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.     

Nutritional aspects of cancer-related fatigue

OBJECTIVE: Recent studies suggest an involvement of the obese (OB) gene and its product leptin in the regulation of body fat. Since adults with growth hormone deficiency (GHD) have a high body fat mass which can be normalized with recombinant human (rh) GH therapy, we investigated whether GH influences serum leptin directly or indirectly via its lipolytic effect. DESIGN: Fourteen adults with GHD were treated with subcutaneous injections of rhGH given every evening for 52 weeks. Serum leptin, fat mass and body fat percentage were measured at baseline and after 4 and 52 weeks of treatment. METHODS: Serum leptin was measured with a commercially available RIA. Total body water was determined by dilution of deuterium. Fat free mass was estimated by assuming a hydration of 73%. Fat mass was estimated by subtracting fat free mass from weight. RESULTS: At baseline, serum leptin levels were exponentially related to body fat percentage (r = 0.88; P < 0.0005). rhGH treatment for 4 weeks did not significantly influence serum leptin levels, whereas treatment for 52 weeks significantly decreased serum leptin levels (15.6 +/- 2.9 to 10.8 +/- 2.1 micrograms/l; P = 0.020). Fat percentage was significantly decreased after 52 weeks of treatment (37.6 +/- 2.1 to 33.8 +/- 2.5%; P < 0.0005). The decrease in serum leptin could largely be explained by the decrease in body fat percentage, whereas the relation between leptin and body fat percentage did not change. CONCLUSIONS: The influence of GH on serum leptin in indirect, via its effect on body fat percentage.     

Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease

The cloning of the obese gene and the characterization of its protein product, leptin, has permitted the study of a new hormone potentially involved in the regulation of adipose tissue mass. The present study examined the gender differences in fasting plasma leptin concentration and its relationship to body fatness, adipose tissue distribution and the metabolic profile in samples of 91 men (mean age +/- SD: 37.3 +/- 4.8 years) and 48 women (38.5 +/- 6.8 years). Plasma leptin concentrations were strongly associated with body fat mass measured by underwater weighing [men: r = 0.80, p < 0.0001; women: r = 0.85, p < 0.0001]. In both genders, plasma leptin levels were also strongly correlated with waist girth as well as cross-sectional areas of abdominal subcutaneous and visceral adipose tissue measured by computed tomography. Women had, on average, plasma leptin concentrations that were three times higher than men. Furthermore, this gender difference remained significant when comparing men and women matched for similar levels of body fat mass. The associations between plasma leptin and lipoprotein concentrations were dependent of adiposity. In both men and women, elevated fasting plasma leptin levels were associated with higher plasma insulin concentrations, but only in women was the association maintained after correction for fat mass. Thus, results of the present study show that women have higher plasma leptin levels compared to men, independent of the concomitant variation in total body fat mass. Furthermore, our results also suggest that, in women, the association between plasma leptin and insulin concentrations is independent of adiposity, a finding which provides further support to the observation that adipose tissue leptin secretion may be upregulated by insulin.     

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.     

Adipose tissue leptin production and plasma leptin kinetics in humans

Abdominal adipose tissue leptin production was determined in vivo by arteriovenous balance in 14 lean and obese men (mean BMI 27.0 +/- 1.9, range 21.4-45.2). Blood samples were taken simultaneously from an abdominal vein that drains subcutaneous adipose tissue and from a radial artery. Adipose tissue blood flow was measured by xenon washout. Abdominal vein leptin concentrations (mean 8.9 +/- 2.4 ng/ml, range 2.1-36.5 ng/ml) were consistently greater than arterial values (mean 6.6 +/- 1.9 ng/ml, range 1.7-28.2 ng/ml) (P < 0.001). The net rate of abdominal adipose tissue leptin production (mean 3.2 +/- 0.5 ng x 100 g(-1) x min(-1)) correlated directly with percentage body fat (rs = 0.59, P = 0.016). Estimated whole-body leptin production rate (797 +/- 283 ng x person(-1) x min(-1)) correlated directly with percent body fat (rs = 0.93, P < 0.0001) and with regional leptin production (rs = 0.81, P < 0.001). In contrast, the rate of leptin clearance from plasma (mean 1.50 +/- 0.23 ml x kg(-1) x min(-1)) and plasma leptin half-life (mean 24.9 +/- 4.4 min) was unrelated to adiposity (rs = 0.06, P = 0.30; rs = 0.16, P = 0.30, respectively). These results provide direct evidence that leptin is produced by adipose tissue in humans and that the rate of production is directly related to adiposity. A combination of greater leptin production per unit of body fat and increased production from expanded total body fat mass, rather than alterations in leptin clearance, account for the increase in plasma leptin concentrations observed in obese humans.     

Serum leptin and energy expenditure in children

Leptin has been hypothesized to play an important role in energy balance by affecting both energy intake and energy expenditure. The purpose of our study was to determine the relationship between fasting serum leptin concentrations and measures of energy expenditure in prepubertal children. We measured total energy expenditure (TEE; by the doubly labeled water technique), resting energy expenditure (REE; after an overnight fast), activity energy expenditure (AEE; TEE-REE), body composition (by dual energy x-ray absorptiometry), and fasting serum leptin concentration (by RIA) in 76 children. Simple correlations showed that all measures of energy expenditure (TEE, REE, and AEE) were positively related to the serum leptin concentration (r = 0.50, P < 0.001; r = 0.45, P < 0.001; and r = 0.30, P < 0.01, respectively). However, after adjusting for body composition (fat-free mass and fat mass), gender, and ethnicity, serum leptin concentrations were not related to any measure of energy expenditure (TEE, P = 0.61; REE, P = 0.97; AEE, P = 0.65). These latter findings were further confirmed using structural equation models with leptin and energy expenditure as dependent variables, and fat-free mass and fat mass as independent variables. Results from these models showed no direct effect of leptin and no indirect effect of fat mass (through leptin) on any measure of energy expenditure, when a path between fat mass and energy expenditure was present in the model. Thus, our data do not support the hypothesis that the serum leptin concentration (independent of fat mass) is related to measures of energy expenditure in children.     

Heart failure and atrial fibrillation: current concepts and controversies

OBJECTIVE: Leptin is the product of ob gene shown to regulate body fat in mice. It is produced by human adipose tissue as well, but its physiological functions in man are not known. We explored if there is a relationship in obese humans with serum leptin and energy and fuel metabolism. DESIGN: Cross-sectional study including 45 obese (10 men, 35 women; age and body mass index: 42 +/- 7 y and 35.1 +/- 3.6 kg/m2, respectively). MEASUREMENTS: Food intake by a four-day-food record, blood samples for serum leptin concentrations and resting energy expenditure by indirect calorimetry. RESULTS: Leptin concentrations showed an inverse association (adjusted for fat mass, age and sex) with resting energy expenditure, respiratory quotient and carbohydrate oxidation rate (r = -0.324, P < 0.05; r = -0.420, P < 0.01; r = 0.478, P = < 0.01, respectively), and interestingly, also with dietary fat intake (unadjusted r = -0.30, P < 0.05). Especially, leptin concentrations were elevated in those with low resting energy expenditure and respiratory quotient (below the median). CONCLUSION: Serum leptin concentrations in obese subjects showed an inverse association with resting energy expenditure, respiratory quotient and carbohydrate oxidation rate. The physiological significance of these associations is unclear at the moment but could indicate that obese subjects show resistance to the actions of leptin also outside the brain in terms of regulating metabolic rate and fuel metabolism.     

Serum insulin but not leptin is associated with spontaneous and growth hormone (GH)-releasing hormone-stimulated GH secretion in normal volunteers with and without weight loss

Weight loss in humans is associated with elevated hypothalamic-pituitary growth hormone (GH) secretion. This study evaluates the effects of weight loss on the hypothalamic-pituitary (GH-releasing hormone [GHRH]-GH) axis in 14 normal-weight (body mass index [BMI], 25+/-1 Kg/m2) subjects, of whom half had undergone a diet-induced weight loss of 14%+/-2% (mean+/-SEM). Insulin-like growth factor-1 (IGF-1), insulin, oral glucose tolerance, leptin, and GH pulse patterns were determined in both groups after weight maintenance for 1 week. Of note, we tested the effects of recent weight loss (3 months) and not a recent dietary intake, since both groups ingested a normal calorie diet for 2 days in the Clinical Research Center (CRC) prestudy. Serum insulin (3.8+/-0.7 v 9.0+/-0.9 microU/mL, P < .01) and C-peptide (0.44+/-0.06 v 0.59+/-0.04 ng/mL, P < .05) were significantly lower in the weight loss group. Serum leptin was not different. Endogenous GH pulse height (11.9+/-4.8 v 1.3+/-0.1 microg/L, P < .05), area per GH pulse ([AUC] 57+/-28 v 6+/-1 microg/L, P < .05), and mean GH (3.91+/-0.76 v 0.85+/-0.16 microg/L, P < .01) were increased in the weight loss group. The serum insulin level was inversely associated with the mean GH concentration (r=-.678, P < .01) and GH pulse height (r=-.733, P < .01). In addition to spontaneous GH secretion, the GHRH-stimulated GH pulse height (41.8+/-18.1 v7.1+/-1.6 microg/L, P < .05) and AUC (161+/-35 v46+/-13 microg/L/min, P < .05) were also increased in the weight loss group. The insulin concentration was also inversely correlated with the GHRH-stimulated GH pulse height (r=-.718, P < .01). The leptin concentration was correlated with the BMI (r=.554, P < .05) and body fat (r=.744, P < .01), but not with GH secretion. In summary, even though these patients were on a normal calorie diet, a history of recent weight loss in young men and women of normal weight and health can be associated with a significant increase in spontaneous GH pulse height and GHRH-stimulated pulse height. Weight loss was also associated with a reduced serum insulin level. The observed increase in GH secretion may be secondary to the reduction in insulin or alterations of other factors acting at the site of the pituitary.     

Effects of pneumoperitoneum with carbon dioxide, argon, or helium on hemodynamic and respiratory function

In this study we investigated ob gene expression and plasma leptin levels in Psammomys obesus (the Israeli Sand Rat), a polygenic animal model of obesity and non-insulin-dependent diabetes mellitus. The ob gene was expressed exclusively in adipocytes of Psammomys obesus. DNA sequencing revealed a high degree of homology with other species (90% with mouse, 88% with rat and 79% with human). No ob gene sequence differences were found between lean and obese Psammomys obesus, and the codon 105 mutation found in ob/ob mice was not detected. Ob gene expression in Psammomys obesus correlated with body weight (r = 0.436, p < 0.001), percent body fat (r = 0.645, p < 0.001) and plasma insulin concentration (r = 0.651, p < 0.001). This is the first time that ob gene expression has been shown to increase steadily over a continuous wide range of body weight or plasma insulin in an animal model of obesity. Ob gene expression was significantly elevated in obese compared with lean Psammomys obesus (p < 0.05). No significant difference in ob gene expression was found between the four adipose tissue depots tested. Psammomys obesus plasma leptin levels correlated with body weight (r = 0.36, p < 0.05), percent body fat (r = 0.702, p < 0.01) and plasma insulin concentration (r = 0.735, p < 0.001). Plasma leptin concentrations were significantly increased in insulin-resistant animals independent of body weight. These results show that Psammomys obesus is an excellent animal model in which to study the ob gene and leptin, and confirm the importance of insulin as a significant factor in the regulation of leptin and ob gene expression.     

Differences in body composition of black and white girls

Adults have racial differences in body composition that may modulate risks resulting from obesity. Although black and white children have been shown previously to have differences in bone mineral density and subcutaneous body fat, differences in visceral adipose tissue have not been evaluated. We studied 20 black and 20 white normal-weight girls aged 7-10 y, who were matched for weight, body mass index (BMI), bone age, chronological age, Tanner breast stage, and socioeconomic status. Each underwent anthropometric measurements, bioelectrical impedance analysis, dual-energy X-ray absorptiometry (DXA), and abdominal magnetic resonance imaging (MRI) for determination of total (TAT), visceral (VAT), and subcutaneous (SAT) adipose tissue. Serum lipids and fasting and 2-h oral-glucose-tolerance test (OGTT) glucose and insulin concentrations were also measured. There were no differences between groups in absolute waist circumference or waist-to-hip ratio, but waist-to-thigh ratio was smaller in black than in white girls. Black girls had greater bone mineral density and less TAT, VAT, and SAT than whites. VAT was not significantly correlated with any measure of insulin, or with serum lipids. However, both basal and 2-h OGTT serum insulin were significantly correlated with SAT as assessed by MRI in black girls (r2 = 0.46 for basal insulin, P = 0.001: r2 = 0.31 for 2-h insulin, P = 0.01) but not in white girls (r2 < 0.05, for basal and 2-h insulin, NS). We conclude that there are significant racial differences in body composition and differences in the strength of association between abdominal adipose tissue depots and insulin sensitivity in black and white girls.     

Promotion of tyrosinase folding in COS 7 cells by calnexin

To evaluate the role of serum free or unbound insulin-like growth factor I (IGF-I) on bone growth, we measured serum free IGF-I levels in 354 healthy children and adults (193 males and 161 females, aged 0-40 yr) and in 21 prepubertal GH-deficient (GHD) children (complete GHD, n = 5; partial GHD, n = 16) using a recently developed immunoradiometric assay. We obtained the following results. 1) In the normal children, the serum free IGF-I levels were low in infancy (<1 yr of age; males, 0.71 +/- 0.26 microg/L, mean +/- SD; females, 1.05 +/- 0.49 microg/L), increased during puberty (males, 5.84 +/- 2.18 microg/L; females, 5.80 +/- 1.49 microg/L), and declined thereafter. 2) Free IGF-I in the serum occupied about 0.95-2.02% of the total IGF-I values, with the highest ratio occurring in infancy (males, 1.77 +/- 0.60%; females, 2.02 +/- 0.87%). 3) The SD scores of serum free IGF-I in the 21 GHD children ranged from -3.30 to 0.30, and the 5 complete GHD children had free IGF-I values more than -2 SD below those of age-matched normal subjects. 4) There was a significant correlation between the SD scores of free IGF-I and those of total IGF-I (r = 0.715; P < 0.0005) in the GHD children. 5) In the 16 partial GHD children receiving GH treatment, the serum free IGF-I levels were elevated to 209% of pretreatment levels after 1 month of GH treatment and remained high during GH therapy. The GH-induced increase in the serum free IGF-I levels was significantly higher than those of the total IGF-I and IGF binding protein-3 levels. 6) The percent increase in the serum free IGF-I level after 1 month of GH treatment showed a significant positive correlation with that of the GH-induced improvement in the percent increase in the height velocity during 1 yr of GH therapy (r = 0.526; P < 0.05). These results show that free IGF-I in the serum has an essential role in bone formation because the higher free IGF-I levels were observed when the growth rate accelerated. The measurement of serum free IGF-I may become a useful tool for both diagnosing GH deficiency and predicting growth responses to long term GH therapy.     

Multihormonal control of ob gene expression and leptin secretion from cultured human visceral adipose tissue: increased responsiveness to glucocorticoids in obesity

The direct role of hormones on leptin synthesis has not yet been studied in cultured adipose cells or tissue from lean and obese subjects. Moreover, this hormonal regulation has never been addressed in human visceral fat, although this site plays a determinant role in obesity-linked disorders. In this study, we investigated the hormonal control of ob expression and leptin production in cultured visceral adipose tissue from lean and obese subjects. We more particularly focused on the interactions between glucocorticoids and insulin. We also briefly tackled the role of cAMP, which is still unknown in man. Visceral (and subcutaneous) adipose tissues from eight obese (body mass index, 41 +/- 2 kg/m2) and nine nonobese (24 +/- 1 kg/m2) subjects were sampled during elective abdominal surgery, and explants were cultured for up to 48 h in MEM. The addition of dexamethasone to the medium increased ob gene expression and leptin secretion in a time-dependent manner. Forty-eight hours after dexamethasone (50 nmol/L) addition, the cumulative integrated ob messenger ribonucleic acid (mRNA) and leptin responses were, respectively, approximately 5- and 4-fold higher in obese than in lean subjects. These responses closely correlated with the body mass index. The stimulatory effect of the glucocorticoid was also concentration dependent (EC50 = approximately 10 nmol/L). Although the maximal response was higher in obese than in lean subjects, the EC50 values were roughly similar in both groups. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion. Singularly, insulin even inhibited the dexamethasone-induced rise in ob mRNA and leptin release. This inhibition was observed in both lean and obese subjects, whereas the expected stimulation of insulin on glucose metabolism and the accumulation of mRNA species for the insulin-sensitive transporter GLUT4 and glyceraldehyde-3-phosphate dehydrogenase occurred in lean patients only. This inhibitory effect was already detectable at 10 nmol/L insulin and was also observed in subcutaneous fat. Although a lowering of intracellular cAMP concentrations is involved in some of the effects of insulin on adipose tissue, this cannot account for the present finding, because the addition of cAMP to the medium also decreased ob mRNA and leptin secretion (regardless of whether dexamethasone was present). In conclusion, glucocorticoids, at physiological concentrations, stimulated leptin secretion by enhancing the pretranslational machinery in human visceral fat. This effect was more pronounced in obese subjects due to a greater responsiveness of the ob gene and could contribute to the metabolic abnormalities associated with central obesity by para/endocrine actions of hyperleptinemia on adipocytes and liver. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion, and even prevented the positive response to dexamethasone by a cAMP-independent mechanism that remained functional despite insulin resistance.     

Hydrogen peroxide is involved in collagen-induced platelet activation

Leptin is a 16-kDa protein secreted by adipocytes that has been proposed to regulate feed intake in mice, rats, and humans. The present study was designed to characterize porcine leptin structure and expression. Successful RT-PCR resulted in development of a cDNA clone to the full length coding region of porcine leptin. Sequence data demonstrate 85% base homology to rodent, 88% to human, and a 92% homology to the bovine sequence. For assessment of porcine leptin gene expression, total RNA was extracted from the subcutaneous adipose tissue of genetically selected high backfat pigs and from contemporary crossbred swine. Total RNA derived from genetically selected high fat pigs contained 113% higher (P < .05) concentrations of porcine leptin mRNA than total RNA derived from contemporary crossbred pigs. Western blotting was used to evaluate serum levels of porcine leptin in genetically selected high backfat and contemporary, crossbred pigs. Relative levels of porcine leptin in sera from obese swine were approximately 306% higher (P < .05) than levels present in sera from contemporary, crossbred swine. These data indicate that leptin is expressed in pigs, the expressed protein is secreted into the bloodstream, and obese swine express higher levels of leptin mRNA and protein than nonobese swine at similar body weight.     

Evidence for leptin regulation of food intake in humans

The adipocyte hormone leptin regulates body weight in mice by decreasing food intake and increasing energy expenditure. Whether leptin is of physiological importance for these processes in humans is, however, not clear. We therefore studied the relation between leptin and habitual food intake in 64 healthy postmenopausal women. Dietary habits were assessed with a modified diet history method. Body fat content was measured using bioelectrical impedance. In the 64 women, aged 58.6+/-0.4 yr (mean+/-SD), serum leptin was 19.3+/-12.7 ng/mL, body mass index was 25.0+/-3.5 kg/m2, body fat content was 31.6+/-4.3%, fasting glucose was 4.6+/-0.5 mmol/L, and fasting insulin was 56+/-21 pmol/L. Leptin levels were negatively correlated to total energy intake (r=-0.34; P=0.006), carbohydrate intake (r=-0.36; P=0.004), and total (r=-0.27; P=0.034) as well as saturated fat intake (r=-0.31; P=0.014). Leptin was correlated to the absolute, but not to the percent, intake of these nutrients. When normalized for body fat content, the correlations remained significant. Our results suggest that plasma leptin is involved in the physiological regulation of food intake in humans, and that leptin is related to the quantity rather than the quality of habitual food intake.     

Insulin-like growth factor-I in growth hormone-deficient adults: relationship to population-based normal values, body composition and insulin tolerance test

BACKGROUND: Although an insulin tolerance test (ITT) is the most commonly used method for detecting growth hormone (GH) deficiency (GHD) in adults, measurements of serum insulin-like growth factor-I (IGF-I) may also be of value. OBJECTIVE: To validate the use of serum IGF-I concentration in the diagnosis of GHD in adults. DESIGN: A cross-sectional study. PATIENTS: One hundred and four patients, 60 men and 44 women, with known pituitary disease and verified GHD based on ITT. MEASUREMENTS: Serum IGF-I was determined by radioimmunoassay after acid-ethanol extraction. Body composition was estimated with total body potassium combined with total body water assessments. RESULTS: According to age- and sex-adjusted population-based references values, 51 patients had serum IGF-I concentrations below -2 SD of the predicted values and 53 had concentrations within 2 SD. Fifty-seven per cent of the patients aged 41 years (25th percentile) or below and 39% of the patients aged 57 years (75th percentile) or above had serum IGF-I concentrations below -2 SD. Women had lower mean IGF-I SD scores than men (P < 0.01). Serum IGF-I was correlated with peak GH response during ITT (r = 0.40; P < 0.001), age (r = -0.27; P < 0.01), duration of hypopituitarism (r = -0.52; P < 0.001), number of pituitary hormonal deficiencies (r = -0.35; P < 0.001), body cell mass (r = 0.30; P < 0.01) and serum insulin (r = 0.21; P < 0.05). The peak GH response during ITT correlated with spontaneous GH secretion, duration (P = -0.48; P < 0.001) and number of deficiencies (r = -0.50; P 0.001). CONCLUSION: The measurement of serum IGF-I concentrations is not suitable as a single diagnostic test for growth hormone deficiency in adults. Even as a screening test, its use appears to be limited, especially in elderly subjects. The serum level of IGF-I was influenced by several factors in addition to GH, such as age, gender, anthropodometry and serum insulin level. The peak GH response during the insulin tolerance test appears to be influenced to a lesser degree by these factors.     

The relationship between growth hormone kinetics and sarcopenia in postmenopausal women: the role of fat mass and leptin

Sarcopenia, the decline in body cell mass (BCM) and especially in muscle mass with age, is an important age-related cause of frailty and loss of independence in the elderly. Because the decline in BCM with age parallels a decline in GH secretion from young adulthood to old age, loss of GH secretion has been considered an important contributory cause of sarcopenia in the elderly. To test this hypothesis in a group of healthy postmenopausal women (n = 15; mean +/- SD age, 66.9 +/- 7.8 yr), 24-h GH concentrations and secretory kinetics were correlated with BCM (measured by whole body counting of 40K) and percent body fat (measured by dual energy x-ray absorptiometry or neutron inelastic scattering). Serum leptin levels were determined as a measure of adipocyte mass. Contrary to prediction, GH secretion was lower in women with higher BCM (r = 0.50; P < 0.05), whereas their mean fat mass was higher (r = 0.51, P < 0.05). These data indicate that sarcopenia in postmenopausal women is not associated with reduced GH secretion and is inversely correlated with fat mass. Serum leptin levels were inversely associated with GH secretion (r = -0.67; P < 0.006). Although a causal relationship has not been demonstrated, these data suggest that leptin could modulate GH secretion through its action on the aging hypothalamic-pituitary axis, or that GH regulates leptin secretion.     

Low leptin gene expression and hyperleptinemia in chronic renal failure

BACKGROUND: The ob gene product leptin is thought to be a key regulator of food intake and body weight. Patients having advanced chronic renal failure (CRF) have markedly higher serum leptin levels. It is not known whether the increase in leptin levels in CRF is caused by a decreased plasma clearance and/or increased production. METHODS: In the present study serum leptin levels and glomerular filtration rate (GFR) were measured in 219 patients having various degrees of renal failure. In addition, serum leptin levels, C-reactive protein (CRP), body composition (by dual-energy x-ray absorptiometry) and ob gene expression (by in situ hybridization histochemistry) were determined in 15 patients with advanced CRF. Seven of the patients were re-evaluated following 12 months of peritoneal dialysis (PD) treatment. RESULTS: Serum leptin levels correlated negatively to GFR (r = -0.26; P < 0.0001). The ob gene expression was significantly lower in patients with CRF than in healthy controls. A negative correlation between serum leptin levels and ob gene expression (r = -0.66; P < 0.05) was found in patients with CRP < 25 mg/liter. The ob gene expression (20.0 +/- 1.8 vs. 15.0 +/- 1.0 nCi/g; P < 0.05) was significantly higher in 5 patients with CRP > 25 mg/liter than in 10 patients with CRP < 25 mg/liter. Following 12 months of PD, the amount of body fat increased by 30% while the ob gene expression remained unchanged. CONCLUSION: The present study shows a correlation between serum leptin levels and GFR, and our results suggest that elevated leptin levels, due to a decreased plasma clearance, down-regulate the expression of the ob gene. We also found that an ongoing inflammation stimulates ob gene expression in patients with CRF. Therefore, it is suggested that the hyperleptinemia induced feedback inhibition of ob gene expression is overcome by inflammatory cytokines.     

Disruption of the relationship between fat content and leptin levels with aging in humans

Leptin released from adipose tissue is believed to participate in a negative feedback loop regulating appetite, and malfunction of this mechanism could lead to obesity. We measured plasma leptin and body composition (dual energy x-ray absorptiometry) in 70 healthy subjects, divided into 3 age groups (young, 25 +/- 1 yr; middle-aged, 53 +/- 1 yr; old, 70 +/- 1 yr), while on a 5-day weight-maintaining diet. Pairwise correlations were assessed using product-moment correlation, and regression analysis was used to evaluate relationships between leptin and other variables. Leptin concentrations and relative body fat content were correlated in young females (r = 0.71; P = 0.009) and in young males (r = 0.76; P = 0.007), but not in the combined middle-aged and elderly groups (r = 0.19; P = 0.36 and r = 0.19; P = 0.38 in females and males, respectively). Regression analysis showed a clear correlation between circulating leptin and relative fat mass in the young subjects (P = 0.0001), but not in the older subjects (P = 0.199). We conclude that body fat content in young subjects correlates with plasma leptin in both genders, whereas this relationship is disrupted in elderly subjects, thus possibly contributing to the obesity occurring with age.     

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.