Recent studies demonstrated significantly higher serum leptin concentrations in females as compared with males, even after correction for differences in body fat mass. The aim of our study was to measure serum leptin concentrations in a large group of obese children and adolescents to determine the possible role of sex steroid hormones on both leptin serum concentrations and production in human adipocytes. Obese girls were found to have significantly higher leptin concentrations than boys at the same degree of adiposity (25.2 Ϯ 14.1 vs. 17.2 Ϯ 12.6 ng/ml, P Ͻ 0.001). In a multiple regression analysis with age and body mass index (percent body fat) as fixed variables, it turned out that testosterone had a potent negative effect on serum leptin in boys, but not in girls. In vitro experiments using newly developed human adipocytes in primary culture showed that both testosterone and its biologically active metabolite dihydrotestosterone are able to reduce leptin secretion into the culture medium by up to 62%. Using a semiquantitative reverse transcriptase-PCR method, testosterone was found to suppress leptin mRNA to a similar extent. These results suggest that, apart from differences in body fat mass, the higher androgen concentrations in obese boys are responsible for the lower leptin serum concentrations compared with obese girls. ( J. Clin. Invest. 1997. 100:808-813.) Key words: androgens • gender difference • human adipose tissue • leptin
Young adults who receive cranial irradiation in childhood are prone to GH deficiency and hyperleptinaemia. The pathophysiological significance of the hyperleptinaemia remains to be established but it has occurred either as a consequence of radiation induced hypothalamic damage or GH deficiency.
Leptin, the protein product of the ob gene, is thought to have a role in signalling satiety through hypothalamic pathways. Glucocorticoids are potent stimulators of both ob gene expression and circulating leptin levels in the rat, yet are powerful appetite stimulants in humans. We have investigated circulating leptin responses to intermediate term and acute administration of dexamethasone. Dexamethasone 2 mg twice daily resulted in a rapid and sustained rise in 08.00 h leptin levels from basal values of 1.36 +/- 0.25 to 3.58 +/- 1.72 microg/l after 24 hours of treatment. Following placebo administration 24 h profiles confirmed a nocturnal rise in leptin levels with an increase of 73 +/- 37% at midnight compared with 0.9.00 h. After dexamethasone mean leptin levels increased by 123 +/- 51% (p = 0.0016), with an accentuation in the diurnal variation and associated hyperinsulinemia. The study confirms a nocturnal rise in leptin in humans, and demonstrates increases in leptin in response to glucocorticoid administration as previously demonstrated in the rodent. The divergence between appetite stimulating effects of glucocorticoids despite induction of a proposed satiety factor suggests that regulation of leptin levels and regulation of appetite is multifactorial, and other neurotransmitter pathways are presumably involved.
Leptin is known to regulate food intake and energy expenditure. Since loss of appetite and bodyweight are important signs and symptoms of major depression we studied leptin plasma concentrations in both depressed patients (n = 24) suffering from loss of appetite and a healthy control group (n = 33). To rule out the possibility of inferences with other endocrine parameters known to be changed in depression or suspected to be related to leptin, we also studied cortisol, insulin, growth hormone (GH) and GH-binding protein (GHBP). We found that leptin plasma concentrations did not differ between depressed patients and healthy controls. However, leptin was positively associated with female gender, body mass index (BMI) and morning insulin. 24-hour mean cortisol was not related to leptin. Also, GH and GHBP were not related to leptin when controlled for BMI in an ANCOVA model. We conclude that leptin plasma concentrations are unchanged in depression and that there is no evidence for leptin playing a major role in loss of appetite and body weight in depressed patients.
Leptin is a newly discovered hormone that acts as a feedback signal from the adipose tissue. It plays a pivotal role in the modulation of neuronal and hormonal systems involved in the regulation of body weight and reproductive functions. This brief overview focuses on the regulation of circulating leptin levels and leptin in extreme clinical states of body weight, summarizing mainly results from the University of Giessen in collaboration with other groups. Finally, a possible role for leptin is presented.
A survey to identify children and adolescents with primary growth hormone insensitivity syndrome (GHIS) yielded 38 patients who were positively identified using a scoring system that included five criteria: height, basal growth hormone (GH), GH binding protein, basal insulin‐like growth factor 1 (1GF‐I) and the increase of IGF‐I after 4 days of GH administration (IGF generation test). Because of an overlap of the accepted and excluded groups with respect to points scored, an attempt was made to improve the scoring system. The new criteria were: height below –3 SDS, basal GH 4 mU/I or above, GH binding below 10%, basal IGF‐I and basal IGF binding protein‐3 (IGFBP‐3) below the 0.1 centile for age, an increase of IGF‐I in the IGF generation test less than 15 μg/1, and the increase of IGFBP‐3 less than 0.4 mg/1. With this scoring system, a clear separation between the accepted and the excluded groups was obtained. IGFBP‐3 was included to give the GH‐dependent parameters of the IGF system more weight and because the accuracy of IGFBP‐3 in the IGF generation tests was greater than the accuracy of IGF‐I, when the group of patients with GHIS was compared with a group of patients with GH deficiency. Unexpectedly, the IGF generation test was unable to segregate both cohorts completely. In the GHIS‐positive group, a significant correlation was found between basal IGF‐I or IGFBP‐3 levels corrected for age (SDS) and height SDS (r= 0.49, p < 0.002 and r= 0.61, p < 0.0001, respectively). There was also a significant correlation between the changes of IGF‐I or IGFBP‐3 in the IGF generation test and height SDS. That is, the patients with a slight response to GH were those with the least growth retardation, suggesting the existence of partial GH insensitivity.
Glucocorticoids inhibit somatic growth in man and laboratory animals, and have long been regarded as suppressors of both stimulated GH secretion and insulin-like growth factor (IGF) activity. Recent evidence suggests, however, that glucocorticoids can be potent GH secretagogues in their own right with concomitant increases in circulating IGF-I levels. IGFs circulate tightly bound to a group of high-affinity binding proteins (IGFBPs) which modulate their actions. In order to investigate the effects of glucocorticoids on serum levels of IGFs and IGFBPs, normal male volunteers were sampled over 24-h periods before and directly after treatment with dexamethasone (2 mg twice daily) for 96 h. Following dexamethasone administration, all volunteers showed a marked increase in mean +/- S.E.M. IGF-I levels over the 24-h sampling period (292.2 +/- 31.8 before dexamethasone, 425.9 +/- 37 micrograms/l after dexamethasone, P < 0.005); there was no change in mean IGF-II levels. Integrated mean insulin levels were raised by dexamethasone treatment (50 +/- 4.6 before dexamethasone, 117 +/- 13.4 mU/l after dexamethasone, P = 0.002) and IGFBP-1 was significantly suppressed (42.9 +/- 8.2 before dexamethasone, 28.0 +/- 7.9 micrograms/l after dexamethasone, P < 0.001). IGFBP-2 levels were similarly suppressed after dexamethasone (319.5 +/- 24.5 before dexamethasone, 214.8 +/- 8.5 micrograms/l after dexamethasone, P = 0.002), and there was a significant increase in IGFBP-3 levels from 3.24 +/- 0.25 to 3.67 +/- 0.32 mg/l (P = 0.0153). Mean IGF bioactivity over the sampling period after dexamethasone was reduced by approximately 60% (0.93 +/- 0.39 before dexamethasone, 0.39 +/- 0.05 U/ml after dexamethasone, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
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