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PubMed2005

Leptin increases small intestinal response to cholecystokinin in leptin-deficient obese mice.

INTRODUCTION: Leptin receptors are present in the jejunum, ileum, and vagal neurons. Leptin increases duodenal secretion of cholecystokinin (CCK) and acts with CCK on vagal mechanoreceptors in the regulation of small intestinal motility. We have demonstrated that leptin-deficient (Lepob) obese mice have increased jejunal and normal ileal responses to CCK. Therefore, we hypothesized that leptin administration alters small intestinal motility observed in leptin-deficient obese mice. MATERIALS AND METHODS: Twelve-week-old female leptin-deficient (Lepob) obese mice received either saline (n=12) or 5 microg/g leptin ip (n=12) injections daily. After 4 weeks, jejunal and ileal segments were harvested, mounted in an organ bath, and reacted with acetylcholine (ACh, 10(-5)M) and CCK (10(-8,-7,-6)M). Data were expressed as N/cm2 and compared by ANOVA and Student's t test. RESULTS: The average body weights in the leptin-treated group were significantly decreased compared to those of the saline-treated group (34 versus 49 g, P <0.01). Jejunal responses to ACh within each group were significantly decreased (P <0.05) when compared to ileal responses. No significant differences in responses to ACh were observed between groups. Jejunal responses to 10(-7,-6)M CCK in the leptin-treated group were significantly greater than those in the saline-treated group. Ileal responses in the leptin group were similarly increased at all CCK concentrations. CONCLUSIONS: These data suggest that daily leptin administration for 4 weeks in leptin-deficient (Lepob) obese mice increases jejunal and ileal responses to CCK and does not alter responses to ACh. Therefore, we conclude that regulation of small intestinal motility may be influenced by synergistic action of cholecystokinin and leptin.

Acetylcholine↗
PubMed2002

Sexual diergism of baseline plasma leptin and leptin suppression by arginine vasopressin in major depressives and matched controls.

Leptin inhibits appetite by activating several neuroendocrine systems, including the hypothalamo-pituitary-adrenal cortical (HPA) axis. In turn, chronically elevated glucocorticoids increase circulating leptin. HPA axis hyperactivity occurs in 30-50% of patients with major depression, but the few prior reports of leptin measurements in this illness have shown inconsistent results. We, therefore, measured plasma leptin in 12 female and 8 male unipolar major depressives and 12 female and 8 male individually matched normal controls administered low-dose physostigmine (PHYSO) and arginine vasopressin (AVP) to stimulate the HPA axis. The subjects underwent four test sessions 5-7 days apart: PHYSO (8 microg/kg IV); AVP (0-08 U/kg IM); PHYSO+AVP; and saline control. Serial blood samples were taken before and after pharmacologic challenge and analyzed for leptin, ACTH(1-39), cortisol and AVP. Estradiol and testosterone also were measured at each test session. PHYSO and AVP produced no side effects in approximately half the subjects and predominantly mild side effects in the other half, with no significant patient-control differences. Correlations between side effects (absent or present) after PHYSO or AVP and the corresponding leptin responses were non-significant in all groups. Baseline plasma leptin concentrations (mean+/-S.D.) were significantly higher in the female patients compared to the female controls (22.5+/-13.9 ng/ml vs. 12.3+/-9.7 ng/ml), whereas they were similar in the male patients and the male controls (3.9+/-1.4 ng/ml vs. 3.6+/-2.0 ng/ml). Leptin concentrations following PHYSO remained unchanged from baseline, indicating that the short-lived ACTH and cortisol increases produced by PHYSO did not affect leptin secretion. In contrast, AVP administration, while also increasing ACTH and cortisol, significantly suppressed leptin, more so in the women than in the men. Baseline leptin and the leptin decrease after AVP were moderately positively correlated with the Hamilton Depression Scale 'somatization' factor in the female patients (r=0.50) and more strongly correlated with the 'mood-depression' factor in the male patients (r=0.81). These findings indicate a sexual diergism (functional sex difference) in plasma leptin measures between major depressives and matched normal controls.

Adrenocorticotropic Hormone↗
PubMed2004

Blunted fasting-induced decreases in plasma and CSF leptin concentrations in obese rats: the role of increased leptin secretion.

Fasting substantially decreases plasma leptin concentration. However, in obesity, the fasting-induced decrease in leptin concentration is blunted or absent. The objective of the current study was to determine in diet-induced obese (DIO) rats the contribution of altered leptin secretion and leptin expression to the blunted nutritional regulation of leptin concentration. Fasting-induced decreases in plasma leptin concentration were greater in lean (standard chow (SC)) rats compared to DIO (approximately 79 vs approximately 48%, P<0.05 for DIO vs SC). CSF leptin was significantly reduced by fasting in SC (approximately 46%) but not in DIO. Fasting decreased adipose tissue leptin secretion in both SC and DIO, but the decrease was greater in SC (average approximately 74%) compared to DIO (average approximately 44%, P<0.05, DIO vs SC). Additionally, leptin secretion in fasted DIO was substantially greater (average approximately 175%) than in fasted SC (P<0.05). Adipose tissue leptin protein content was increased by approximately 80% in DIO compared to SC (P<0.05). We conclude that a probable cause of blunted fasting-induced decreases in leptin concentration in obesity is elevated leptin secretion, which possibly results from increased leptin gene expression.

Adipose Tissue↗
PubMed2004

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults.

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 +/- 2.5 (mean +/- SEM) at baseline to 26.9 +/- 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.

Adult↗
PubMed1999

Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice.

Leptin controls feeding behavior and insulin secretion from pancreatic beta-cells. Insulin stimulates the production of leptin, thereby establishing an adipoinsular axis. Earlier we identified leptin receptors on pancreatic beta-cells and showed leptin-mediated inhibition of insulin secretion by activation of ATP-sensitive potassium channels. Here we examine transcriptional effects of leptin on the promoter of the rat insulin I gene in rodent beta-cells. A fall in levels of preproinsulin mRNA is detected in vivo in islets of ob/ob mice 24 h after a single injection of leptin, in isolated ob/ob islets treated with leptin in vitro and in the beta-cell line INS-1 on leptin exposure when preproinsulin mRNA expression is stimulated by 25 mM glucose or 10 nM glucagon-like peptide 1. Under these conditions, transcriptional activity of -410 bp of the rat insulin I promoter is inhibited by leptin, whereas transactivation of a 5'-deleted promoter (-307 bp) is not. The -307 sequence contains the known glucose-responsive control elements (E2:A3/4). Constitutive activation of ATP-sensitive potassium channels by diazoxide does not alter leptin inhibition of preproinsulin mRNA levels. Distinct protein-DNA complexes appear on the rat insulin I promoter sequences located between -307 and -410 with nuclear extracts from ob/ob islets in response to leptin, including a signal transducer and activator of transcription (STAT)5b binding site. These results indicate that leptin inhibits transcription of the preproinsulin gene by altering transcription factor binding to sequences upstream from the elements (307 bp) that confer glucose responsivity to the rat insulin I gene promoter. Thus leptin exerts inhibitory effects on both insulin secretion and insulin gene expression in pancreatic beta-cells, but by different cellular mechanisms.

Animals↗
PubMed2002

Establishment of a highly sensitive leptin radioimmunoassay and detection of increased leptin levels in hyperlipidemia and pregnancy.

The highly effective antibody has been obtained by immunizing rabbits with recombinant leptin many times. The leptin is iodinated with the chloramine-T method and purified with a Sephadex-G25 chromatography column. The reaction between antigen and antibody is carried out by a one-step balance method and cultured at 4 degrees C for 24 h; the binding and free antigen was then separated by PR reagent. The determining range of this method is about 0.5-24 ng/mL; limited detection level is 0.45 ng/mL, relative standard deviation in a group, and among groups, are less than 5.4% and 8%, respectively. The level of blood leptin in 277 samples of normal persons, in 112 samples of overweight persons (weight/hieght m2 > or = 25) and 224 samples of hyperlipidemic patients have been measured by this method. It is demonstrated that the level of blood leptin in males is much lower than that of the females, and becomes elevated with increased age. Serum leptin level in overweight persons and hyperlipidemic patients is also much higher than that of normal groups (P < 0.01). Serum leptin of 21 workers in our lab at 8:00 AM and 4:00 PM has been tested. It was found that there are no differences between the two time points. The same results are obtained within age groups. Leptin levels of pregnant women's serum is higher than those of the control group (P < 0.001). Leptin in newborn's serum is significantly lower than those of mothers (P < 0.01). There is no obvious correlation between leptin level of mother and newborns by correlation analysis (r = 0.19, P > 0.05). The body weight and body weight index of pregnant women are well correlated with their serum leptin levels (r = 0.33 and 0.35, P < 0.05). The body weight and body weight index of newborns are well correlated with their serum leptin levels (r = 0.54 and 0.49, P < 0.001). The serum leptin level of pregnant women is not correlated with newborn's body weight (r = 0.10). These results have shown that the proposed method is stable, simple, and specific, being sensitive enough to determine leptin levels in human serum or plasma.

Adolescent↗
PubMed2001

Effect of cyclic 3',5'-adenosine monophosphate, glucocorticoids, and insulin on leptin messenger RNA levels and leptin secretion in cultured human trophoblast.

Leptin is a polypeptide hormone originally thought to be produced exclusively by adipocytes. However, both leptin mRNA and leptin protein were identified in human placental trophoblast cells, suggesting a potential role in human pregnancy. In the present report, we examined the regulation of leptin mRNA levels and secretion by cAMP, glucocorticoids, and insulin in term human placental tissue. Placentae were obtained immediately after delivery from mothers with uncomplicated pregnancies. Leptin concentrations were measured by ELISA in the cultured media of trophoblast maintained in monolayer culture for 24, 48, and 72 h. Likewise leptin mRNA levels in these cultured human trophoblast cells were determined by reverse transcription-polymerase chain reaction. Treatment with forskolin and (Bu)(2) cAMP led to a time- and dose-dependent increase in leptin release, significant after 48 and 72 h. Moreover, incubation with forskolin for 48 h also clearly increased leptin mRNA concentration. Leptin secretion and mRNA levels were also assessed after treatment with insulin or dexamethasone. We found a time- and dose-dependent increase in leptin release, significant after 48 and 72 h. Leptin mRNA levels were also increased after these treatments. All this supports a stimulatory role of cAMP pathway, insulin and dexamethasone in the leptin mRNA levels, and leptin release in trophoblast cells in vitro.

Bucladesine↗
PubMed2005

Hypothalamic phosphatidylinositol 3-kinase-phosphodiesterase 3B-cyclic AMP pathway of leptin signalling is impaired following chronic central leptin infusion.

Leptin signalling in the hypothalamus is critical for the maintenance of normal body weight. Although hyperleptinaemia in obese people suggests a state of leptin resistance, and diet-induced obesity in rodents is associated with central leptin resistance, the underlying mechanisms remain unclear. Recent evidence suggests that, in addition to the signal transducer and activator of the transcription-3 (STAT3) pathway, leptin action is critical for energy homeostasis through an insulin-like signalling pathway involving an increase in phosphatidylinositol 3-kinase (PI3K) and phosphodiesterase 3B (PDE3B) activities and reduction in cyclic AMP (cAMP) levels in the hypothalamus. Here, we show that chronic central leptin (160 ng/h) infusion, which resulted in the development of resistance to the satiety action of leptin, impaired the PI3K-PDE3B-cAMP pathway of leptin signalling in the hypothalamus in that PI3K and PDE3B activities were increased and cAMP levels were decreased in the hypothalamus on day 2 of leptin infusion but remained unchanged on day 16. Additionally, induction of tyrosyl phosphorylation of insulin receptor substrate-1 observed on day 2 was not evident on day 16 of leptin infusion. By contrast, signalling through the STAT3-pathway remained activated in the hypothalamus throughout 16 days of leptin infusion. These findings show a differential response in PI3K-PDE3B-cAMP (impaired) and STAT3 (up-regulated) pathways to chronic central leptin infusion, and suggest a selective resistance in the PI3K-PDE3B-cAMP pathway of leptin signalling following a chronic increase in hypothalamic leptin tone attained by central infusion of this peptide hormone.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

No influence of surgical stress on postoperative leptin gene expression in different adipose tissues and soluble leptin receptor plasma levels.

UNLABELLED: As part of the postsurgical stress response, plasma leptin levels increase in-between 12 h postoperatively. OBJECTIVE: To study the kinetics of leptin gene expression in different adipose tissues before and after severe surgical trauma in children and adults. METHODS: In 22 adults and 23 children with cardiac and 19 adult patients with abdominal surgery, we measured plasma leptin concentrations preoperatively, 4 and 10-17 h postoperatively and quantified leptin mRNA expression by TaqMan real-time PCR in adipose tissue taken at the beginning and the end of surgery from subcutaneous, intrathoracic, omental and mesenteric fat. Plasma-soluble leptin receptor levels were measured in 23 children after cardiosurgery. RESULTS: Plasma leptin levels doubled between 4 and 10-17 h postoperatively in adults (p < 0.001) as well as in children (p = 0.0002) with cardiac surgery. After abdominal surgery, 10-17 h postoperatively, plasma leptin concentrations increased significantly (p < 0.05). During the operation, leptin gene expression did not change in neither of the patient groups. Plasma-soluble leptin receptor levels decreased immediately after the onset of surgery and remained unchanged thereafter. CONCLUSIONS: Leptin gene expression is not up-regulated during surgery. The measured increase in plasma leptin after surgery does not result from elevated levels of soluble leptin receptor but may follow an up-regulation of leptin gene expression later after the operation due to postsurgical metabolic changes.

Abdomen↗
PubMed2004

Leptin modulates orexigenic effects of ghrelin and attenuates adiponectin and insulin levels and selectively the dark-phase feeding as revealed by central leptin gene therapy.

We tested the hypothesis that leptin acts centrally and peripherally by different mechanisms to control peripheral hormones that normally regulate weight homeostasis. The paradigm of selectively increasing leptin transgene expression with a single intracerebroventricular injection of adeno-associated viral vectors encoding leptin (rAAV-lep) or green fluorescent protein (control) in the hypothalamus of mutant leptin-deficient ob/ob and wild-type (wt) mice was employed in these experiments. rAAV-lep injection increased hypothalamic leptin expression in the complete absence of peripheral leptin in ob/ob mice; suppressed body weight and adiposity; voluntarily decreased dark-phase food intake; suppressed plasma levels of adiponectin, TNFalpha, free fatty acids and insulin, concomitant with normoglycemia; and elevated ghrelin levels for extended period. Body weight and plasma levels of leptin and metabolic variables were suppressed to a lesser extent in rAAV-lep wt mice without decreasing food intake. The sustained high leptin transgene expression decreased only the dark-phase phagia in both genotypes, but wt mice escaped from leptin restraint during the lights-on phase, resulting in normal overall food intake. Leptin administration rapidly decreased plasma gastric ghrelin and adipocyte adiponectin but not TNFalpha levels, thereby demonstrating a peripheral restraining action of leptin on the secretion of hormones of varied origins. Whereas ghrelin administration readily stimulated feeding in controls, it was completely ineffective in rAAV-lep-treated wt mice. Thus, leptin expressed locally in the hypothalamus counteracted the central orexigenic effects of peripheral ghrelin. Cumulatively, these results identify newer central and peripheral modulatory influences of leptin on hormonal signals of disparate origin implicated in weight homeostasis and metabolic disorders.

Adipocytes↗
PubMed2004

Region-specific reduction in leptin-induced phosphorylation of signal transducer and activator of transcription-3 (STAT3) in the rat hypothalamus is associated with leptin resistance during pregnancy.

Leptin concentrations increase during pregnancy, but this does not prevent the pregnancy-induced increase in food intake, suggesting a state of leptin resistance. This study investigated the response to intracerebroventricular leptin administration in pregnant rats. After fasting, nonpregnant, d-7 and d-14 pregnant rats received leptin (4 microg) or vehicle, then food intake was measured. Serial blood samples were collected in another group of rats to determine plasma leptin concentrations. Further groups of d-14 pregnant and nonpregnant rats were killed after leptin or vehicle treatment, and brains were collected. Hypothalamic nuclei were microdissected, and levels of signal transducer and activator of transcription (STAT)3 phosphorylation were measured using Western blot analysis. Fasting decreased leptin concentrations in both pregnant and nonpregnant rats. Leptin treatment significantly reduced food intake in nonpregnant and d-7 pregnant rats but not in d-14 pregnant rats. In addition, there was no postfasting hyperphagic response in the pregnant rats. In the pregnant rats, leptin-induced STAT3 phosphorylation was suppressed in the arcuate nucleus and, to a lesser extent, in the ventromedial hypothalamus (VMH), compared with nonpregnant rats. Unstimulated STAT3 levels were also decreased in the VMH during pregnancy. Leptin-induced phosphorylation of STAT3 in the dorsomedial and lateral hypothalamus was not different between pregnant and nonpregnant rats. These data indicate that pregnant rats become resistant to the satiety action of leptin. Furthermore, leptin-induced activation of the STAT3 is impaired during pregnancy, specifically in the arcuate nucleus and VMH. These data support the hypothesis that pregnancy is a state of hypothalamic leptin resistance.

Animals↗
PubMed1998

Leptin is not necessary for gestation and parturition but regulates maternal nutrition via a leptin resistance state.

Leptin levels are significantly elevated in pregnant mice, rats and humans suggesting a critical role for leptin during gestation. To address whether leptin plays a putative role in the physiology of pregnancy, we asked whether a mouse pregnancy would be affected by the complete absence of leptin from both the mother and fetuses. Thus, leptin-deficient ob/ob females were first treated with exogenous leptin and then mated to similarly treated ob/ob males. All resulting fetuses have an ob/ob genotype and lack like their mothers any endogenous leptin production. Withdrawal of leptin treatment at 0.5, 6.5, 10.5 and 19.5 days p.c. did not affect any stage of the pregnancy despite a gradual return of the mothers to an obese state. However, some mice had delayed gestation periods of 21-23 days which were associated with prolonged parturition. The pups were normally delivered with no obvious signs of deformities although none survived beyond a day after delivery due to failure of lactation. Monitoring daily food intake of pregnant ob/ob females treated throughout gestation with leptin revealed significantly elevated levels of food intake from day 10 p.c. and onward demonstrating an attenuation of a leptin response during pregnancy and a leptin resistance effect. These studies demonstrate that in the mouse, leptin is not a critical molecule for implantation, gestation, fetal growth and parturition but that the leptin resistance effect at mid-gestation aims to stimulate food intake thus providing sustained energy resources for pregnancy.

Animal Nutritional Physiological Phenomena↗
PubMed2005

Leptin profile in neonatal gonadotropin surge and relationship between leptin and body mass index in early infancy.

AIM: This study was designed to investigate the longitudinal and dynamic profile of leptin and its relationship with sex hormones including luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) and testosterone (TTE) in neonatal 'minipuberty'. We also investigated the effects of leptin in the regulation of body weight gain and body mass index (BMI) in the first 3 months of life. METHODS: A longitudinal study was carried out in a cohort of 15 male and 15 female term infants during the first 3 months of life. Blood samples were collected in the morning from the infants on the 3rd, 15th, 30th, and 90th days of life. At each sample collection, anthropometric measurements were recorded. Serum leptin, LH, FSH, E2 (girls only) and TTE (boys only) concentrations were analyzed using standard biochemical methods. Association of leptin with weight gain, BMI, and these hormones during infancy was evaluated. RESULTS: Leptin levels increased significantly between the 3rd and 90th days of life in both boys and girls. BMI of both groups increased significantly from the 3rd to the 90th day. There was no significant difference in the leptin levels and leptin/BMI ratios of the two sexes at different time points. Leptin levels on the 30th and 90th days correlated significantly with BMI in both sexes. LH and FSH levels in both groups were found to be significantly higher on the 15th day of life. No correlation was observed between leptin and LH, FSH, E2 or TTE levels throughout the study. CONCLUSIONS: Leptin levels do not differ between the two sexes during early infancy and possibly there is no role for leptin in the surge of gonadotropins or sex steroids in neonatal minipuberty. The relationship between leptin and BMI could not be seen in the first postnatal days and the transient lack of the regulatory effect of BMI on leptin concentrations might reflect an adaptive resistance in the production of leptin to support catch-up growth after initial physiological weight loss in newborns.

Anthropometry↗
PubMed2002

Effects of leptin administration and feed restriction on thecal leucocytes in the preovulatory rat ovary and the effects of leptin on meiotic maturation, granulosa cell proliferation, steroid hormone and PGE2 release in cultured rat ovarian follicles.

Leptin is expressed by adipocytes and is thought to play a role in regulating food intake and in reproduction. It has been demonstrated that acute leptin administration to immature gonadotrophin-primed rats in vivo inhibits ovulation and causes a decline in food intake. However, feed restriction alone does not inhibit ovulation. Two experiments were designed to investigate the mechanism of leptin-induced inhibition of ovulation. In the first experiment, which was prompted by the importance of ovarian leucocytes in ovulation, the role of leucocytes in leptin-induced inhibition of ovulation was investigated. The second experiment investigated whether high leptin concentrations could inhibit other factors important to ovulation, such as meiotic competence of oocytes, granulosa cell proliferation, steroid or PGE(2) release, and interleukin 1beta production, in vitro. In the first experiment, the populations of neutrophils and monocytes-macrophages in the preovulatory follicles of gonadotrophin-primed, leptin-treated and -untreated rats were examined. A decrease in food intake, as a result of either leptin treatment or feed restriction, specifically reduced the numbers of neutrophils and monocytes-macrophages infiltrating the theca interna of preovulatory follicles without affecting the numbers found in the stroma. The findings show that reduced infiltration of thecal neutrophils and macrophages into preovulatory follicles is a response to reduced food intake. Furthermore, this reduction is not the direct cause of the leptin-induced inhibition of ovulation. In the second experiment, ovarian follicles were cultured for 4 or 12 h in the presence or absence of the following hormones: FSH (500 miu), insulin-like growth factor I (IGF-I) (50 ng ml(-1)), LH (100 ng ml(-1)) and leptin (300 ng ml(-1)). The results demonstrated that high concentrations of leptin in follicle culture do not affect meiotic maturation or steroid release, but tend to inhibit release of PGE 2 (although this result was not significant). DNA synthesis in granulosa cells was not inhibited by leptin in FSH- and IGF-I-supplemented culture media. These results are in agreement with previous studies that have shown that leptin inhibits the stimulatory effects of IGF-I on FSH-stimulated oestradiol production in rat granulosa cells without affecting progesterone production. In summary, leptin does not appear to have an adverse effect on the components of ovulation tested in this study, and therefore must impact on the ovulatory cascade in a way that remains to be defined.

Animals↗
PubMed2003

Leptin messenger ribonucleic acid (mRNA) content in the human placenta at term: relationship to levels of leptin in cord blood and placental weight.

During fetal life, placental tissue represents an additional source of leptin for the mother and conceptus. It has been suggested that feto-placental production of leptin may be involved in placental and fetal growth regulation. The aim of this study was to examine the correlation between leptin mRNA expression in the placenta and the concentrations of leptin in cord blood. A total of 30 healthy, pregnant women who gave birth to healthy neonates were included in the study. Maternal blood (obtained from the cubital vein) and umbilical cord blood were drawn immediately after birth. Serum leptin concentration was determined by enzyme-linked immunosorbent assay and serum insulin concentration was measured by radioimmunoassay. Leptin mRNA was measured in placental tissue by a reverse transcriptase-polymerase chain reaction. The estimated mean leptin mRNA expression in placenta was 4.65 +/- 1.83 pg mRNA/microg DNA. Leptin mRNA correlated with cord serum leptin concentrations (r = 0.3691, p = 0.045). Placental weight correlated with placental leptin mRNA (r = 0.3686, p = 0.045). The mean leptin concentration in cord serum at birth was slightly lower (3.1 +/- 1.9 ng/ml) than that found in maternal serum (3.9 +/- 1.2 ng/ml). A positive correlation was observed between cord and maternal serum leptin levels (r = 0.58, p = 0.001). The mean insulin concentration in maternal serum was not significantly higher than that in umbilical serum: 22.2 +/- 17.8 microIU/ml vs. 6.9 +/- 3.6 microIU/ml; r = 0.069, p = 0.71). Neither maternal nor umbilical insulin concentrations correlated with leptin concentration in cord or maternal peripheral serum.

Adolescent↗
PubMedDate not supplied

The-2548G/A polymorphism in the human leptin gene promoter region is associated with plasma free leptin levels; interaction with adiposity and gender in healthy subjects.

A common -2548G/A promoter variant of the human leptin gene has recently been shown to be associated with variations in circulating leptin levels but available data are still conflicting. The aim of this study was to explore potential associations between the -2548G/A polymorphism and adiposity-related variables, plasma total leptin levels, as well as soluble leptin receptor (sOB-R) levels and free leptin in a group of healthy Greek subjects. One hundred eighteen consecutively enrolled subjects [62 females, 56 males; mean age+/-SD: 17.7+/-1.8 years; body mass index (BMI) range: 15.4-35.9 kg/m2] were genotyped for the -2548G/A polymorphism and their BMI, fat free mass, % fat mass, fasting plasma total leptin and sOB-R levels were determined. The ratio leptin/sOB-R was used as an index of free leptin. No significant differences in genotype and allele frequencies of the -2548G/A polymorphism were detected between normal weight and overweight subjects, and no association was found between this polymorphism and BMI, fat mass or plasma total leptin levels. However, the -2548G/A polymorphism was found to be associated with circulating free leptin levels in a gender specific manner. More specifically, compared to carriers of the -2548G allele, female subjects with the A/A genotype had higher age and fat mass adjusted mean (+/-SE) plasma concentrations of sOB-R (32.9+/-7.2 vs. 25.6+/-3.8 ng/ml, P=0.05), and significantly lower (approx. 50%) leptin/sOB-R values (0.74+/-0.25 vs. 1.42+/-0.13, P=0.02). Furthermore, multiple regression analysis revealed that, after adjustment to fat mass, the -2548G/A genotype and gender are significantly associated with free leptin index in the entire study sample. Similar regression models revealed a significant interaction of gender and genotype when considered in addition to fat mass, or fat mass and genotype when considered in addition to gender, as predictors of free leptin index. In conclusion, the common -2548G/A promoter variant of the human leptin gene is associated with plasma free leptin levels through an interaction with adiposity and gender in healthy subjects.

Journal Article↗
PubMed2005

Leptin-directed embryo implantation: leptin regulates adhesion and outgrowth of mouse blastocysts and receptivity of endometrial epithelial cells.

Leptin is a 16-kDa multifunctional protein. Recent reports indicate that leptin is an important molecule during implantation and placentation, implicated in embryonic-maternal cross-talk and cytotrophoblast invasiveness, however, the role of leptin playing in the process of normal blastocyst implantation has not been well characterized. In the present study, the possible mechanisms of leptin playing in mouse blastocyst implantation were investigated. Leptin and receptor isoforms mRNAs were detected in whole mouse uteri during estrous cycle and peri-implantation periods. Immunofluorescent analysis further confirmed Ob-R protein was present in mouse uterus. The differential amounts of leptin and Ob-R isoforms suggested a role for leptin in such endometrial issues as blastocyst implantation. In vitro culture model for studying embryo implantation, leptin promoted mouse blastocyst adhesion and blastocyst outgrowth on fibronectin. Blastocysts treated with 300 ng/ml leptin had the greatest adhesion rate of 76.58+/-6.41% (P=0.046), and blastocysts treated with 30 ng/ml leptin had the greatest outgrowth rate of 78.64+/-8.48% (P=0.005). In isolated endometrial epithelial cells, leptin upregulated amounts of alpha v and beta 3 integrin, and promoted cell adhesion to such extracellular matrix proteins as fibronectin, laminin and type IV collagen, showing a dose- and time-dependent cell-adhesive capacity. Collectively, the information from the present study may partly account for leptin-induced mouse blatocyst implantation.

Animals↗
PubMed2006

Serum soluble leptin receptor levels and free leptin index in women with polycystic ovary syndrome: relationship to insulin resistance and androgens.

OBJECTIVE: To evaluate levels of soluble receptor (sOB-R) and free leptin in women with polycystic ovarian syndrome (PCOS) and note any relationships with insulin resistance, adiposity, and androgens. Leptin is an adipokine that circulates in a free form and bound to an sOB-R. Only free leptin is biologically active. DESIGN: Prospective, case-control study. SETTING: University-based reproductive endocrinology practice. PATIENT(S): Forty women with PCOS and severe insulin resistance and 15 body mass index (BMI)-matched ovulatory controls. INTERVENTION(S): Measurements of serum insulin, leptin, sOB-R at fasting and during a standard oral glucose tolerance test (OGTT), and measurements before and after treatment with rosiglitazone. MAIN OUTCOME MEASURE(S): Fasting glucose, insulin, leptin, sOB-R, T, and DHEAS levels in women with PCOS and controls were measured to investigate the relationship of sOB-R and the free leptin index (FLI) to insulin, adipocity, and androgens and to investigate the effect of acute hyperinsulinemia during OGTT and the effect of improvement of insulin resistance with rosiglitazone on the leptin system. FLI was calculated by dividing leptin levels by sOB-R. RESULT(S): Total leptin and FLI correlated significantly with BMI in both patients with PCOS and in controls. There was a significant negative correlation between DHEAS and sOB-R in PCOS. Leptin, sOB-R, and FLI were not significantly different in the two groups, and neither sOB-R nor FLI correlated with insulin or glucose levels. The sOB-R levels increased significantly 3 hours after oral glucose ingestion, resulting in a significant decline in FLI. CONCLUSION(S): [1] Adiposity rather than insulin resistance appears to be the main determinant of leptin levels and FLI. [2] Acute increase in insulin levels during OGTT is associated with an increase in levels of sOB-R. [3] DHEAS may play a role in leptin bioavailability by modulating sOB-R levels.

Acanthosis Nigricans↗