Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of leptin, the product of the obese gene, on synaptic transmission in the arcuate nucleus in rat hypothalamic slices. Both leptin and neuropeptide Y (NPY) reduced the evoked glutamatergic excitatory postsynaptic current in the arcuate nucleus. NPY also depressed the GABAergic inhibitory postsynaptic current, although leptin had no effect. Leptin also decreased the input resistance of arcuate neurons, and this was accompanied by the activation of an outward current at depolarized potentials. Leptin modulated Ca2+ signals in acutely isolated arcuate neurons. In some cells, the intracellular calcium concentration rise produced by 50 mM K+ was decreased, whereas in others it was increased. However, leptin produced no effects on synaptic transmission and little or no effect on Ca2+ signaling in the hypothalamus of Zucker fatty rats that contain mutated leptin receptors. On the other hand, NPY exhibited synaptic modulatory effects in Zucker lean and fatty rats. These data suggest that leptin can produce rapid synaptic modulatory effects in the arcuate nucleus, which may contribute to its effects on food intake.
Mol Pharmacol 1996 Aug
PMID:Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus. 870 Jan 28

Leptin, the product of the ob gene, is an adipose tissue-derived hormone that appears to regulate both satiety and thermogenesis. In the present report, we have reexamined the relationship between circulating leptin concentration and body fat in humans using a more valid measure of adiposity (hydrodensitometry) and have extended these observations to examine the influence of regional body fat distribution and cardiorespiratory fitness. Fasting serum leptin concentration was 6.9 +/- 0.3 ng.ml-1 in males (N = 333) and 15.2 +/- 1.3 ng.ml-1 in females (N = 63). Interestingly, total fat mass did not differ between groups (males 20.5 +/- 0.5 kg; females 20.4 +/- 1.5 kg), suggesting that females have higher leptin levels per unit fat mass. In a multiple regression model, fat mass was the best predictor of serum leptin concentration in males, accounting for 51% of the variance in leptin concentration. In females, percentage body fat was the best predictor of leptin, accounting for 49% of the variance. In both groups, the relationship between leptin and adiposity remained significant after adjusting for age, maximal treadmill time, waist circumference, and fasting insulin concentration. These observations support previous conclusions that circulating leptin is primarily a function of adiposity and demonstrate for the first time that this relationship is independent of fat distribution or cardiorespiratory fitness. The data also suggest that there is a gender dichotomy in the relationship between leptin and body fat mass in humans.
Biochem Mol Med 1996 Oct
PMID:Gender differences in serum leptin levels in humans. 890 86

Leptin, the product of the ob gene, is a hormone secreted by fat cells which is primarily involved in the regulation of body weight. We have generated a leptin immunoadhesin (leptin-IgG) which was more potent than leptin alone at reducing body weight and food intake when injected into ob/ob mice. This molecule was used to identify high affinity binding sites on human embryonic 293 kidney cells and subsequently to isolate a cDNA encoding the leptin receptor from this cell line by expression cloning. This receptor corresponds to the short form of the recently isolated leptin receptor. Analysis of the expression pattern of the two forms of receptor by Northern blot, in situ hybridization and quantitative PCR showed that the receptor is expressed in most tissues but that the long form is prevalent in the hypothalamus.
J Mol Endocrinol 1997 Feb
PMID:Cloning and characterization of a human leptin receptor using a biologically active leptin immunoadhesin. 906 9

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Serum leptin concentrations increase in correlation with the percentage of body fat, but besides that little is known about the physiological actions of leptin in humans. In order to understand the role of leptin in severe malnutrition, in the present work 10 patients recently diagnosed with anorexia nervosa were studied both before and 2 months later, after partial weight recovery, and were compared with 18 normal-weight women as controls. Leptin was measured by a newly developed radioimmunoassay and both IGF-I and IGFBP-3 were measured by commercial radioimmunoassays. The mean (+/-SE) serum leptin concentrations (in microgram/liter) were 18.1 +/- 2.0 in control women with BMI of 21.1 +/- 0.3, significantly higher (P < 0.01) than that in the anorexia nervosa patients at diagnosis (2.2 +/- 0.1, BMI 15.3 +/- 0.6). These differences were also observed in IGF-I values (microgram/liter) that were 228.0 +/- 14.6 in controls and 157.4 +/- 28.7 in anorexia nervosa patients (P < 0.02). No differences were observed in IGF-BP3. After treatment, patients with anorexia nervosa experienced an increase in BMI (17.1 +/- 0.5, P < 0.0001 vs before) although they were still underweight. The partial recovery in weight led to a complete normalization of IGF-I levels (214.0 +/- 21.0 micrograms/liter) and to an enhancement in leptin levels (3.3 +/- 0.5 micrograms/liter; P < 0.03 vs before treatment), though still lower than those in normal-weight women (P < 0.05). Individually analyzed, a large dispersion was observed in control subjects, with leptin levels ranging from 5.5 to 38.7 micrograms/liter, while in all anorexia nervosa patients leptin levels were under 3 micrograms/liter. A treatment-induced increase in body weight led to an increase in leptin levels in 7 out of the 10 anorexia nervosa patients studied and the 3 patients with no increase in leptin were all initially under the 14.5 BMI. In conclusion, leptin levels are severely reduced in anorexia nervosa patients with severe malnutrition, and a significant rise occurred after partial weight recovery. There seems to be a level of BMI below which leptin levels do not drop further but also do not increase despite weight gain. While IGF-I reflects the energy intake of the previous few weeks, the serum leptin concentration reflects the true status of the adipose stores, a fact that has useful clinical implications.
Biochem Mol Med 1997 Apr
PMID:Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery. 916 91

Leptin, a hormone secreted by adipocytes, plays a pivotal role in the control of body weight. Rodents with mutations in the leptin receptor gene develop morbid obesity. It is possible, therefore, that leptin receptor gene mutations contribute to human obesity. To test this possibility, we determined the entire coding sequence of the human leptin receptor cDNA from peripheral blood lymphocytes of 22 morbidly obese patients with body-mass index (BMI) between 35.1 and 60.9 kg/m2. We identified five common DNA sequence variants distributed throughout the coding sequence at codons 109, 223, 343, 656 and 1019, one rare silent mutation at codon 986 and one novel alternatively spliced form of transcript. None of the five common variants, including the three that predict amino acid changes, are null mutations causing morbid obesity, because homozygotes for the variant sequences were also found in lean subjects. Furthermore, the frequency of each variant allele and the distribution of genotypes and haplotypes were similar in 190 obese (BMI >28 kg/m2) and 132 lean (BMI <22 kg/m2) white British males selected from a population-based epidemiological survey. In these subjects, there was no evidence for a significant effect of the common variants on obesity or obesity-related phenotypes. These results suggest that mutations in the leptin receptor gene are not a common cause of human obesity.
Hum Mol Genet 1997 Jun
PMID:Leptin receptor gene variation and obesity: lack of association in a white British male population. 917 32

The expression of leptin and its receptors was examined by reverse transcriptase-polymerase chain reaction and immunofluorescence in granulosa and cumulus cells of pre-ovulatory follicles and in meiotically mature oocytes obtained from women undergoing in-vitro fertilization. Leptin concentrations were measured in newly aspirated follicular fluids and in maternal serum before and after the administration of an ovulatory dose of human chorionic gonadotrophin. The findings demonstrate leptin expression at the mRNA and protein levels by granulosa and cumulus cells, and the presence of leptin in mature human oocytes. While an association between follicular leptin concentration and embryo development was not observed, a post-ovulatory increase in serum leptin concentration was associated with implantation potential. The results are discussed with respect to possible roles of leptin in early human development.
Mol Hum Reprod 1997 Jun
PMID:The expression of leptin and its receptors in pre-ovulatory human follicles. 923 34

Leptin plays an important role in the control of food intake and energy metabolism by interacting with its receptor (OB-R) in the brain. Several alternatively spliced isoforms of OB-R have been identified. To study the expression patterns and the potential biological function of these OB-Rs in the brain, the distribution of mRNA encoding OB-R isoforms was examined by in situ hybridization. In agreement with previous studies, strong signals for OB-R mRNA were detected in the hypothalamus, thalamus and choroid plexus. In addition, intense signals were observed in several other brain areas including piriform cortex, granule cell layer of the cerebellum and substantia nigra. With isoform-specific probes, a differential expression pattern of OB-Rs was revealed: OB-Ra and OB-Rb, but not OB-Rc and OB-Rf, are abundantly expressed in the hypothalamus, whereas OB-Ra, OB-Rc and OB-Rf, but not OB-Rb, are significantly expressed in the choroid plexus. The preferential expression of OB-Rb in the hypothalamus is in support of its role in mediating the satiety effect of leptin. The co-expression of OB-Ra with OB-Rb in the hypothalamus may suggest a possible interaction between the two isoforms. Finally, the detection of OB-R mRNA in a number of other brain regions may indicate the involvement of leptin in additional as yet undefined physiological functions.
Mol Cell Endocrinol 1997 Sep 30
PMID:Differential expression of mRNA for leptin receptor isoforms in the rat brain. 935 67

Leptin is a peptide secreted by adipose tissue, which regulates satiety, metabolic rate, and thermogenesis. Since corticosteroids regulate the mass of adipose tissue, and leptin synthesis and secretion by adipocytes, we have examined whether leptin in turn is able to directly affect adrenal steroid secretion. Recombinant murine leptin was found to increase basal aldosterone and corticosterone production by dispersed rat zona glomerulosa and zona fasciculata-reticularis cells, respectively. In contrast, leptin did not affect maximally ACTH (10(-9) M)-stimulated steroid secretion. These findings, coupled with the recent observation that leptin is able to stimulate hypothalamo-pituitary CRH-ACTH system, may indicate a role for leptin as a regulator of adrenocortical function in the rat.
J Steroid Biochem Mol Biol
PMID:Effects of recombinant murine leptin on steroid secretion of dispersed rat adrenocortical cells. 944 13

Unique protein domains, concentration gradients, and asymmetric protein distributions or polarities are principle forces establishing the identity and fate of individual cells during early development in lower vertebrates and invertebrates. Here, we present evidence that these same forces exist during mammalian development in the form of two representative regulatory proteins, leptin and STAT3. Leptin, the 16 kDa cytokine product of the obese gene (ob) is involved in the activation of STAT3, a member of the signal transducer and activation of transcription family of proteins. We examined the temporal and spatial aspects of leptin and STAT3 immunofluorescence in mouse and human oocytes and preimplantation stage embryos. The findings demonstrate that both leptin and STAT3 are polarized in the oocyte and, as a consequence of their location and the position of the cleavage planes with respect to these protein domains: (i) differences in allocation of these proteins between blastomeres occur at the first cell division such that by the 8-cell stage; (ii) unique cellular domains consisting of leptin/STAT3 rich and leptin/STAT3 poor populations of cells are generated. By the morula stage, a cell-borne concentration gradient of these proteins extending along the surface of the embryo is observed. A potential role of these proteins in early development is indicated at the morula stage where the 'inner' cells consist of blastomeres that contain little, if any, leptin/STAT3 while 'outer' cells contain both leptin/STAT3 rich and poor cells. This pattern persists through the hatched blastocyst stage with little, if any, leptin/STAT3 detected in the inner cell mass and populations of leptin/STAT3 rich and poor cells forming the trophoblast. We have examined oocytes from mutant C57BL/6J ob/ob mice which are both obese and infertile (although fertility can be restored by the exogenous provision of leptin) and have found STAT3 and the mutant (truncated) leptin protein to be present and polarized, suggesting the possibility that the truncated leptin protein may still contain operational domains which are functional during oocyte development and early embryogenesis. Furthermore, analysis of leptin and STAT3 in intact ovarian follicles suggests that these proteins may be maternally derived and in particular, that a subpopulation of follicle cells may be partly responsible for the establishment of their polarized distribution in the oocyte. The results are discussed with respect to the proposition that leptin and STAT3 have critical roles in early mammalian development, and may be involved in the determination of the animal pole of the oocyte and in the establishment of the inner cell mass and trophoblast in the preimplantation stage embryo.
Mol Hum Reprod 1997 Dec
PMID:Oocyte influences on early development: the regulatory proteins leptin and STAT3 are polarized in mouse and human oocytes and differentially distributed within the cells of the preimplantation stage embryo. 946 52

The thiazolidinedione BRL 49653 and the thiazolidinedione derivative CGP 52608 are lead compounds of two pharmacologically different classes of compounds. BRL 49653 is a high affinity ligand of peroxisome proliferator-activated receptor gamma (PPARgamma) and a prototype of novel antidiabetic agents, whereas CGP 52608 activates retinoic acid receptor-related orphan receptor alpha (RORA) and exhibits potent antiarthritic activity. Both receptors belong to the superfamily of nuclear receptors and are structurally related transcription factors. We tested BRL 49653 and CGP 52608 for receptor specificity on PPARgamma, RORA, and retinoic acid receptor alpha, a closely related receptor to RORA, and compared their pharmacological properties in in vitro and in vivo models in which these compounds have shown typical effects. BRL 49653 specifically induced PPARgamma-mediated gene activation, whereas CGP 52608 specifically activated RORA in transiently transfected cells. Both compounds were active in nanomolar concentrations. Leptin production in differentiated adipocytes was inhibited by nanomolar concentrations of BRL 49653 but not by CGP 52608. BRL 49653 antagonized weight loss, elevated blood glucose levels, and elevated plasma triglyceride levels in an in vivo model of glucocorticoid-induced insulin resistance in rats, whereas CGP 52608 exhibited steroid-like effects on triglyceride levels and body weight in this model. In contrast, potent antiarthritic activity in rat adjuvant arthritis was shown for CGP 52608, whereas BRL 49653 was nearly inactive. Our results support the concept that transcriptional control mechanisms via the nuclear receptors PPARgamma and RORA are responsible at least in part for the different pharmacological properties of BRL 49653 and CGP 52608. Both compounds are prototypes of interesting novel therapeutic agents for the treatment of non-insulin-dependent diabetes mellitus and rheumatoid arthritis.
Mol Pharmacol 1998 Jun
PMID:Specific activation of the nuclear receptors PPARgamma and RORA by the antidiabetic thiazolidinedione BRL 49653 and the antiarthritic thiazolidinedione derivative CGP 52608. 961 18


1 2 3 4 5 6 7 8 9 10 Next >>