptin level would be elevated in cirrhosis. The aim of this study was to investigate the relationship of serum leptin to gender, body composition, and tumor necrosis factor (TNF). METHODS: Male (n = 18) and female (n = 10) abstinent alcoholic cirrhotic patients were studied and compared with control subjects (15 male and 8 female). Fat mass, fat-free body mass, and body cell mass were calculated by using H2[18O] and bromide dilution methodology. Serum leptin and TNF concentrations were measured by immunoassays. RESULTS: Fat mass was decreased only in male cirrhotics (P < 0.05), whereas body cell mass was decreased in both male and female cirrhotics (P < 0.01). Leptin levels were elevated in female (P < 0. 001) but not male cirrhotics compared with controls. When expressed per kilogram of fat mass, leptin was elevated in both male (P < 0. 01) and female (P < 0.01) cirrhotics. Women in both cirrhotic and control groups had higher leptin levels than men. TNF was elevated in both male and female cirrhotics and did not correlate with leptin levels. CONCLUSIONS: Cirrhotics have elevated serum leptin levels, which are related to both gender- and gender-dependent alterations in body composition.     

Plasma leptin is not associated with insulin resistance and proinsulin in non-diabetic South Asian Indians

In an earlier study, we observed only a weak association between plasma insulin (non-specific assay) and leptin in South Asian Indians. This was in contrast to the observations in many other ethnic groups. With the availability of measurements of specific insulin (SI) and proinsulin (PI) in the same study group, we have reanalysed the data to look for possible correlation of leptin with proinsulin and with insulin resistance calculated from the fasting values of specific insulin and glucose using the HOMA model. Subjects with normoglycaemia (n = 117) and impaired glucose tolerance (n = 27, WHO criteria) were included in the analysis. Leptin values were higher in women. Multiple linear regression analysis showed that the variations in leptin concentrations in men were associated with BMI, WHR, and 2 h SI values (R2 = 56.2%) while fasting SI and proinsulin concentrations had no significant association. In women BMI and age showed a significant association with serum leptin values (R2 = 40.1%). Univariate and multivariate analyses using insulin resistance as the dependent variable showed that it had no association with leptin in both genders. Leptin had no correlation with proinsulin also. This study confirmed that in Asian Indians the association between plasma leptin and insulin concentrations is weak and that leptin has no influence on insulin resistance. Proinsulin and leptin are also not correlated in this population. Insulin resistance shows correlation with the beta-cell function both in men and women.     

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.     

Increased leptin messenger RNA and serum leptin levels in children with Prader-Willi syndrome and nonsyndromal obesity

To study the potential role of the ob gene pathway in childhood obesity, we have investigated leptin mRNA levels in s.c. adipose tissue obtained from nonobese prepubertal children (n = 20), obese nonsyndromal children (n = 6), and children with Prader-Willi syndrome (n = 6) by in situ hybridization histochemistry. We have also investigated the fasting serum leptin levels in such children. Compared with nonobese children, leptin mRNA expression was higher both in children with Prader-Willi syndrome and in children with nonsyndromal obesity (p < 0.01). Furthermore, the serum leptin levels were also significantly higher in both children with Prader-Willi syndrome and nonsyndromal obesity compared with the nonobese children (p < 0.001). However, no significant differences in adipose tissue leptin mRNA or serum leptin levels were observed between children with Prader-Willi syndrome and nonsyndromal obese children. As expected both fasting serum leptin levels and leptin mRNA expression levels correlated to body mass index (rs = 0.80 and 0.73, respectively, p < 0.005). No difference in leptin expression between Prader-Willi syndrome and nonsyndromal childhood obesity could be revealed in the present study. However, differences in the hypothalamic response to leptin between the two forms of obesity cannot be excluded.     

Increase in serum leptin and uterine leptin receptor messenger RNA levels during pregnancy in rats

Pregnancy is a physiological state associated with significant changes in appetite, thermogenesis, and lipid metabolism, functions which are regulated in part by a hormone, leptin, secreted by adipocytes. Leptin has also been shown to have a role in reproduction, promoting centrally-regulated maturation of the reproductive system and signaling the presence of adequate maternal energy stores for fertility. Here we demonstrate that serum leptin levels are modulated during normal rat pregnancy with a 1.8-fold increase during pregnancy followed by a decrease just before parturition. Leptin receptor mRNA levels in the uterus are also regulated with an increase about 2.7-fold during this same period, whereas there is no change in other tissues examined. The results suggest that leptin may play a role during pregnancy, perhaps regulating energy utilization.     

Serum leptin levels do not rise during pregnancy in age-matched rats

The serum leptin profile and its production in adipose tissue during pregnancy and lactation were investigated along with changes in appetite and factors reflecting nutritional status in 11-week-old rats. Serum leptin levels in pregnant rats were stable except on day 20 of pregnancy and significantly reduced during lactation compared to nonpregnant rats (P < 0.001). Circulating leptin levels corresponded with changes in appetite during pregnancy and postparturition. Leptin mRNA in parametrial adipose tissue reflected the circulating levels, also being significantly reduced during late pregnancy and during lactation (P < 0.05). Leptin mRNA expression was observed in placenta, but the amount suggested little influence on circulating leptin levels. These results indicate that reduction in leptin mRNA in parametrial adipose tissue and circulating leptin levels may increase appetite during late pregnancy and lactation and may play a role in regulating metabolic homeostasis around parturition in rats.     

Thyroid dysfunction in pregnancy

Thyroid dysfunction is the second most common endocrine disorder among women of childbearing age. When thyroid dysfunction is well controlled, pregnancy outcomes are similar to those of women without thyroid disease. Perinatal nurses can support the woman affected by a thyroid dysfunction by being knowledgeable about the disorder and by providing support and education. The article provides an introduction to the physiology and pathophysiology of the thyroid, the effect of common thyroid disorders on pregnancy, and clinical management implications for perinatal nurses.     

Sphincter of Oddi dysfunction is associated with chronic pancreatitis

To clarify whether the content of glutathione (GSH) in the brain can be estimated by the uptake of 99mTc-meso-HMPAO, we conducted the following in vivo and in vitro experiments. METHODS: We investigated the effect of diethyl maleate (DEM) and buthionine sulfoximine (BSO) administration on the brain uptake of 99mTc-meso-HMPAO in the mouse, rat and rabbit, and the chemical specificity of in vitro interaction of 99mTc-HMPAO to GSH using measurements of octanol-extractable radioactivity as an index of remaining intact tracer. RESULTS: The uptake of 99mTc-meso-HMPAO in the mouse and rat brain were reduced together with decreased content of GSH by preloading of DEM, a GSH depletor that acts through glutathione S-transferase. Neither 99mTc-meso-HMPAO uptake nor GSH content was affected in the rabbit brain. Similarly, the uptake of 99mTc-meso-HMPAO and GSH content in the mouse brain was reduced by preinjection of BSO, a GSH depletor that acts through gamma-glutamylcysteine synthetase. In an in vitro study, 99mTc-HMPAO showed reactivity to the molecules possessing a -SH group, but were not specific to GSH. The order of 99mTc-meso-HMPAO reactivity to the mouse brain homogenate agreed with the order of GSH concentration: normal > BSO > DEM. GSH was a major contributor to the conversion reaction of 99mTc-meso-HMPAO to hydrophilic complex in mouse brain homogenate. CONCLUSION: GSH may have a major responsibility for trapping 99mTc-HMPAO in the brain, suggesting the possibility of in vivo measurement of brain GSH with 99mTc-meso-HMPAO.     

Low sodium levels in serum are associated with subsequent febrile seizures

Fever plays an important role in causing disturbances in fluid and electrolyte balance. Hyponatraemia has been thought to enhance the susceptibility to seizures associated with febrile illnesses in childhood. We have studied serum electrolyte levels in children with simple and complicated febrile convulsions. Sodium levels were lower in those children with complicated convulsions in comparison with those having simple convulsions (136.07 +/- 3.06 mmoll-1, mean +/- SD, n = 42, and 137.62 +/- 2.63 mmoll-1, n = 71, respectively; p < 0.01, Student's t-test). The sodium concentrations were lowest in children with repeated seizures (134.20 +/- 2.30 mmoll-1, n = 15) compared with children having simple (p < 0.01, ANOVA, Duncan's test) or other complicated types of febrile convulsions: focal seizures (137.08 +/- 3.82 mmoll-1, n = 12, p < 0.01), seizures lasting longer than 15 minutes (138.00 +/- 2.45 mmoll-1, n = 5, p < 0.05) and children over 5 years (136.70 +/- 2.06 mmoll-1, n = 10, p < 0.05). Serum potassium levels showed no statistically significant differences between the patient groups. Our results show that hyponatraemia may increase the risk for multiple convulsions during the same febrile illness.     

Leptin in human reproduction: serum leptin levels in pregnant and lactating women

Experiments in ob/ob female mice demonstrated that leptin injections not only reduced weight and fat mass, but also restored fertility and partial lactation. To explore factors regulating ob gene expression in reproductive women, we measured serum leptin, body fat, energy expenditure, and milk production in 65 women at 36 weeks of gestation, and at 3 and 6 months postpartum. Serum leptin was measured by solid-phase sandwich enzyme immunoassay, and serum insulin and PRL by solid-phase 125I RIA. Total body water by deuterium dilution, body volume by hydrodensitometry, and bone density by dual-energy x-ray absorptiometry were used to estimate body fat. Serum leptin per unit fat mass was significantly higher at 36 weeks of pregnancy than at 3 and 6 months postpartum (1.25 vs. 0.75, 0.73 ng.mL-1.kg-1). Postpartum normalization of leptin was associated with changes not only in weight and fat mass, but also serum insulin. Leptin was not different between lactating and nonlactating women. Leptin may have affected milk production indirectly through its negative effect on serum PRL. Adjusted for fat-free mass and fat mass, rates of energy expenditure were not significantly correlated with leptin. Our results provide evidence that factors other than fat mass alone modulate serum leptin in reproductive women.     

A common pentanucleotide polymorphism of the 3'-untranslated part of the leptin receptor gene generates a putative stem-loop motif in the mRNA and is associated with serum insulin levels in obese individuals

OBJECTIVE: To find out whether genetic alterations of the leptin receptor gene underlie human forms of obesity. DESIGN: Among 249 morbidly obese adults (body mass index, BMI > or = 40 kg/m2), we screened 30 patients with the highest serum leptin levels for alterations of their leptin receptor gene by single-strand conformation polymorphism (SSCP) technique. SUBJECTS: 249 severely obese subjects (present or past BMI > or = 40 kg/m2) and 138 lean controls (BMI < or = 25 kg/m2). MEASUREMENTS: DNA analysis was carried out using SSCP technique, sequencing and polymerase chain reaction (PCR) followed by digestion with the restriction enzyme Rsal. Serum leptin, glucose, insulin and lipid concentrations were determined in obese subjects. RESULTS: We were able to detect a pentanucleotide insertion (CTTTA) in the 3'-untranslated region of the leptin receptor gene. The presence of this pentanucleotide insert generates a putative stem-loop structure in the mRNA. Association studies were carried out on this variant. The frequency of the insertion allele did not differ between 249 obese (12.4%) and 138 lean (12.0%) subjects. There was no association of serum leptin, glucose or lipid levels with the pentanucleotide genotype in the obese individuals. However, when subjects without medication affecting insulin or glucose levels were considered, serum insulin levels were found to be lower in the heterozygous carriers of the insertion allele (15.1 +/- 9.2 mU/l) than in the subjects homozygous for the deletion allele (21.8 +/- 13.7 mU/l, P = 0.0035). CONCLUSIONS: We were able to confirm the presence of a frequent insertion/deletion polymorphism close to the 3'-end of the leptin receptor gene. We also showed that serum insulin levels in morbidly obese subjects are associated with 3'-UTR variant genotype.     

Serum leptin levels in women with anorexia nervosa

Leptin is a protein encoded by the ob gene that is expressed in adipocytes and regulates eating behavior via central neuroendocrine mechanisms. Serum leptin levels have been shown to correlate with weight and percent body fat in normal and obese individuals; however, it is not known whether the regulation of leptin is normal below a critical threshold of body fat in chronic undernutrition. We investigated serum leptin levels in 22 women, aged 23 +/- 4 yr, with anorexia nervosa. Duration of disease, weight, BMI, percent body fat, and serum leptin levels were determined for each patient. Nutritional status was assessed further by caloric intake and measurement of insulin and insulin-like growth factor I (IGF-I) levels. Twenty-three healthy women, aged 23 +/- 4 yr, taking no medications, with normal menstrual function and body mass index (BMI) between 20-26 kg/m2 (mean, 23.7 +/- 1.7 kg/m2), served as a control population for comparison of leptin levels. Subjects with anorexia nervosa were low weight (BMI, 16.3 +/- 1.6 kg/m2; normal, 20-26 kg/m2) and exhibited a striking reduction in percent body fat (7 +/- 2%; normal, 20-30%). The mean serum leptin level was significantly decreased in subjects with anorexia nervosa compared with that in age- and sex-matched controls of normal body weight (5.6 +/- 3.7 vs. 19.1 +/- 8.1 ng/mL; P < 0.0001). Serum leptin levels were correlated highly with weight, as expressed either BMI (r = 0.66; P = 0.002) or percent ideal body weight (r = 0.68; P = 0.0005), body fat (r = 0.70; P = 0.0003), and IGF-I (r = 0.64; P = 0.001), but not with caloric intake or serum levels of estradiol or insulin in subjects with anorexia nervosa. The correlation between leptin and body fat was linear, with progressively lower, but detectable, leptin levels measured even in patients with less than 5% body fat, but was not significant when the effects of weight were taken into account. In contrast, the correlation between leptin and IGF-I remained significant when the effects of weight, body fat, and caloric intake were taken into account. In normal controls, leptin correlated with BMI (r = 0.55; P = 0.007) and IGF-I (r = 0.44; P < 0.05), but not with fat mass. These data demonstrate that serum leptin levels are reduced in association with low weight and percent body fat in subjects with anorexia nervosa compared to normal controls. Leptin levels correlate highly with weight, percent body fat, and IGF-I in subjects with anorexia nervosa, suggesting that the physiological regulation of leptin is maintained in relation to nutritional status even at an extreme of low weight and body fat.     

Thyroid hormone-induced alterations in phospholamban-deficient mouse hearts

Total serum IgE, Phadiatop, and the skin prick test (SPT) are commonly used to diagnose atopic diseases. However, no large study has ever been done to test their diagnostic efficiency. We studied the diagnostic value of these three atopic markers in 8329 well-randomized adults from the Swiss Population Registry. The prevalence of current allergic asthma (CAA) was 1.8% and of current allergic rhinitis (CAR) 16.3%. The prevalences of positive Phadiatop, positive SPT (at least, one out of eight SPT to common aeroallergens with a wheal of > or = 3 mm), and positive total IgE (IgE > or = 100 kU/l) were 29, 23, and 23%, respectively. To diagnose CAA and CAR, the sensitivity of Phadiatop was significantly higher than that of SPT (72.5% vs 65.4%, 77.1% vs 68.4% respectively; P < 0.01 and < 0.001) and IgE (72.5% vs 56.9%, 77.1% vs 43.9%, respectively; both P < 0.001). The sensitivity of SPT was significantly higher (68.4% vs 43.9% P < 0.001) than that of IgE to diagnose CAR. When CAA and CAR were excluded, the SPT specificity was significantly higher than that of Phadiatop (77.8% vs 71.9% and 85.9% vs 80.5%, respectively; both P < 0.001): when CAR was excluded, SPT was significantly higher than IgE (85.9 vs 81.4%; P < 0.001). SPT had significantly the best positive predictive value for CAA (5.2% for SPT vs 4.6% for both IgE and Phadiatop; both P < 0.001) and CAR (48.7% for SPT vs 43.5% for Phadiatop and 31.6% for IgE; both P < 0.001). The three markers of atopy had roughly the same negative predictive value (NPV) for CAA, but IgE had a significantly lower NPV for CAR than SPT and Phadiatop (88.1% vs 93.3% and 94.7%, respectively; both P < 0.001). The diagnostic efficiency of SPT was significantly higher than that of Phadiatop (83.1% vs 79.9% and 77.6 vs 71.9%, respectively; both P < 0.001) to diagnose CAR and CAA. IgE and SPT had equal efficiency (77.6%), which was significantly higher than that of Phadiatop, to diagnose CAA (71.9%; both P < 0.001). In conclusion, SPT have the best positive predictive value and the best efficiency to diagnose respiratory atopic diseases. Furthermore, SPT give information on sensitivity to individual allergens and should therefore be used primarily by clinicians to assess respiratory allergic diseases. Moreover, they are cheaper and provide immediate, educational information for both patient and physician.     

Lack of effects of circulating thyroid hormone levels on serum leptin concentrations

A newly developed nonparametric multipoint linkage analysis (NPL) by Kruglyak et al. [1996] was applied to the data set from the Johns Hopkins Bipolar Study available through the GAW10 workshop. Our results from GENEHUNTER do not support the analyses of Stine et al. [1995]. Some possible extensions to incorporate unaffecteds are also discussed.