Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Evidence that leptin plays an important role in reproductive function is accumulating rapidly. We hypothesized that low leptin synthesis is associated with amenorrhea. We therefore determined serum leptin levels in 43 underweight female students, who were screened for lifetime occurrence of amenorrhea. We assessed the predictive value of leptin, body mass index (BMI), fat mass and percent body fat, respectively, for lifetime occurrence of amenorrea. Factors predicting amenorrhea were tested for their capability to predict current amenorrhea in a second cohort of 63 inpatients with anorexia nervosa (AN) or bulimia nervosa (BN). Furthermore, the relationships between serum leptin levels and of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol and progesterone, respectively, were evaluated. Only leptin predicted lifetime occurrence of amenorrhea in the student cohort. The critical leptin level was in the range of 1.85 micrograms L-1. This level served to largely separate anorectic from bulimic patients. In patients with AN mean serum log10 leptin levels over the first 4 weeks of inpatient treatment were correlated with mean FSH, LH and estradiol levels, respectively. Evidently, a critical leptin level is needed to maintain menstruation. In affluent populations eating disorders are likely to be a major cause of a low leptin synthesis.
Mol Psychiatry 1997 Jul
PMID:Low leptin levels predict amenorrhea in underweight and eating disordered females. 924 58

Psychometrically defined restrained eaters consume fewer calories, take fewer meals, show higher preference for low calorie foods, have lower energy expenditure and a higher rate of ovarial dysfunction than unrestrained eaters. We hypothesized that restrained eaters as assessed with the factor cognitive restraint of the Three-Factor Eating Questionnaire have low leptin levels; therefore, we measured serum leptin levels in 136 underweight students and 49 overweight students, who had filled out the Three-Factor Eating Questionnaire. Body mass indexes, fat mass and percent body fat were determined. Spearman correlations revealed that log10 leptin levels of only the 67 underweight females were negatively correlated with cognitive restraint scores (r = -0.5; nominal P-value < 0.001). The restraint score explained 22% of the total variance of leptin levels in underweight females; in combination with percent body fat, 52% of the variance was accounted for. To our knowledge this is the first study to identify a relationship between a score on a psychometric scale and leptin levels. Restrained eating has a biological correlate in underweight females.
Mol Psychiatry 1997 Sep
PMID:Restrained eating is associated with low leptin levels in underweight females. 932 39

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

The leptin receptor is a member of the class I cytokine receptor family and is involved in the control of appetite and body weight. The predicted amino acid sequence of the extracellular region of the cloned leptin receptor differs from that of many other cytokine receptors in that it contains two homologous segments representing potential ligand binding sites. After the analysis of various deletion and substitution mutants of the leptin receptor, we found that the first potential binding motif is not required for leptin binding and receptor activation, whereas modification of the second potential binding motif can lead to inactive receptor mutants. Further deletion analysis generated a minimal binding domain that retains high affinity leptin binding. The leptin binding domain thus has been localized to residues 323-640, which contain the second segment of cytokine receptor domain/fibronectin type 3 domain (residues 428-635). Coexpression of the active isoform of leptin receptor (OB-Rb) with an inactive mutant lacking high affinity leptin binding site led to suppression of the activity mediated by OB-Rb, suggesting that the leptin receptor may exist as a multimeric complex in the absence of leptin.
Mol Pharmacol 1998 Feb
PMID:Localization of leptin binding domain in the leptin receptor. 946 81

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

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor implicated in adipocyte differentiation, lipid and glucose metabolism. A polymorphism corresponding to a silent C-->T substitution was detected in exon 6 of the PPAR gamma gene. We analysed the relationships between this genetic polymorphism and various markers of the obesity phenotype (body weight, body mass index, waist:hip ratio and plasma leptin levels) in a representative sample of 820 men and women living in northern France. The frequencies of the C and T alleles were 0.860 and 0.140 respectively. In the whole sample no association of the polymorphism with the markers tested was observed but a statistically significant interaction ( P < 0.03) existed between this polymorphism and body mass index for plasma leptin levels. This result suggested that the impact of the PPAR gamma gene polymorphism on plasma leptin levels differed according to the BMI of the subjects. Indeed, obese subjects (BMI >30 kg/m2) bearing at least one T allele ( CT + TT ) had higher plasma leptin levels than subjects who did not (35.0 +/- 17.4 ng/ml versus 28.3 +/- 14.8 ng/ml respectively; P < 0.001). This effect existed in both genders, despite the higher plasma leptin levels observed in women. The plasma leptin level increase was not associated with elevation of body mass index, even though these two variables were highly correlated. Thus for a given leptin level the BMI was relatively lower in obese subjects carrying at least one T allele than in obese CC homozygotes. Our results show that in obese subjects variability within the PPAR gamma gene locus is associated with circulating leptin levels and may modify the relationship between leptin levels and adipose tissue mass.
Hum Mol Genet 1998 Mar
PMID:A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese humans. 946 1

Weight gain is a major side-effect of treatment with clozapine. In order to investigate the influence of the atypical neuroleptic clozapine on leptin secretion, serum leptin levels were measured in 12 patients at baseline and for a 10-week period after initiation of treatment. Serum clozapine levels and levels of its metabolites were simultaneously assessed. Alterations of body weight and body composition were determined. During the 10-week observation period leptin levels differed significantly from the levels determined at baseline (P < 0.0001). During the first 2 weeks of treatment serum leptin levels at least doubled in eight of the 12 patients. The maximal relative increase over baseline was 536%. Low doses of clozapine were sufficient to induce this effect. Within a 10-week period mean body weight, mean body mass index, mean fat mass and mean lean body mass all increased. Based on the results we suggest that in predisposed individuals clozapine induces an increased appetite; overeating and weight gain can ensue, which in turn underlie elevated leptin secretion.
Mol Psychiatry 1998 Jan
PMID:Serum leptin levels increase rapidly after initiation of clozapine therapy. 949 17

Approximately one-third of Americans are classified as obese. There has long been an interest in drug therapies for obesity. Interest in obesity research and in drug interventions in obesity has greatly increased since the discovery of a protein named leptin, one of apparently many competing biological signals in energy metabolism. The complexity of the obesity problem demands new non-invasive and non-destructive methods for monitoring lipid metabolism and energy expenditure to study the competing biological signals and their effects. A new computer algorithm for spectrometric imaging of living subjects is used to remove artifacts arising from subject motion from spectra and images. The algorithm is sufficiently simple to be implemented easily in hardware for real-time video processing. Because the algorithm can be applied to images, thermogenesis and lipid metabolism in interscapular adipose tissue can be observed directly in unrestrained and unanesthetized subjects using an InSb focal plane array video camera. The accuracy and precision of temperature and spectral measurements are established using laboratory references and prototype drugs in test subjects.
Cell Mol Biol (Noisy-le-grand) 1998 Feb
PMID:Near-IR and IR imaging in lipid metabolism and obesity. 955 37

Leptin affects food intake and body weight by actions on the hypothalamus. Although leptin resistance is common in obesity, mechanisms have not been identified. We examined the effect of leptin on expression of the suppressors-of-cytokine-signaling (SOCS) family of proteins. Peripheral leptin administration to ob/ob, but not db/db mice, rapidly induced SOCS-3 mRNA in hypothalamus, but had no effect on CIS, SOCS-1, or SOCS-2. A leptin-dependent increase of SOCS-3 mRNA was seen in areas of hypothalamus expressing high levels of the leptin receptor long form. In mammalian cell lines, SOCS-3, but not CIS or SOCS-2, blocked leptin-induced signal transduction. Expression of SOCS-3 mRNA in the arcuate and dorsomedial hypothalamic nuclei is increased in Ay/a mice, a model of leptin-resistant murine obesity. In conclusion, SOCS-3 is a leptin-inducible inhibitor of leptin signaling, and a potential mediator of leptin resistance in obesity.
Mol Cell 1998 Mar
PMID:Identification of SOCS-3 as a potential mediator of central leptin resistance. 966 Sep 46


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