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Research Notes: LeptinGrowth Horm IGF Res. 2003 Dec. Prader-Willi syndrome (PWS) is a complex genetic disorder characterised by mild mental retardation and distinct physical, behavioural, and psychiatric features. One of the cardinal symptoms is excessive eating, which - if left untreated - leads to extreme obesity. In the present study we have examined circulating levels of peptides with documented association to hyperphagia in young adults with PWS. Since growth hormone (GH) is often used nowadays to correct GH insufficiency during childhood PWS, we also studied the impact of GH administration on the peptides. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-3.2 kg/m(2) participated. All had clinical PWS (Holm's criteria). Genetic testing was performed in all patients and in 11 the diagnosis was confirmed. They were randomized to treatment with either placebo or GH (Genotropin, Pharmacia Corporation) for 6 months. Subsequently all received open label treatment to provide all subjects with 12 months active GH treatment. Doses were individually titrated. Weight, BMI, oxytocin (baseline only), leptin, Neuropeptide Y (NPY), and ghrelin were evaluated at baseline and after 6 and 12 months. At baseline plasma mean oxytocin was within and serum ghrelin just above the normal range (14.7+/-1.2 pmol/L and 0.87+/-0.12 microg/L, respectively). Serum leptin levels were high above and plasma NPY levels within the lower normal range (47.8+/-29.1 microg/L and 13+/-1 pmol/L, respectively). Results were independent of genotype. No changes in mean BMI, ghrelin, leptin or NPY were seen following GH treatment. Conclusion: Leptin levels were in general high reflecting obesity and as a consequence NPY levels were low. In simple obesity oxytocin levels are high, while ghrelin levels are suppressed. In view of the adiposity oxytocin circulated in abnormally low and ghrelin in abnormally high concentrations in our patients. GH treatment of PWS patients did not change ghrelin, leptin or NPY. We suggest that both oxytocin and ghrelin are involved in the pathogenesis of hyperphagia seen in PWS. Am J Clin Nutr. 2002 Mar. Background: Obesity in Prader-Willi syndrome (PWS) may be related to abnormalities in the adipocyte-leptin-hypothalamic pathway and may be exacerbated by reductions in the resting metabolic rate (RMR). Objective: We compared body composition, body-composition- adjusted RMR, and adiposity-adjusted plasma leptin between women with PWS and control women. We also examined leptin receptor expression in the PWS group. Design: We studied body composition using whole-body magnetic resonance imaging and measured plasma leptin by radioimmunoassay in 45 control women aged 18-56 y and in 13 women with PWS aged 20-38 y. RMR was measured by indirect calorimetry in 41 control women and in 8 women with PWS. Age, body composition, and regional adipose tissue (AT) depots were corrected for by multiple regression analysis. Messenger RNA expression of the leptin receptor was examined by reverse transcriptase-polymerase chain reaction in lymphocytes. Results: In the PWS group, fat mass was greater after correction for fat-free mass, and RMR was normal after correction for both fat-free mass and fat mass. Leptin was influenced primarily by subcutaneous AT volume in both subject groups. Leptin concentrations were not significantly different between the 2 groups after adjustment for age and AT content or distribution. Full-length leptin receptor messenger RNA was expressed in the lymphocytes of the PWS group. Conclusions: Differences in RMR in women with PWS are explained by abnormal body composition, suggesting that energy expenditure is normal at the tissue level in PWS. There is no evidence that defective leptin production causes obesity in PWS, and leptin receptor deficiency is not a primary consequence of the gene defects leading to leptin resistance. J Pediatr Endocrinol Metab. 2000 Apr. There is limited information on the underlying physiological mechanisms promoting obesity in patients with Prader-Willi syndrome (PWS). The aim of this study was to investigate whether body fat regulation in children with PWS is similar to that in children with non-syndromal obesity and non-obese children. We studied three groups: 1) 72 non-obese children and adolescents; 2) 68 children with non-syndromal obesity; and 3) 11 patients with PWS. Height and weight were measured and body mass index (BMI) and BMI SDS were calculated. Fasting serum leptin concentrations were determined. Median leptin serum concentrations were similar in PWS patients and children with non-syndromal obesity. Median leptin serum concentrations were higher in these two groups than in the non-obese group. Log leptin serum concentrations and BMI SDS showed significant correlations in the three groups of patients; correlation coefficients were 0.525, 0.285 and 0.854, respectively. In conclusion, median leptin serum concentrations are similar in PWS patients and children with non-syndromal obesity. The relationship between log serum leptin concentrations and BMI SDS was different in the three groups of patients studied. Clin Endocrinol (Oxf). 2000 Jan. Objective: This study explored leptin concentrations in Prader-Willi syndrome (PWS), a genetic disorder characterized by significant obesity and presumed hypothalamic dysfunction. The potential interaction of leptin metabolism with the growth hormone (GH) axis was also studied. Study design: Plasma leptin concentrations and percent body fat were determined by radioimmunoassay and dual energy x-ray absorptionmetry, respectively, in 23 children with Prader-Willi syndrome and 23 children with exogenous obesity. Results: Log plasma leptin concentrations were positively correlated with percentage body fat in PWS (r = 0.844) and exogenous obesity (r = 0.869). When the regression lines for the two groups were compared, there were no differences in their slopes (P = 0.737) or intercepts (P = 0.701). Administration of recombinant human growth hormone to PWS children for 12 months significantly reduced both percentage body fat and plasma leptin concentrations, but the relationship of log plasma leptin to percentage body fat was unchanged. Conclusion: Prader-Willi syndrome is not accompanied by deranged leptin concentrations and there was no evidence of an interaction of the GH axis with leptin metabolism in these GH-deficient children. Am J Med Genet. 1998 Jan 6. Prader-Willi syndrome (PWS) is characterized by early childhood obesity, mental deficiency, hypogonadism, hypotonia, hypopigmentation, short stature, small hands and feet, and a characteristic face. It is the most common genetic cause of obesity and obesity is the most significant health problem for PWS patients. Ob protein (leptin), which is produced by adipose tissue, is thought to play a significant role in obesity; thus, unusually low plasma leptin levels, or relative loss of sensitivity to leptin in PWS subjects, could be an important factor in their obesity. We measured plasma leptin levels in 19 obese and 14 non-obese PWS patients [mean body mass index (BMI) 37.2 and 22.0, respectively] and compared these levels to those of 28 obese controls (mean BMI 35.5) and 16 non-obese control individuals (mean BMI 21.6). The mean plasma leptin concentration (ng/ml) for obese PWS subjects was 33.4 and 23.6 for non-obese PWS subjects. Obese control leptin was 36.2 ng/ml and non-obese control was 9.9. Among the control groups, leptin levels in females were significantly higher than those in males; the obese males and females had significantly higher leptin than their respective non-obese counterparts. These differences did not hold true for the PWS subjects. Leptin levels in obese PWS males and females were similar, and the same was true of the non-obese PWS males and females. The differences between obese and non-obese PWS subjects of both sexes were small and not significant. Comparing control groups with their PWS counterparts revealed no significant differences, with one exception: circulating plasma leptin levels in non-obese PWS males were nearly five times higher than in non-obese control males with similar BMI. This difference may reflect a more female pattern of fat distribution and hypogonadism, which are characteristic of PWS males. Leptin levels in PWS patients were not obviously correlated with the chromosome 15 finding seen in the patients. Pediatr Res. 1997 Nov. 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. Peptides. 2007 Jul 12. In human monocytes 100ng/mL leptin increased both statin-inhibitable free radical and cholesterol production in vitro. In our recent study, we aimed to elucidate the concentration dependence of observed leptin-effect. Following leptin stimulation cholesterol synthesis was measured in the presence of inhibitors to determine affected signal pathways. Leptin at low (10-100ng/mL) concentrations increased [(14)C]acetate incorporation, whereas at 250ng/mL and higher concentrations it suppressed cholesterol synthesis. HMG CoA reductase, phosphatidyl-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) were involved in mediating leptin effects at low concentrations, whereas the cholesterol synthesis suppression was abolished by inhibitors of protein kinase C (PKC) and PI3K. Int J Biochem Cell Biol. 2007. The role of leptin in the pathomechanism of atherosclerosis, through its free radical generating ability is established. Its effect however, on the regulation of intracellular cholesterol synthesis has not been studied. The aim of the present study was to elucidate whether leptin influences endogenous cholesterol synthesis in monocytes. Furthermore, leptin signaling to HMG CoA reductase in control and hypercholesterolemic monocytes were compared. The in vitro effect of leptin was studied on freshly isolated human monocytes obtained from healthy control volunteers and patients with hypercholesterolemia. Our results can be summarized as follows: (1) Leptin is able to increase endogenous cholesterol synthesis in human monocytes in vitro. (2) The cholesterol synthesis increasing effect of the hormone is more pronounced in hypercholesterolemic monocytes with high basal cholesterol biosynthesis. (3) The leptin-induced Ca(2+) signal was involved in the enhancement of HMG CoA reductase activation in monocytes from both controls and hypercholesterolemic patients. (4) In control monocytes the Ca(2+) signal originated from intracellular pools, whereas in patients, Ca(2+)-influx and protein kinase C activation were found to be responsible for the leptin-effect. Mevalonate cycle inhibiting fluvastatin and 25-hydroxycholesterol decreased cholesterol production in leptin-stimulated monocytes. Our present study provides the first proof of the cholesterol synthesis enhancing effect of leptin through a statin-sensitive pathway in circulating monocytes. Furthermore our results suggest that leptin can be involved in the pathomechanism of atherosclerotic plaque formation also through its effect on cholesterol biosynthesis in monocytes. Neuropeptides. 2006 Oct. Angiotensin II (Ang II) and leptin generate statin-inhibitable superoxide anion production that accounts for only part of the entire superoxide anion production. In our recent studies, we aimed at elucidating whether Ang II and leptin, affecting the intensity of the mevalonate cycle, are able to increase endogenous cholesterol synthesis. Furthermore, we compared the superoxide anion and cholesterol production capability of monocytes of healthy control volunteers and monocytes obtained from patients with hypercholesterolemia (HC). We also studied the differences of the produced statin-inhibitable superoxide anion and cholesterol synthesis in control and HC-monocytes, depending on the applied stimulating ligands. In control and HC-monocytes--stimulated by Ang II, leptin, fenyl-Me-Leu-Phe (FMLP), phorbol-12-myristate-13-acetate (PMA) and A23187--we determined the proportion of mevalonate cycle-dependent and -independent superoxide and cholesterol production, using lovastatin (Lov), and 25-hydroxycholesterol (25-HC). According to our results; (1) superoxide anion generation in HC-monocytes was elevated after Ang II, leptin and FMLP-stimulation, whereas PMA and A23187-stimulation had lower stimulating effect in HC than in control cells. (2) Cholesterol synthesis was increased only after stimulation with Ang II and leptin. (3) The Ang II and leptin-induced total superoxide anion generation and cholesterol synthesis were more elevated in HC than in control monocytes. (4) In contrast, the increase in Lov and 25-HC sensitive cholesterol synthesis were higher in resting, but lower in stimulated HC monocytes than in control cells. Summarizing our results, we concluded that Ang II and leptin are involved in enhancement of endogenous cholesterol synthesis through a statin-sensitive pathway. Intern Med. 2006 Sep 15. Since first cloned and reported by Zhang et al in 1994 (Nature 372:425), the obese gene and its product - leptin - has been studied profoundly. Our knowledge in body weight regulation and the role played by leptin has increased substantially. Leptin serves as an adiposity signal to inform the brain of the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Many articles have reported weight loss at high altitude, but the explanation has been limited to loss of appetite. New ideas were highlighted after studies by Grosfeld et al and Ambrosini et al on the obese gene under hypoxia condition. Cells with hypoxia treatment upregulated obese gene transcription and suggested that enhancement of leptin secretion in vivo under hypoxia environment may be one of the potential therapeutic methods for obesity treatment. J Biol Chem. 2002 Nov 8. Increased placental leptin has been demonstrated in preeclampsia, a pregnancy disorder associated with placental hypoxia. This suggests that leptin gene expression is enhanced in response to oxygen deficiency in this organ. In support of this hypothesis, we have previously shown that hypoxia activates the leptin promoter in trophoblast-derived BeWo cells. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric HIF-1alpha/HIF-1beta complex that regulates the transcription of hypoxia-responsive genes. To test whether this factor is involved in hypoxia-induced leptin promoter activation, BeWo cells were transiently transfected with a HIF-1alpha expression vector. Exogenous HIF-1alpha markedly increased luciferase reporter activity driven by the leptin promoter when HIF-1beta was co-expressed in the same cells. This effect was similar to that elicited by CoCl2, an agent known to stabilize endogenous HIF-1alpha. These data suggest that HIF-1alpha/HIF-1beta dimers are involved in the effect of CoCl2 to activate the leptin promoter. To confirm the implication of HIF-1, the cells were transfected with a dominant negative form of HIF-1alpha producing transcriptionally inactive HIF-1beta/HIF-1alpha dimers. This mutant HIF-1alpha protein abolished CoCl2 activation of the leptin promoter, providing direct evidence that the effect of CoCl2 is mediated by endogenous HIF-1alpha. Deletion analysis and site-specific mutagenesis demonstrated that a HIF-1 consensus binding site (HRE) spanning -120 to -116 bp relative to the start site was required for CoCl2 and exogenous HIF-1alpha induction of leptin promoter activity. Electrophoretic mobility shift assays performed with in vitro-translated HIF-1alpha and HIF-1beta proteins demonstrated binding to this HRE and not to mutated sequences only when both subunits were used together. These data demonstrate that leptin is a new hypoxia-inducible gene, which is stimulated in a placental cell line through HIF-1 interaction with a consensus HRE site located at -116 in the proximal promoter. J Biol Chem. 2002 Sep 13. In addition to having a major role in energy homeostasis, leptin is emerging as a pleiotropic cytokine with multiple physiological effector functions. The recently discovered proangiogenic activity of leptin suggested the hypothesis that its production might be regulated by hypoxia, as are other angiogenic factors. To examine this proposal, the expression of leptin protein and mRNA was measured and found to be markedly up-regulated in response to ambient or chemical hypoxia (upon exposure to desferrioxamine or cobalt chloride), an effect that requires intact RNA synthesis, suggesting a transcriptional mechanism. Transient transfection of cultured cells with deletion constructs of the leptin gene promoter linked to a reporter gene revealed a functional hypoxia response element (HRE) located at position -116 within the proximal upstream region. This putative HRE harbors a characteristic 5'-RCGTG-3' core motif, a hallmark of hypoxia-sensitive genes and recognized by the hypoxia-inducible factor 1 (HIF1), which consists of a HIF1alpha/HIFbeta heterodimer. Constructs harboring this -116/HRE supported reporter gene expression in response to hypoxia but not when mutated. Expression of HIF1alpha cDNA in normoxic cells mimicked hypoxia-induced reporter gene expression in cells cotransfected with the wild type leptin -116/HRE construct but not with the mutant. Gel shift assays with a (32)P-labeled leptin promoter -116/HRE probe and nuclear extracts from hypoxia-treated cells indicated binding of the HIF1alpha/beta heterodimer, which was blocked with an excess of unlabeled -116/HRE probe or a HIF1-binding probe from the erythropoietin gene enhancer. Taken together, these observations demonstrate that the leptin gene is actively engaged by hypoxia through a transcriptional pathway commonly utilized by hypoxia-sensitive genes. |