The obese phenotype-inducing N82K mutation in human leptin disrupts receptor-binding and biological activity

Niv-Spector, Leonora; Shpilman, Michal; Grupi, Asaf; Gertler, Arieh

doi:10.1016/j.ymgme.2010.02.015

Cited by 15 publications

(20 citation statements)

References 25 publications

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“…The effect of this missense mutation involves a change of asparagine to lysine at position 103 in the final protein resulting in very low serum leptin levels as observed in the current study as well as the original report of two Egyptian patients [4]. Although the effect of this amino acid change on the synthesis, secretion and biological activity of leptin was not clearly demonstrated, the assessment of altered biological activity in vitro was checked in a study by Niv-Spector et al [29]. In this study, a prokaryotic expression system was used to produce p. N103K leptin and it was shown that this results in a drastic reduction in biological activity of the mutant leptin protein.…”

Section: Discussionsupporting

confidence: 59%

The p. N103K mutation of leptin (LEP) gene and severe early onset obesity in Pakistan

Shabana

Hasnain

2016

Biol Res

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BackgroundObesity is a complex disorder and has been increasing globally at alarming rates including Pakistan. However, there is scarce research on understanding obesity genetics in Pakistan. Leptin is a hormone secreted by adipocytes in response to satiety and correlates with body weight. Any mutations in the LEP gene have an adverse effect on energy regulation pathway and lead to severe, early onset obesity. To date, only eight mutations have been described in the LEP gene of which p. N103K is one.MethodsWe aimed to analyze the prevalence of this mutation in Pakistani subjects. A total of 475 subjects were genotyped by PCR–RFLP analysis and their serum profiling was done.ResultsResults showed that this mutation was present only in one male child with early onset obesity (10 year). He had very low serum leptin levels suggestive of functional impact of the mutation. The prevalence of such mutations is, however, low due to the drastic effects on the energy regulation.ConclusionIn conclusion, LEP gene mutations contribute significantly to the monogenic forms of obesity and are important due to the availability of treatment options. Such mutations may exert their effect by directly affecting energy regulation pathway and are more prominent in the early stages of life only.

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Section: Discussionsupporting

confidence: 59%

The p. N103K mutation of leptin (LEP) gene and severe early onset obesity in Pakistan

Shabana

Hasnain

2016

Biol Res

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“…Among LEPTIN mutations reported thus far in human obesity, ΔG133 and R105W mutations result in an inability to produce/secrete the leptin protein, with undetectable levels in the serum of affected individuals [9], [10]. To our knowledge, the N103K mutation in patients with severe obesity is the only known human mutation that has been demonstrated to disrupt receptor binding [33]. However, our results suggest that the V145E mutation does not affect the binding of leptin to its receptor.…”

Section: Discussioncontrasting

confidence: 48%

ENU Mutagenesis Identifies Mice with Morbid Obesity and Severe Hyperinsulinemia Caused by a Novel Mutation in Leptin

Chen

Tsai

Cheng³

et al. 2010

PLoS ONE

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BackgroundObesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals.Methodology/Principal FindingsTo better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin145E/145E mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin145E/145E mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin145E/145E mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region.Conclusions/SignificanceThus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome.

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“…To explore the leptin antagonist's potential to induce appetite and enhance body growth rate in chickens, as we previously showed in mice (Benoit et al, 2013;Chapnik et al, 2013;Elinav et al, 2009;Niv-Spector et al, 2012;Niv-Spector et al, 2010;Shpilman et al, 2011), lean male chickens at 2 weeks of age were subjected to daily administration of the leptin antagonist. As demonstrated in Fig.…”

Section: Administration Of Leptin Antagonist To Chickensmentioning

confidence: 99%

Pegylated leptin antagonist with strong orexigenic activity in mice is not effective in chickens

Gertler

Shinder

Yosefi

et al. 2013

Journal of Experimental Biology

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A chicken gene orthologous to human leptin receptor (LEPR) has been characterized and found to be active in leptin signaling in vitro in response to a variety of recombinant leptins and leptin-containing blood samples. However, the endogenous ligand of chicken LEPR (cLEPR) -the putative chicken leptin -has been reported by us and others to be undetectable at the DNA, mRNA, protein and activity levels. These reports have raised questions as to cLEPR's role. Here we analyzed the effects of a pegylated superactive mouse leptin antagonist (PEG-SMLA) in chicken. We showed that the leptin antagonist efficiently and specifically blocks leptin signaling through the cLEPR in vitro. The effect of the leptin antagonist was then studied in vivo by daily administration of 10 mg kg -1 for 10 consecutive days to white leghorn female chickens (Gallus gallus) at the age of 2 weeks. Despites the efficient attenuation of the cLEPR in vitro, no effect was observed on body mass, feed intake, feed efficiency or fat accumulation in the treated birds. Because similar treatment in rodents leads to a highly pronounced increase in appetite and body mass that are observed from the first day of treatment, it is concluded that the cLEPR is not implicated in the control of appetite or adipose homeostasis in chickens.

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The obese phenotype-inducing N82K mutation in human leptin disrupts receptor-binding and biological activity

Cited by 15 publications

References 25 publications

The p. N103K mutation of leptin (LEP) gene and severe early onset obesity in Pakistan

The p. N103K mutation of leptin (LEP) gene and severe early onset obesity in Pakistan

ENU Mutagenesis Identifies Mice with Morbid Obesity and Severe Hyperinsulinemia Caused by a Novel Mutation in Leptin

Pegylated leptin antagonist with strong orexigenic activity in mice is not effective in chickens

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