Leptin Receptor Gene in a Large Cohort of Massively Obese Subjects: No Indication of the fa/fa Rat Mutation. Detection of an Intronic Variant with No Association with Obesity

Rolland, Violaine; Clément, Karine; Dugail, Isabelle; Guy‐Grand, Bernard; Basdevant, Arnaud; Froeuel, Philippe; Lavau, M

doi:10.1002/j.1550-8528.1998.tb00325.x

Cited by 19 publications

(13 citation statements)

References 24 publications

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“…15 This is, however, a very rare condition and in most obese humans, no such mutation can be found. 10,16 In contrast, several common polymorphisms of the LEPR gene have been uncovered. 10,16 ± 20 None of them seems to have a major effect on obesity.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women

et al. 2001

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OBJECTIVE:Leptin is an adipocyte-secreted hormone involved in body weight regulation, acting through the leptin receptor, localised centrally in the hypothalamus as well as peripherally, amongst others on adipose tissue. The aim of this study was to evaluate whether polymorphisms in the leptin receptor (LEPR) gene were related to obesity and body fat distribution phenotypes, such as waist and hip circumferences and the amount of visceral and subcutaneous fat. METHODS: Three known LEPR polymorphisms, Lys109Arg, Gln223Arg and Lys656Asn, were typed on genomic DNA of 280 overweight and obese women (body mass index (BMI) b 25), aged 18 ± 60 y. General linear model (GLM) analyses were performed in 198 pre-and 82 postmenopausal women, adjusting the data for age and menopausal state, plus fat mass for the fat distribution phenotypes. RESULTS: No associations were found between the LEPR polymorphisms and BMI or fat mass. In postmenopausal women, carriers of the Asn656 allele had increased hip circumference (P 0.03), total abdominal fat (P 0.03) and subcutaneous fat (P 0.04) measured by CT scan. Total abdominal fat was also higher in Gln223Gln homozygotes (P 0.04). Also in postmenopausal women, leptin levels were higher in Lys109Lys homozygotes (P 0.02). CONCLUSION: In conclusion, polymorphisms in the leptin receptor gene are associated with levels of abdominal fat in postmenopausal overweight women. Since body fat distribution variables were adjusted for fat mass, these results suggest that DNA sequence variations in the leptin receptor gene play a role in fat topography and may be involved in the predisposition to abdominal obesity.

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Section: Introductionmentioning

confidence: 99%

Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women

et al. 2001

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“…Variations in leptin receptor sequences have also been identified in humans but most appear to be polymorphisms due to their lack of association with obesity [16, 17, 18, 19]. However, a homozygous mutation of the human leptin receptor has been described; resulting in early-onset obesity and pituitary dysfunction [20].…”

Section: Introductionmentioning

confidence: 99%

Cyclical Variations in the Abundance of Leptin Receptors, but not in Circulating Leptin, Correlate with NPY Expression during the Oestrous Cycle

Bennett¹,

Lindell

Wilson³

et al. 1999

Neuroendocrinology

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We have demonstrated previously that pharmacological doses of oestradiol decreased leptin receptor expression in the hypothalamus. We therefore analysed leptin receptor expression during the oestrous cycle in the rat, to establish if acute changes in oestradiol affect leptin receptor expression under physiological conditions. Radioactive in situ hybridization histochemistry was used to measure the gene expression under investigation. Total leptin receptor transcript levels were lowest in pro-oestrus in the choroid plexus, these changes correspond inversely with levels of circulating oestradiol in the rat 4-day oestrous cycle. In contrast full-length leptin receptor levels in both arcuate and ventromedial nuclei did not correspond to the levels of total leptin receptor in the same areas of the hypothalamus or serum levels of oestradiol. Full-length leptin receptor expression in the arcuate nucleus was negatively correlated with neuropeptide Y (NPY) expression (r = 0.447, p < 0.05) in the same nucleus. Arcuate nucleus NPY expression did not correlate significantly with the expression of total leptin receptors in the arcuate nucleus (r = 0.080) or serum leptin levels (r = 0.251). Our results demonstrate that leptin receptor expression is regulated during the oestrous cycle. The unchanged serum leptin levels during the oestrous cycle together with the correlation between the expression of leptin-RL and NPY provide circumstantial evidence that regulation of leptin receptor abundance in the hypothalamus governs the biological actions of leptin.

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“…The weight-lowering effects of leptin are likely to be mediated by activation of the JAK-STAT signal transduction in the intracellular domain of the OB-Rb in the hypothalamus. Evaluation of the possibility of human obesity being secondary to a mutation of the OB-R was studied by two different groups who found no defect in the OB-R sequence in obese individuals [21, 22]. Our group has recently shown in presence and distribution of the OB-R protein in the human brain [23]; however, the specific expression of the OB-Rb mRNA has not been described.…”

Section: Introductionmentioning

confidence: 99%

The Long Form of the Leptin Receptor (OB-Rb) Is Widely Expressed in the Human Brain

Burguera¹,

et al. 2000

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Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin action is mediated by the interaction with a receptor that is alternatively spliced, resulting in at least five different isoforms. The long form (OB-Rb) has a long intracellular domain that is essential for intracellular signal transduction. The specific aim of this study was to further investigate the role that the brain may play in the pathogenesis of obesity in humans. We studied the expression of OB-R mRNA (both short or common and long isoforms) in the brains of obese, lean and diabetic subjects, by in situ hybridization, semiquantitative RT-PCR and Northern blots analysis. We used two alternative probes: one that recognizes all known splice variants (OB-Ra) and a second that recognizes only the long form, OB-Rb. Several brain regions, including hypothalamus, cerebellum, neocortex, entorrhinal cortex, amygdala, and rostral medulla, were evaluated. In situ hybridization studies revealed that both OB-Ra and OB-Rb mRNAs are widely distributed in the human brain. The specific hybridization signal with both probes was detected exclusively in the cytoplasm of the cell body, dendrites and proximal axons of neurons. Hypothalamic nuclei, Purkinje cells and dentate nuclei of the cerebellum, inferior olivary and cranial nerves nuclei in the medulla, amygdala and neurons from both neocortex and entorrhinal cortex demonstrated positive signals. The hybridization signal obtained in ependyma was lower than that in neurons and no specific hybridization was detected in glial cells. No significant differences were identified among the regions or among the three groups studied. These results match those previously obtained by us [Couce et al.: Neuroendocrinology 1997;66:145] in which the distribution of the OB-R protein in the human brain was first described. RT-PCR indicated that the OB-Rb was highly expressed in the hypothalamus and cerebellum. No significant differences of OB-Ra or OB-Rb mRNA expression were identified in lean or obese individuals in these two cerebral regions. The levels of OB-Rb were significantly higher in cerebellum compared to hypothalamus in lean and obese individuals. The original hypothesis that OB-Rb is present only in the hypothalamus needs to be reconsidered. This OB-Rb isoform seems to be widely expressed in the human brain with highest levels in the cerebellum. Obesity and hyperleptinemia appears not to be associated with down-regulation of the OB-Rb in the human brain.

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Leptin Receptor Gene in a Large Cohort of Massively Obese Subjects: No Indication of the fa/fa Rat Mutation. Detection of an Intronic Variant with No Association with Obesity

Cited by 19 publications

References 24 publications

Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women

Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women

Cyclical Variations in the Abundance of Leptin Receptors, but not in Circulating Leptin, Correlate with NPY Expression during the Oestrous Cycle

The Long Form of the Leptin Receptor (OB-Rb) Is Widely Expressed in the Human Brain

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