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

The antiobesity effects of leptin are mediated by the obese receptor (OB-R), a member of the cytokine receptor superfamily. Several isoforms of OB-R that differ in the length of the cytoplasmic domain have been described. An isoform with a long cytoplasmic domain of 302 amino acids, termed OB-Rb, contains the conserved box 1 and box 2 motifs and is likely to be responsible for leptin-induced signaling. A point mutation in the OB-R gene of diabetes (db) mice generates a new splice donor that interferes with the correct splicing of the OB-Rb mRNA and is predicted to cause absence of the OB-Rb protein in db/db mice. Here we examined the signaling potential of the long isoform, OB-Rb, and of a short isoform, OB-Ra, in BaF3 cells, a factor-dependent hematopoietic cell line. The long isoform was able to generate a proliferative signal and upon leptin binding, activated janus kinase 2 (Jak2). Consistently, antibodies directed against the extracellular domain of OB-R coprecipitated Jak2. The short isoform, OB-Ra, was inactive in both proliferation and Jak activation. These results provide further support for the long isoform, OB-Rb, being the principal mediator of the effects of leptin and help to explain why db/db mice are resistant to leptin, despite the presence of the short OB-R isoforms.
Mol Endocrinol 1997 Apr
PMID:The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. 909 91

The three-dimensional fold of a protein is described by the organization of its secondary structure elements in 3D space, i.e. its "topology". We find that the protein topology can be recognized from the ID sequence of secondary structure states of the residues alone. Automated recognition is facilitated by use of hidden Markov models (HMMs) to represent topology families of proteins. Such models can be trained on the experimentally observed secondary structure sequences of family members using well established algorithms. Here, we model various topology groups in the alpha class of proteins and identify, from a large database, those proteins having the topology described by each model. The correct topology family for protein secondary structure sequences could be recognized 12 out of 14 times. When the observed secondary structure sequences are replaced with predicted sequences recognition is still achievable 8 out of 14 times. The success rate for observed sequences indicates that our approach will become increasingly useful as the accuracy of secondary prediction algorithms is improved. Our study indicates that the HMMs are useful for protein topology recognition even when no detectable primary amino acid sequence similarity is present. To illustrate the potential utility of our method, protein topology recognition is attempted on leptin, the obese gene product, and the human interleukin-6 sequence, for which fold predictions have been previously published.
J Mol Biol 1997 Mar 28
PMID:Protein topology recognition from secondary structure sequences: application of the hidden Markov models to the alpha class proteins. 909 37

Dominant mutations at the agouti locus induce several phenotypic changes in the mouse including yellow pigmentation (phaeomelanization) of the coat and adult-onset obesity. Nonpigmentary phenotypic changes associated with the agouti locus are due to ectopic expression of the agouti-signaling protein (ASP), and the pheomelanizing effects on coat color are due to ASP antagonism of alpha-MSH binding to the melanocyte MC1 receptor. Recently it has been demonstrated that pharmacological antagonism of hypothalamic melanocortin receptors or genetic deletion of the melanocortin 4 receptor (MC4-R) recapitulates aspects of the agouti obesity syndrome, thus establishing that chronic disruption of central melanocortinergic signaling is the cause of agouti-induced obesity. To learn more about potential downstream effectors involved in these melanocortinergic obesity syndromes, we have examined expression of the orexigenic peptides galanin and neuropeptide Y (NPY), as well as the anorexigenic POMC in lethal yellow (A(y)), MC4-R knockout (MC4-RKO), and leptin-deficient (ob/ob) mice. No significant changes in galanin or POMC gene expression were seen in any of the obese models. In situ hybridizations using an antisense NPY probe demonstrated that in obese A(y) mice, arcuate nucleus NPY mRNA levels were equivalent to that of their C57BL/6J littermates. However, NPY was expressed at high levels in a new site, the dorsal medial hypothalamic nucleus (DMH). Expression of NPY in the DMH was also seen in obese MC4-RKO homozygous (-/-) mice, but not in lean heterozygous (+/-) or wild type (+/+) control mice. This identifies the DMH as a brain region that is functionally altered by the disruption of melanocortinergic signaling and suggests that this nucleus, possibly via elevated NPY expression, may have an etiological role in the melanocortinergic obesity syndrome.
Mol Endocrinol 1997 May
PMID:Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. 913 6

The cloning of human and mouse cDNAs from brain that encode high affinity leptin receptors was recently reported. We have physically localized the human leptin receptor gene (LEPR) to a region at 1p31, between the anonymous microsatellite markers D1S515 and D1S198. The genomic structure of the human leptin receptor gene, corresponding to the published human brain cDNA sequence, spans over 70 kb and includes 20 exons. Since the leptin receptor gene is a candidate gene for obesity, and because of its proximity to D1S198, a marker previously linked to insulin secretion, the LEPR gene was sequenced in 20 non-diabetic Pima Indians chosen for extremes in percent body fat and in their acute insulin response to intravenous glucose. Seven polymorphic sites were identified. Two of these polymorphisms, Lys109Arg and Gln223Arg, are amino acid substitutions in the extracellular domain of the leptin receptor, one polymorphism is a silent substitution, and four occur in non-coding regions of the leptin receptor. Four of these sites are in linkage disequilibrium with one another. Nucleotides at three noncoding polymorphic sites were found exclusively in obese Pima Indians. This demonstrates an association between variation at the leptin receptor gene and obesity in humans.
Hum Mol Genet 1997 May
PMID:Structure and sequence variation at the human leptin receptor gene in lean and obese Pima Indians. 915 41

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

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

Circulating leptin concentrations are known to be low in acute anorexia nervosa (AN), which is characterized by low weight, amenorrhea and specific psychopathological features. In this study plasma leptin concentrations were determined during inpatient treatment of 23 adolescent females with AN using a sensitive radioimmunoassay (RIA) and set into relationship to leptin levels of females matched for age, body mass index (BMI; kg m-2) and/or percent body fat. At referral patients had leptin concentrations well below the female controls. Weight gains led to steep increases of leptin levels which peaked at values well in excess of those observed in controls matched for BMI. In patients who reached the final treatment stage and who were followed-up after discharge, levels subsequently fluctuated and finally dropped into or below the control range. The low leptin levels at referral are likely to be involved in the pathogenesis of amenorrhea and the reduced metabolic state of acutely ill patients. Peak leptin levels reached after weight gain are possibly the cause of increased energy expenditure during this stage of the disorder.
Mol Psychiatry 1997 Jul
PMID:Leptin levels in patients with anorexia nervosa are reduced in the acute stage and elevated upon short-term weight restoration. 924 58


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