Disease relevance of LEPR

• CONCLUSION LEPR polymorphism may influence obesity in female survivors of childhood ALL, particularly those exposed to cranial radiation [1].
• Because radiation at a young age may affect the hypothalamus causing leptin receptor insensitivity, we hypothesized that a polymorphism in the leptin receptor (LEPR) gene, Gln223Arg, might influence susceptibility to obesity in survivors of childhood ALL [1].
• When BMI and leptin are elevated, increased blood pressure is found only with the most prevalent LEPR genotype at codons 109 and 223, whereas variants of this receptor seem to protect from hypertension [2].
• OBJECTIVE: To investigate the association between leptin levels, polymorphisms in the leptin receptor (LEPR) gene, and weight gain [3].
• Variations at the LEPR locus could be involved in the regulation of body weight [4].

Psychiatry related information on LEPR

• We tested the hypothesis that common exonic variants in the leptin (LEP) and leptin receptor (LEPR) genes modify the effects of regular physical activity on glucose homeostasis in nondiabetic whites (n = 397) and blacks (n = 143) [5].
• The aim of our study was to measure S-LEPR levels in patients with anorexia nervosa (AN) before and 6 weeks after partial refeeding [6].
• Opposite modifications in circulating leptin and soluble leptin receptor across the eating disorder spectrum [7].
• These data support a critical role for VTA Lepr in regulating feeding behavior and provide functional evidence for direct action of a peripheral metabolic signal on VTA dopamine neurons [8].
• Fluorescent analogues (DB1 and TA1) of the secondary metabolites didemnin B (DB) and tamandarin A (TA) were synthesized to investigate the potential chemical defense mechanisms of tunicates in the family Didemnidae [9].

High impact information on LEPR

• OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus [10].
• These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling [11].
• Obesity: leptin receptor weighs in [12].
• Leptin mediates its effects on food intake through the hypothalamic form of its receptor OB-R [13].
• Here, an OB-R variant was found in human hepatic cells [13].

Chemical compound and disease context of LEPR

• CONCLUSIONS: The obesity that occurs after treatment of hypothalamic tumors is not due to dysregulation of leptin secretion because it and plasma soluble leptin receptor remain regulated by factors like testosterone [14].
• The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism [15].
• We measured serum concentrations of leptin, soluble leptin receptor, insulin, ghrelin, and thyroid hormones [thyrotropin, triiodothyronine (T(3)), and thyroxine]; fat mass (FM) and fat-free mass (FFM); resting energy expenditure (REE); energy intake; and eating behavior [16].
• Short-day weight loss was accompanied by reduced POMC and leptin receptor (OB-Rb) mRNA in the arcuate nucleus but elevated cocaine- and amphetamine-regulated transcript [17].
• Furthermore, polymorphisms have been identified in the regulatory domain of the GR gene that are associated with elevated cortisol secretion; polymorphisms in dopamine and leptin receptor genes are associated with sympathetic nervous system activity, with elevated and low blood pressure, respectively [18].

Biological context of LEPR

• We have physically localized the human leptin receptor gene (LEPR) to a region at 1p31, between the anonymous microsatellite markers D1S515 and D1S198 [19].
• The assignment of the leptin receptor gene (LEPR) to pig chromosome 6q32-35 excluded LEPR as a candidate gene for a QTL on pig chromosome 4 with a major effect on fatness [20].
• The decrease in insulin was strongest in the LEP A19A homozygotes who carried the LEPR 109R allele [5].
• Therefore, 51-yr-old men (N = 284) were selected; and anthropometric, endocrine, metabolic, and hemodynamic variables were examined in relation to polymorphisms of the leptin receptor gene (LEPR), by restriction fragment length polymorphism technique [2].
• We evaluated whether leptin levels and polymorphisms in the leptin receptor (LEPR) gene were associated with energy expenditure phenotypes [21].

Anatomical context of LEPR

• Leptin plays an important role in the regulation of body fat homeostasis, and potential associations of leptin receptor gene (LEPR) polymorphisms with obesity have been suggested [22].
• To enable a detailed analysis of leptin signalling in pancreatic beta cells, LEPR point mutants with single or combined exchanges of the three intracellular tyrosines were expressed in HIT-T15 insulinoma cells [23].
• Previous studies demonstrated that lymphocyte development is impaired in leptin receptor (Ob-R)-deficient db/db mice [24].
• Using PC12 cells as an in vitro model system, we have identified a series of transcripts induced through activation of the leptin receptor [25].
• Leptin-receptor gene transfer into the arcuate nucleus of female Fatty zucker rats using recombinant adeno-associated viral vectors stimulates the hypothalamo-pituitary-gonadal axis [26].

Associations of LEPR with chemical compounds

• Variations in the LEP and LEPR genes are associated with the magnitude of the effects of regular exercise on glucose homeostasis in nondiabetic individuals [5].
• Serum bone-specific alkaline phosphatase (S-BAP) was associated with LEPR genotypes (P = 0.05) and urinary C-terminal telopeptides of type I collagen (U-CTX) were associated with leptin levels (P = 0.03), independently from age, fat mass and free estradiol [27].
• Other significant linkages observed were between LEP and waist/hip ratio (P = 0.010), total cholesterol (P = 0.030), and HDL cholesterol (P = 0.026) and between LEPR and fasting blood glucose (P = 0.018) and diastolic blood pressure (P = 0.003) [28].
• Furthermore, the sequence motifs surrounding the three tyrosine residues are conserved in LEPR from mammals, birds and in a LEPR-like cytokine receptor from pufferfish [23].
• METHODS: Anthropometric variables, serum leptin, S-LEPR, insulin, cortisol and TNF-alpha were measured in 15 AN patients before and after partial refeeding and 15 healthy control women [6].

Physical interactions of LEPR

• Phosphorylated JAK2 was primarily bound to a short 106kDa leptin receptor isoform and to a lesser extent to a 210kDa molecule [29].
• Here, we show that CIS (cytokine-inducible SH2 protein) and SOCS2 can also interact with the leptin receptor [30].
• Apolipoprotein D interacts with the long-form leptin receptor: a hypothalamic function in the control of energy homeostasis [31].
• 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 [32].

Enzymatic interactions of LEPR

• Only the leptin receptor-derived peptide corresponding to tyrosine 974 was dephosphorylated by recombinant purified SHP-2 [33].

Co-localisations of LEPR

• Leptin receptor mRNA expression was colocalized with NPY mRNA-containing cell bodies in those regions [34].

Regulatory relationships of LEPR

• The TGF-beta synthesis induced by leptin was amplified by glucose through increased leptin receptor expression [35].
• Both leptin receptor dimerization and the leptin-induced energy transfer were Janus kinase 2-independent [36].
• The results suggest that leptin can act directly on L6 muscle cellsvia a short leptin receptor isoform to acutely stimulate basal (but not insulin-stimulated) glucose uptake via a PI3K-dependent pathway [37].
• These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and alpha-melanocyte stimulating hormone/MC4-R in human energy homeostasis [38].
• Estrogen receptor alpha gene polymorphisms Pvu II and Xba I influence association between leptin receptor gene polymorphism (Gln223Arg) and bone mineral density in young men [39].

Other interactions of LEPR

• While multiple alternatively spliced LR isoforms exist, only the long (LRb) form associates with the Janus kinase 2 (Jak2) tyrosine kinase to mediate intracellular signaling [40].
• It has been demonstrated that the SH2 domain-containing tyrosine phosphatase 2 (SHP-2) negatively regulates STAT3-mediated transcriptional activation through long form leptin receptor (OBRb) [41].
• CONCLUSION: Only variations in the ADRB2 gene and LEPR gene, may contribute to susceptibility to weight gain [42].
• Moreover, the presence of the LEP (-2548) A allele showed a significant association with decreased disease-free survival in breast carcinoma patients, and the presence of the LEPR 223R allele showed a significant association with decreased overall survival [43].
• The structure of leptin receptor (OB-R) is highly homologous to that of gp130, the common signal transducing receptor component for the interleukin-6 family of cytokines [44].

Analytical, diagnostic and therapeutic context of LEPR

• There was no difference in genotypic frequency of the LEPR Q223R polymorphism between the extreme obese and control groups [45].
• RESULTS: There was a strong association with significantly elevated serum leptin levels, high body mass index, and higher frequency of LEPR longer alleles in patients with prostate cancer than in control subjects [46].
• DESIGN: This was a cross-sectional study to investigate the impact of the Q223R polymorphism of the LEPR gene on insulin sensitivity [47].
• CONCLUSIONS: In women, genetic variations at the LEPR gene level are associated with overweight and fat mass in a cross sectional study and with response to low calorie diet in an intervention study [4].
• We assessed placental gene expression of leptin, LEPR A-D and ADIPOR1 and 2 by real time PCR using mRNA from maternal and fetal biopsies [48].

References