Exonic and Intronic Sequence Variation in the Human Leptin Receptor Gene (<i>LEPR</i>)

Chung, Wendy K.; Power-Kehoe, Loraine; Chua, Melvin L.K.; Chu, Florence C. H.; Aronne, Louis J.; Huma, Zilla; Sothern, Melinda; Udall, John N.; Kahle, B; Leibel, Rudolph L.

doi:10.2337/diab.46.9.1509

Cited by 98 publications

(75 citation statements)

References 17 publications

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“…The Zucker rat mutation in the leptin receptor (Lepr fa ) is located in human exon 7, closed to exon 6 and also in the ®rst C domain of LEPR (Figure 1). 31 Lepr fa involves the substitution of a Q residue at position 269 (270 in human) for a P residue which affects the functionality of the receptor. 13,14,18 The Q223R polymorphism has been shown to be linked to FM and FFM in the QFS, and to be associated with FFM in the QFS or the BMI in a British population.…”

Section: Discussionmentioning

confidence: 99%

“…The three RFLPs and the two microsatellite markers used in the study, have been described elsewhere. 30,31 Polymerase chain reaction (PCR) was performed using 100 ng genomic DNA, 30 pmoles of each primer, 250 uM dNTP's and 1 U Taq polymerase in PCR buffer (Boehringer Mannheim, Mannheim, Germany) with 1.5 mM MgCl 2 for a ®nal volume of 20 ul. PCR cycles consisted of 30 ± 35 cycles at 94 C for 30 s, annealing at 55 C for 30 s and extension at 72 C for 30 s (Perkin Elmer 9600).…”

Section: Molecular Analysismentioning

confidence: 99%

“…We used restriction fragment length polymorphisms (RFLPs) detecting amino acid substitutions in exon 4, 6, and 14, 31 and microsatellite repeats located in intron 3 and 16 30 of the LEPR gene (underlined in Figure 1), to test for linkage and association with adiposity-related and body composition variables in the QFS. Linkages were observed with four of the ®ve phenotypes considered, and positive associations were detected with body composition phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Québec Family Study

et al. 1999

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OBJECTIVE: To investigate linkage and association between the leptin receptor (LEPR) gene and body composition variables in the Que Â bec Family Study (QFS). DESIGN: Single-point linkage analysis using families, and covariance and chi-square analyses using normal weight and obese unrelated subjects from QFS. SUBJECTS: 169 nuclear families were used for linkage study. 308 unrelated subjects (146 males; 162 females) from these families were used for chi-square testing of genotype and allele distributions between subjects with body mass index (BMI)`27 kgam 2 (n 167) and those with BMI ! 27 kgam 2 (n 141), and for a series of covariance analyses using age, plus height for fat mass (FM) and fat free mass (FFM), as covariates. A corrected P value (P*) for multiple tests has been calculated according to P* 1-(1-P) number of phenotypes . MEASUREMENTS: Variables were BMI (in kgam 2 ), sum of six skinfolds (SF6 in mm), FM (in kg), percent body fat (%FAT) and FFM (in kg). Polymerase chain react restricted fragment length polymorphisms PCR-RFLP) was used to identi®ed a K109R substitution in exon 4, a Q223R in exon 6, a K656N in exon 14 and an automatic DNA sequencer for a CA microsatellite repeat in intron 3, and heteroduplex pattern on non-denaturing gel for a CTTT repeat in intron 16. RESULTS: Good evidence of linkage was observed for Q223R with FM (P 0.005; P* 0.02), and for the CTTT repeat with FFM (P 0.007; P* 0.03). Weaker linkages (0.02 P 0.05) were also observed between Q223R and BMI, SF6 and FFM, between the CA repeat and BMI, SF6 and FM, and between the CTTT repeat and FM. Moreover, FFM values were found to be different among genotypes for the CTTT repeat polymorphism with heavier females, carriers of the 123* allele at the CTTT repeat, showing 4 kg less of FFM (43.6 AE 1.0, n 21 vs 47.7 AE 0.8, n 30; P 0.005; P* 0.02) than non-carriers. Also, at the Q223R polymorphism, in lower BMI males, carriers of the Q223 allele were 4 kg lighter in FFM (53.4 AE 0.6, n 47 vs 56.6 AE 0.9, n 18; P 0.005; P* 0.02) than non-carriers. No signi®cant differences were observed between lower and higher BMI subjects in genotype and allele frequency distributions for any of the polymorphisms. CONCLUSIONS: These results indicate that the LEPR gene is involved in the regulation of the body composition in human particularly of FFM in the QFS.

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Section: Discussionmentioning

confidence: 99%

Section: Molecular Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Québec Family Study

et al. 1999

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“…For each subject, the allelic structure of the leptin receptor (long form-Rb) was determined at those locations within exons 2, 4, and 12 known to be associated, respectively, with amino acid polymorphisms Lys109Arg, Gln223Arg, and Lys656Asn (12). These determinations were made by direct sequencing of genomic DNA extracted from whole blood in the laboratory of Dr. Rudolph Leibel at the College of Physicians and Surgeons, Columbia University.…”

Section: Drug Placebomentioning

confidence: 99%

The Effects of Leptin Administration in Non‐obese Human Subjects

Mackintosh

Hirsch

2001

Obesity Research

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MACKINTOSH, RONALD M. AND JULES HIRSCH.The effects of leptin administration in non-obese human subjects. Obes Res. 2001;9:462-469. Objective: Body fatness is partly under hypothalamic control with effector limbs that include the endocrine system and the autonomic nervous system (ANS). In previous studies of both obese and never-obese subjects, we have shown that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the effect of leptin, independent of weight change, on the ANS. Research Methods and Procedures:Normal weight males (ages 20 -40 years) were fed a solid food diet, measured carefully to maintain body weight, for 3 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single-blind, 22-day, placebo/drug/placebo design, six subjects received leptin 0.3 mg/kilogram subcutaneously for 6 days. ANS measures of amount of parasympathetic control and sympathetic control of heart period (interbeat interval) were made by sequential pharmacological blockade with intravenous atropine and esmolol. Norepinephrine, dopamine, and epinephrine levels in 24-hour urine collections were also measured as well as resting metabolic rate. Results: Sufficient food intake maintained constant body weight in all subjects. There was no evidence that leptin administration led to changes in energy metabolism sufficient to require additional food intake or to alter resting metabolic rate. Likewise, leptin administration did not alter autonomic activity. Parasympathetic control and sympathetic control, as well as the urinary catecholamines, were not significantly affected by leptin administration. Glucose and insulin levels were increased by food intake as expected, but leptin had no affect on these levels before or after food intake. Discussion: ANS responses to changes in energy metabolism found when food intake and body weight are altered were not found in these never-obese subjects given leptin for 6 days. Although exogenous leptin administration has profound effects on food intake and energy metabolism in animals genetically deprived of leptin, we found it to have no demonstrable effect on energy metabolism in neverobese humans. The effects of longer periods of administration to obese individuals and to those who have lost weight demand additional investigation.

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“…In contrast to congenital leptin deficiency, the majority of obese individuals have higher leptin concentrations than lean individuals and are leptin resistant (Considine et al 1996a;Moon et al 2011). Hyperleptinemia in humans can be due to mutations at highly conserved positions of the extracellular domain of the leptin receptor gene (Chung et al 1997;Francke et al 1997; Thompson et al 1997;Clément et al 1998). In 1966, Hummel et al described a spontaneous mutation in a C57BL/Ks mouse colony that provoked hyperphagia, decreased energy expenditure and obesity, fasting hyperglycemia increasing with age and increase in plasma insulin and leptin concentration (Hummel et al 1966;Coleman and Hummel 1967;Frederich et al 1995;Chen et al 1996;Chua et al 1996; Lee et al 1996;Madiehe et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Chronic stress aggravates glucose intolerance in leptin receptor-deficient (db/db) mice

et al. 2015

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Genetic predisposition and environmental challenges interact to determine individual vulnerability to obesity and type 2 diabetes. We previously established a mouse model of chronic subordination stress-induced hyperphagia, obesity, metabolic like-syndrome and insulin resistance in the presence of a high-fat diet. However, it remains to be established if social stress could also aggravate glucose intolerance in subjects genetically predisposed to develop obesity and type 2 diabetes. To answer this question, we subjected genetically obese mice due to deficiency of the leptin receptor (db/db strain) to chronic subordination stress. Over five weeks, subordination stress in db/db mice led to persistent hyperphagia, hyperglycemia and exacerbated glucose intolerance altogether suggestive of an aggravated disorder when compared to controls. On the contrary, body weight and fat mass were similarly affected in stressed and control mice likely due to the hyperactivity shown by subordinate mice. Stressed db/db mice also showed increased plasma inflammatory markers. Altogether our results suggest that chronic stress can aggravate glucose intolerance but not obesity in genetically predisposed subjects on the basis of a disrupted leptin circuitry.

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Exonic and Intronic Sequence Variation in the Human Leptin Receptor Gene (LEPR)

Cited by 98 publications

References 17 publications

Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Québec Family Study

Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Québec Family Study

The Effects of Leptin Administration in Non‐obese Human Subjects

Chronic stress aggravates glucose intolerance in leptin receptor-deficient (db/db) mice

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