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PubMed1997

Ligand-independent dimerization of the extracellular domain of the leptin receptor and determination of the stoichiometry of leptin binding.

The leptin receptor is a class I transmembrane protein with either a short or a long cytoplasmic domain. Using chemical cross-linking we have analyzed the binding of leptin to its receptor. Cross-linking of radiolabeled leptin to different isoforms of the leptin receptor expressed on COS-1 cells reveals leptin receptor monomer, homodimer, and oligomer complexes. Cotransfection of the long and short form of the leptin receptor did not provide any evidence for the formation of heterodimer complexes. Soluble forms consisting of either the entire extracellular domain or the two cytokine receptor homologous domains of the leptin receptor were purified to homogeneity from recombinant baculovirus-infected insect cells by leptin affinity chromatography. Gel filtration chromatography showed that these proteins exist in a dimeric form. Analysis of the complex formed between soluble leptin receptor and leptin by native polyacrylamide gel electrophoresis, and data obtained from the amino acid composition of the complex provide direct evidence that the extracellular domain of the leptin receptor binds leptin in a 1:1 ratio.

Amino Acid Sequence↗
PubMed2001

Hexosamines and nutrient excess induce leptin production and leptin receptor activation in pancreatic islets and clonal beta-cells.

Activation of the hexosamine biosynthesis pathway leads to insulin resistance in muscle and adipose tissue. In these tissues leptin gene expression is increased by glucosamine. In the present study we found that glucosamine rapidly activates the production of leptin and OB-Rb, which encodes the functional leptin receptor, in both primary pancreatic islets and clonal beta-cells. Secretion of leptin from clonal beta-cells into the medium was detected readily. In addition, the level of the transcripts encoding signal transducer and activator of transcription-3 and -5, both implicated in leptin signal transduction in islet beta-cells, was increased by glucosamine, although to a lesser degree than mRNA levels of leptin and OB-Rb. High glucose (16.7 mM) induced leptin biosynthesis in primary pancreatic islet cells, and the addition of 1 mM palmitate caused an additional incremental effect. The hexosamine-mediated induction of the leptin system in clonal beta-cells was associated with increased responsiveness to leptin, as demonstrated by a 2.6 +/- 0.3-fold (P < 0.01) increase in tyrosine phosphorylation of signal transducer and activator of transcription-3. These findings are the first evidence of inducible leptin production in pancreatic islets and suggest that islet cells, like skeletal muscle, demonstrate a linkage between increased nutrient availability and both leptin expression and leptin responsiveness.

Animals↗
PubMed2002

Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity.

Leptin deficiency causes obesity in rodents and humans, but circulating levels of leptin are paradoxically elevated in obesity. The mechanisms underlying this leptin resistance are unknown, but may involve reduced leptin transport across the blood-brain barrier via short isoforms of the leptin receptor (Ob-R). Here, we first quantified short Ob-R mRNA expression in isolated rat cerebral microvessels constituting the blood-brain barrier and found that Ob-Ra and Ob-Rc mRNA were abundantly expressed in similar amounts. Second, brain uptake of leptin was reduced in mice lacking Ob-R. Third, brain uptake of leptin in New Zealand Obese mice, a strain that responds to central, but not peripheral, leptin, was reduced, suggesting that their obesity is at least partly due to deficient leptin transport into the brain. Fourth, brain uptake of leptin was significantly reduced in diet-induced obese mice. Neither New Zealand Obese mice nor diet-induced obese mice exhibited significant decreases in Ob-R mRNA expression in isolated cerebral microvessels. These data support the ideas that short isoforms of Ob-R are involved in brain uptake of leptin and that impaired blood-brain barrier function contributes to the pathogenesis of obesity. However, the mechanisms by which obesity-related deficits in brain uptake of leptin occur remain to be defined.

Animals↗
PubMed2003

Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans.

The adipocyte-derived hormones leptin [which circulates in a free form and bound to a soluble leptin receptor (sOB-R)], adiponectin, and resistin play a key role in regulating energy homeostasis and metabolism. We assessed the association between body composition, total energy, and macronutrient intake and serum leptin, sOB-R, free leptin index, adiponectin, and resistin concentrations in 61 female and 53 male consecutively enrolled healthy Greek students. In this cross-sectional study, total energy and macronutrient intake were determined using 3-d food records. Body composition was assessed by bioelectrical impedance analysis; fasting blood samples were taken for the measurement of total leptin, sOB-R, adiponectin, and resistin; and the ratio leptin/sOB-R was used as an index of free leptin. Serum sOB-R concentrations were lower in the female subjects compared with the males (27.24 +/- 29.06 vs. 50.14 +/- 39.74 ng/ml, P < 0.001), whereas leptin, adiponectin, and resistin concentrations were significantly higher in females (leptin: 9.93 +/- 6.01 vs. 3.27 +/- 2.54 ng/ml, P < 0.001; adiponectin: 11.40 +/- 6.73 micro g/ml vs. 4.90 +/- 2.79 micro g/ml; P < 0.001; resistin: 16.86 +/- 5.39 ng/ml in females vs. 14.00 +/- 7.16 ng/ml in males, P < 0.02). Simple regression analysis showed that, in both genders, leptin, free leptin index, adiponectin, and resistin correlated positively with body fat mass and negatively with waist to hip ratio. sOB-R correlated negatively with body fat mass and positively with waist to hip ratio. Multiple regression analysis models controlling for gender, body fat, and total energy intake demonstrated that sOB-R is positively associated with energy intake from carbohydrates and negatively with energy intake from dietary fat, whereas free leptin index is negatively associated with energy intake from carbohydrates and positively with energy intake from dietary fat. No statistically significant correlations were observed between serum adiponectin or resistin concentrations and total energy or macronutrient intake. Thus, total energy intake and macronutrient composition of the diet are associated with sOB-R and free leptin index but do not play a role of comparable significance in predicting adiponectin and resistin concentrations in healthy young subjects.

Adiponectin↗
PubMed2002

Leptin and soluble leptin receptor levels in obese and weight-losing individuals.

To investigate soluble leptin receptor (sLR) in plasma, specific anti-sLR monoclonal antibodies were developed. Western blot analysis and size exclusion fractionation demonstrated sLR in plasma with a molecular mass of approximately 180,000. Next to this, the presence of sLR-leptin complexes in plasma was confirmed. Using the developed monoclonal antibodies, a specific sLR ELISA was developed, which measured in plasma both free and sLR bound to leptin. sLR appeared to inhibit leptin concentrations measured in four different leptin assays indicating that these assays primarily measure free leptin and underestimate the total leptin present in plasma. Furthermore, plasma levels of sLR and leptin were measured in 21 lean individuals and in 30 morbidly obese subjects before and 3, 6, and 12 months after gastric restrictive surgery. Preoperatively, leptin concentrations significantly correlated with body mass index (r = 0.796, P < 0.001). In contrast, sLR significantly inversely correlated with body mass index (r = -0.294, P < 0.05). In lean subjects, the molar ratio of free leptin to sLR was 1:1, whereas in morbidly obese subjects a ratio of 25:1 was found. After weight loss due to surgery, leptin levels rapidly decreased and sLR levels slowly increased to reach normal values at 12 months postoperatively. We conclude that sLR levels are significantly decreased, whereas leptin levels are significantly increased in morbidly obese subjects compared with lean individuals.

Adult↗
PubMed2003

A peptide derived from the human leptin molecule is a potent inhibitor of the leptin receptor function in rabbit endometrial cells.

In this article we show that rabbit endometrial cells express leptin receptor and that human leptin triggers phosphorylation of signal transducer and activator of transcription 3 and up-regulates the expression of interleukin- 1 receptor type I as was previously found in human endometrial cells. Interestingly, leptin also upregulates the secretion of leukemia inhibitory factor and expression of its receptor by rabbit endometrial cells. Analysis of a structural model of the leptin-leptin receptor complex suggested that helices I and III of the human leptin structure were likely sites of interaction with the cytokine binding domain of leptin receptor. Accordingly, we synthesized a peptide (LPA-2) comprising helix III (residues 70-95) and investigated its ability to inhibit leptin receptor function. The effects of LPA-2 were assayed in rabbit endometrial cells, and an antileptin receptor antibody and a scrambled version of LPA-2 were used as positive and negative controls, respectively. LPA-2 binds specifically and with high affinity (Ki ~ 0.6 x 10-10 M) to leptin receptor and is a potent inhibitor of its functions in rabbit endometrial cells. Because leukemia inhibitory factor and interleukin- 1 have been implicated in embryo implantation, our results raise the possibility that the LPA-2-induced inhibition of leptin receptor may be exploited to study the actions of leptin in endometrium and in other tissues under conditions characterized by abnormal leptin production.

Animals↗
PubMed2000

Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture.

Leptin is mainly produced in white adipose tissue and acts both at distant sites and locally at the tissue from which it originates. The cellular and subcellular localization of leptin and its receptor (Ob-receptor [Ob-R]) and their relationship to various stages of fat cell maturation have not been characterized as yet. Therefore, we analyzed leptin and Ob-R by using reverse transcriptase-polymerase chain reaction, immunohistochemistry, and ultrastructural immunogold labeling in human white adipose tissue and in human adipocyte cell cultures at early and late stages of differentiation. Both leptin and its receptor were present in mature unilocular fat cells. The thin cytoplasmic rim of the adipocytes exhibited the strongest expression of both leptin and Ob-R. At early stages of differentiating human adipocytes, leptin was mainly expressed in multilocular preadipocytes, whereas the Ob-R was found predominantly on fibroblast-like cells. Other cellular components of human white adipose tissue were characterized by anti-CD31 for endothelial cells, anti-CD68 for macrophages, and antibodies specifically labeling B-cells and T-cells. In addition to fat cells, endothelial cells were immunopositive for the full-length leptin receptor. On the ultrastructural level, leptin was mainly found attached to cellular membranes and in small alveolate vesicle-like structures in the cytoplasm of adipocytes. Leptin was also present on the cell membranes of endothelial cells and macrophages. We conclude that the expression of the Ob-R in human white adipose tissue is not restricted to adipocytes but is present in resident endothelial and immune cells. Ultrastructural localization studies revealed an association of leptin with cell membranes and small vesicles. The cellular and subcellular distribution of leptin and its receptor suggests an important autocrine and paracrine role for leptin in human adipose tissue.

Adipose Tissue↗
PubMed2003

Duodenal leptin stimulates cholecystokinin secretion: evidence of a positive leptin-cholecystokinin feedback loop.

Some of the actions of leptin depend on cholecystokinin (CCK). However, it is unknown whether leptin modulates the release of CCK. Here, we demonstrate in vitro that leptin induces the phosphorylation of extracellular signal-related kinase (ERK)-1/2 proteins and increases CCK release (EC(50) = 0.23 nmol/l) in CCK-secreting STC-1 cells. We showed that rat duodenal juice contains leptin that circulates free and bound to macromolecules, suggesting that leptin has a lumenal action on the intestine. In vivo in the rat, duodenal infusion of leptin increased plasma CCK at levels comparable to those induced by feeding. Moreover, meal-induced increases in plasma CCK were markedly reduced in obese fa/fa rats, whereas the mobilization of the gastric leptin pool was similar in lean and obese Zucker rats. The release of CCK by leptin presumably generates a positive feedback loop. Indeed, the blockade of CCK receptors reversed the meal reduction of the stomach leptin pool and the meal-increased plasma insulin, consistent with the previous concept of an entero-insular axis. Collectively, these data support a novel mode of action of leptin where leptin and CCK may potentiate their own effects by cross-stimulating their secretion. The impairment of this leptin-CCK loop may have pathological implications related to obesity and diabetes.

Animals↗
PubMed2002

[Serum levels of leptin and soluble leptin receptors in women after bilateral ovariectomy].

OBJECTIVE: To determine whether the blood concentrations of leptin and soluble leptin receptor (LEPR) hang in women after bilateral ovariectomy, and whether there is a relationship between the concentrations of leptin, LEPR and LH, FSH and 17 beta-estradiol before and after castration. DESIGN: Prospective clinical study. SETTING: Department of Obstetrics and Gynaecology, First Faculty of Medicine, Charles University and the General Faculty Hospital, Prague. METHODS: 10 women of reproductive age (31-37 years) with a regular menstrual cycle were included in the study. Blood samples were always taken during the follicular phase of the menstrual cycle and 5 days after bilateral ovariectomy. In 9 women, hysterectomy was performed with the bilateral ovariectomy. Evaluated parameters: leptin, soluble leptin receptor, FSH, LH, 17 beta-estradiol and BMI. Serum soluble leptin receptor and leptin concentrations were determined using commercial ELISA kits. Serum concentrations of FSH, LH, and 17 beta-estradiol were determined using commercial RIA kits. RESULTS: We did not find any statistically significant changes in the concentration of leptin (8.9 +/- 5.5 vs 7 +/- 5.6) and LEPR (16.2 +/- 5.6 vs 20.9 +/- 8.9) before and after surgical castration. After surgery, according to expectations, the concentration of LH and FSH significantly increased while the concentration of 17 beta-estradiol decreased (P < 0.05). Five days after surgical castration we found only a tendency toward decrease in the concentration of leptin and an increase in the LEPR concentration. The differences were not statistically significant. Except for the positive correlation between leptin concentration and BMI, we did not find any statistically significant correlation between the concentrations of leptin and LEPR and any of the other evaluated parameters in both groups. CONCLUSION: In our study, there was a significant decrease in 17 beta-estradiol concentration five days after surgery. In contrast, the concentrations of FSH and LH significantly increased after surgery, which is in agreement with the expected endocrinological changes after ovariectomy. There was a tendency toward a decrease in serum concentrations of leptin and increase in serum concentration of LEPR after surgery, but it was not statistically significant, which is in contrast to another study published regarding this topic.

Adult↗
PubMed2003

[Expression of leptin and leptin receptor system in woman reproductive organs].

OBJECTIVE: To explore the expression of leptin, leptin receptor (Ob-R) and related signaling proteins in woman reproductive organs. METHODS: Thirty-nine women, aged 27 - 37, with normal menstrual cycle of which 24 being in proliferative phase and 15 in secretive phase, underwent uterine curettage, to obtain the endometrium. The uterine cervix, vaginal wall, and oviducts were resected from 3 women with hysteromyoma. The expression of mRNA of leptin and long isoform of leptin receptor (Ob-Rb) was detected by in situ hybridization. The expression of leptin and Ob-Rb proteins was examined by immunohistochemical staining. Immunohistochemical staining was used to study the expression of the leptin-related signaling proteins: phosphated signal transducers and activator of transcription (p-STAT3), suppressor of cytokine signaling 3 (SOCS3), and protein inhibitor of activated STAT3 (PIAS3). RESULTS: The mRNA and protein of leptin and the mRNA and protein of Ob-Rb were expressed in the glands and mesenchyma of endometrium. The expression of Ob-Rb protein was significantly stronger in secretive phase than in proliferative phase (P < 0.01). No significant difference was found between the expression of leptin protein in proliferative phase and that in secretive phase. In the endothelium SOCS3 and PIAS3 were expressed, however, p-STAT3 protein was only weakly expressed or not expressed. Leptin protein and Ob-Rb protein were expressed in the uterine cervix, vagina wall, and epithelium of oviduct, including glands. However, leptin mRNA and Ob-Rb mRNA were only expressed in the ciliated epithelium of oviduct. CONCLUSION: Leptin may have an effect on women's reproductive function through leptin receptor systems.

Adult↗
PubMed2005

Relationship between soluble leptin receptor, leptin, lipid profiles and anthropometric parameters in overweight and obese Thai subjects.

Median, range and 95% confidence interval (CI) for median of age, anthropometric variables, soluble leptin receptor, serum leptin and lipid profile levels of 48 overweight (Body mass index (BMI) = 25.00-29.99 kg/m2) and obese (BMI > or = 30. 00 kg/m2) Thai males and 166 overweight and obese Thai females, compared with 26 males and 81 females in a control group (BMI = 18.50-24.99 kg/m2), were determined The study subjects were persons who turned up regularly for physical check-ups at the Out-patient Department, General Practice Section, Ratchawithi Hospital, Bangkok, aged between 18-60 years. Serum leptin, triglyceride and low density lipoprotein cholesterol/high density lipoprotein cholesterol ratios (LDL-C/ HDL-C ratio) were significantly higher in the overweight and obese males and females. Soluble leptin receptor and HDL-C were significantly lower in the overweight and obese males and females. Cholesterol and LDL-C were significantly higher in the overweight and obese females, but there was no significant difference in the overweight and obese males when compared with the control males. Low soluble leptin receptor levels were found in 38.1% (8/21) of the overweight and obese males, while 31.5% (29/92) were found in the overweight and obese females. Elevated leptin levels were found in 66.7% (32/48) and 89.8% (149/166) of the overweight and obese males and females, respectively. Both low soluble leptin receptor levels and elevated leptin levels were found in 9.5% (2/21) and 29.4% (27/92) of the overweight and obese males and females, respectively. A significant positive correlation was found between soluble leptin receptor and cholesterol, and between weight, BMI, waist, hip and HDL-C, with leptin. Serum soluble leptin receptor levels were significantly negatively correlated with leptin and BMI. The results can elucidate the causes and consequences of obesity, and are expected to aid the provision of care for overweight and obese Thai people.

Adolescent↗
PubMed2006

Studies on leptin and leptin receptor gene expression in myometrium and uterine myomas of gnRH analogue-treated women.

AIM: To test if treatment with GnRH analogue, which leads to a significant reduction in myoma volume, changes expression of leptin genes and gene coding leptin receptor isoforms in uterine myomas and in the surrounding unaltered myometrium. METHODS: Using RT-PCR, expression of leptin genes and leptin receptor genes was studied in myomas and in the surrounding myometrium in women with uterine myomas, untreated or treated with GnRH analogue. In the randomly selected cases presence of leptin protein and of leptin receptor proteins was examined also by Western blotting. RESULTS: Expression of leptin genes was demonstrated both in myomas and in the surrounding myometrium, and a similar pattern of expression was found for leptin receptor isoforms. The results of RT-PCR were confirmed by Western blotting, which documented the identical distribution of leptin proteins and leptin receptor proteins in studied tissues. Treatment with GnRH analogue had no effect on the expression pattern of studied genes. CONCLUSION: The results of the present study on the administration of GnRH analogue to females with myomas suggest that no direct or immediate inter-relationship exists between expression of leptin genes in uterine myomas on one hand and estrogen, progesterone and leptin levels in the blood on the other. Expression seems to be of a more durable nature but factors that induce such expression remain unknown.

Adult↗
PubMed2005

A retinoid X receptor antagonist, HX531, improves leptin resistance without increasing plasma leptin level in KK-Ay mice under normal dietary conditions.

4-(5 H -2,3-(2,5-Dimethyl-2,5-hexano)-5-methyl-8-nitrodibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX531) is a novel retinoid X receptor antagonist. This study provides evidence that HX531 improves leptin resistance without increasing plasma leptin levels in KK-A y mice, an animal model with high plasma leptin levels and leptin resistance. Under normal dietary conditions, 3 weeks of treatment with HX531 (0.03% and 0.06% food admixture) in KK-A y mice decreased plasma leptin levels in a dose- and time-dependent manner, in addition to decreasing body weight and mesenteric fatty tissue weight. To evaluate the effect of HX531 on leptin resistance, leptin was injected intraperitoneally in the KK-A y mice for 4 days after 1 week of treatment with HX531 (0.06% food admixture). This pretreatment with HX531 resulted in exogenously administered leptin causing a significant decrease in food intake. These results suggested that HX531 decreased plasma leptin levels accompanied by a decrease in fatty tissue content in the KK-A y mice and a simultaneous improvement in leptin resistance. This is the first report that HX531 improves leptin resistance without increasing plasma leptin level in KK-A y mice, under normal dietary conditions.

3-Hydroxybutyric Acid↗
PubMed2002

Central leptin gene delivery evokes persistent leptin signal transduction in young and aged-obese rats but physiological responses become attenuated over time in aged-obese rats.

The purpose of this study was to determine if long-term leptin treatment desensitizes leptin signal transduction and the subsequent downstream anorexic and thermogenic responses in normal and leptin-resistant age-related obese rats. To this end, we administered, i.c.v., recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control virus into young and aged-obese rats and after 9 or 46 days, examined food intake, oxygen consumption, body weight, serum leptin, STAT3 phosphorylation, hypothalamic NPY and POMC mRNAs, and UCP1 expression and protein level in brown adipose tissue (BAT). In young rats, rAAV-leptin depleted body fat and both anorexic and thermogenic mechanisms contributed to this effect. Moreover, leptin signal transduction was not desensitized, and there were persistent physiological responses. Similarly, in the aged-obese rats, there was unabated leptin signal transduction, however, both the anorexic and thermogenic responses completely attenuated sometime after day 9. This attenuation, downstream of the leptin receptor, may be contributing to the leptin-resistance and age-related weight gain in these aged-obese rats. Finally, in young rats, although the initial responses to rAAV-leptin were dominated by anorexic responses, by 46 days, the predominant response was thermogenic rather than anorexic, suggesting that energy expenditure may be an important component of long-term weight maintenance.

Adipose Tissue, Brown↗
PubMed2003

Leptin concentrations in semen are correlated with serum leptin and elevated in hypergonadotrophic hypogonadism.

Leptin seems to play a role in both food intake and energy balance as well as in the regulation of reproductive features. In order to investigate the regulation of testicular functions by leptin we analysed leptin concentrations in the semen of men with different andrological diseases. It was demonstrated that semen leptin concentrations were inversely correlated with serum testosterone levels and directly with serum leptin concentrations. Furthermore, semen leptin concentrations display only a fraction of serum leptin levels. Semen leptin levels of patients with azoospermia due to hypergonadotrophic hypogonadism, associated with increased follicle-stimulating hormone levels and of high-grade oligozoospermia, were significantly elevated (1.19 +/- 0.46 and 1.09 +/- 0.54 microg l(-1), respectively), while semen levels of leptin in patients with obstructive azoospermia (0.54 +/- 0.41 microg l(-1)) and low-grade oligozoospermia (0.54 +/- 0.34 microg ml(-1)) were comparable with those of normozoospermic men (0.21 +/- 0.21 microg l(-1)). Our data suggest that dysfunction of testicular epithelia as found in hypergonadotrophic hypogonadism and high-grade oligozoospermia with decreased testosterone levels causes elevated spermal leptin concentrations. However, the correlation of semen with serum leptin concentrations indicates that leptin is not actively transported but rather leaks through the blood-testis barrier.

Adult↗
PubMed2000

Leptin and leptin binding activity in the preovulatory follicle of polycystic ovary syndrome patients.

To investigate the clinical importance of leptin's intraovarian effects, we studied the concentration of leptin and leptin binding activity in the plasma and in the follicular fluid of PCOS patients (n=20; median BMI: 27.1 kg/m2, range 19.7-36.3) undergoing controlled ovarian stimulation with long-term GnRH agonist, recombinant FSH, and in vitro fertilization. Follicular fluid and blood samples were collected during follicle aspiration for IVF. Total leptin concentration was measured by radioimmunoassay, and specific leptin binding activity was accessed by a gel filtration column assay. Follicular fluid and plasma leptin levels were similar (median 1135 pmol/l vs. 1409 pmol/l; p=0.81). Follicular fluid to plasma leptin ratio was independently associated with cumulative FSH dose (r=0.63; p=0.006) and insulin resistance index (r=-0.45; p=0.04). Specific leptin binding activity was higher in the plasma than in the follicular fluid [median 7.94% vs. 3.49%; p<0.001]. When multivariate analysis was used to predict FSH consumption, only follicular fluid leptin levels were significantly associated with cumulative FSH dose (r=0.46; p=0.04). We infer that at least in part by increased intrafollicular leptin levels, obesity directly affects ovarian function in PCOS, and may induce a relative resistance to gonadotropin stimulation. This intraovarian effect of leptin can be even more profound because of low leptin binding activity in the preovulatory follicle of obese patients.

Adult↗
PubMed2000

Effects of recombinant murine leptin[1-147] and leptin fragment 116-130 on steroid secretion and proliferative activity of the regenerating rat adrenal cortex.

Leptin, the product of the ob gene, is a hormone mainly secreted by the adipose tissue, which acts through specific receptors (Ob-R) widely distributed in the body tissues. Ob-Rs are present in the mammalian hypothalamo-pituitary-adrenal axis, and evidence indicates that leptin regulates adrenocortical secretion. Moreover, leptin is known to act as a growth promoting factor in some tissues, including the endocrine ovary. We have investigated the effects of three subcutaneous injections of 2 nmol/100 g of native murine leptin[1-147] and of its biologically active fragment 116-130 on the secretory and proliferative activity of the regenerating rat adrenal cortex. Leptin[1-147] increased plasma aldosterone concentration at day 8 and plasma corticosterone concentration (PBC) at day 5 of regeneration, without affecting mitotic index. In contrast, leptin[116-130] lowered PBC and mitotic index at both times of adrenal regeneration. In light of the fact that adrenal regeneration is at least in part dependent on the pituitary ACTH, we conclude that: (i) native leptin moderately stimulates steroid secretion, acting directly on the adrenal cortex, through signaling mechanisms other than those involved in the ACTH action; (ii) native leptin is unable to enhance the proliferative activity of regenerating adrenals, which conceivably is maximally stimulated by ACTH; (iii)leptin[1-147] and leptin[116-130] differently interact with Ob-Rs or interact with different receptors; and (iv) leptin[116-130] inhibits the signaling pathways mediating both the secretagogue effect of native leptin and the proliferogenic effect of ACTH.

Adrenal Cortex↗