Leptin deficiency and<i>leptin</i>gene mutations in obese children from Pakistan

Fatima, Warda; Shahid, Adeela; Imran, Muhammad; Manzoor, Jaida; Hasnain, Shahida; Rana, Sobia; Mahmood, Saqib

doi:10.3109/17477166.2011.608431

Cited by 79 publications

(72 citation statements)

References 24 publications

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“…10,12,13 To date, reported cases of congenital leptin deficiency have been characterized by circulating leptin levels that are undetectable or very low as a result of defects in either synthesis or secretion of leptin. 2,3,[5][6][7][8] Likewise, the corresponding ob/ob mouse model lacks leptin in the circulation. 9 However, a novel mutation in the murine gene encoding leptin (p.V145E) was generated by means of N-ethyl-N-nitrosourea mutagenesis.…”

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confidence: 98%

“…Seven additional mutations have since been reported. [3][4][5][6][7][8] The type I cytokine leptin is mainly produced by adipocytes to signal the energy state of the body and exerts its function as a satiety signal in the hypothalamus. 9 Clinical hallmarks of congenital leptin deficiency include early-onset extreme obesity, marked hyperphagia, and hormonal as well as metabolic disturbances.…”

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confidence: 99%

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Biologically Inactive Leptin and Early-Onset Extreme Obesity

et al. 2015

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Mutations in the gene encoding leptin (LEP) typically lead to an absence of circulating leptin and to extreme obesity. We describe a 2-year-old boy with early-onset extreme obesity due to a novel homozygous transversion (c.298G→T) in LEP, leading to a change from aspartic acid to tyrosine at amino acid position 100 (p.D100Y) and high immunoreactive levels of leptin. Overexpression studies confirmed that the mutant protein is secreted but neither binds to nor activates the leptin receptor. The mutant protein failed to reduce food intake and body weight in leptin-deficient ob/ob mice. Treatment of the patient with recombinant human leptin (metreleptin) rapidly normalized eating behavior and resulted in weight loss.

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confidence: 98%

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confidence: 99%

Biologically Inactive Leptin and Early-Onset Extreme Obesity

et al. 2015

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“…With the exception of one Egyptian boy [24], transaminases levels are not reported for the other published leptin-deficient patients [1,21,22,23,24,25,26,34] or for the published patients with leptin receptor mutation [35,36]. Given the fact that ob/ob mice typically develop hepatic steatosis [3], it is surprising that this has not been reported for the other leptin-deficient patients.…”

Section: Discussionmentioning

confidence: 85%

“…In contrast to the ob/ob mouse, among the 35 leptin-deficient patients reported so far in the literature [1,21,22,23,24,25,26], only our patient and a 3-year-old boy from Egypt [24] have been shown to suffer from hepatic steatosis.…”

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confidence: 87%

Rapid Improvement of Hepatic Steatosis after Initiation of Leptin Substitution in a Leptin-Deficient Girl

Schnurbein¹,

Heni²,

Moß³

et al. 2013

Horm Res Paediatr

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Background: Leptin deficiency is associated with severe obesity and metabolic disturbances. Increased liver fat content has been reported in only one case beforehand, even though hepatic steatosis is a typical comorbidity of common obesity. It is also frequent in patients with lipodystrophy where it resolves under leptin therapy. Subject and Methods: In 2010, we reported a leptin-deficient patient with a novel homozygous mutation in the leptin gene and severe hepatic steatosis. We have now studied serum changes and changes in liver fat content during the substitution with recombinant methionyl human leptin. Results: After 23 weeks of leptin substitution, elevated transaminases, total cholesterol and low-density lipoprotein levels normalized. After 62 weeks, homeostasis model assessment of insulin resistance improved from 10.7 to 6.0 and body fat mass dropped from 50.2 to 37.8%. Liver fat content was drastically reduced from 49.7 to 9.4%. The first changes in liver fat content were detectable after 3 days of therapy. Conclusion: Our patient showed a remarkable reduction of liver fat content during the treatment with recombinant methionyl human leptin. These changes occurred rapidly after initiation of the substitution, which implies that leptin has a direct effect on hepatic lipid metabolism in humans as it is seen in rodents.

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“…In these very rare genetic disorders, most reports have only described the profound adverse metabolic changes that these people experience [48,49] . In 1 case report, leptin replacement was reported to improve some neurocognitive domains in a developmentally delayed child with congenital leptin deficiency, in addition to dramatic weight reduction and resolution of hypertension, dyslipidemia, and hyperinsulinemia [50] .…”

Section: Discussionmentioning

confidence: 99%

Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study

Romo¹,

Schooling²

2017

Neuroendocrinology

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Background: Observational evidence regarding the role of leptin in Alzheimer disease (AD) is conflicting. We sought to determine the causal role of circulating leptin and soluble plasma leptin receptor (sOB-R) levels in AD using a separate-sample Mendelian randomization study. Methods: Single nucleotide polymorphisms (SNPs) independently and solely predictive of log-transformed leptin (rs10487505 [LEP], rs780093 [GCKR], rs900400 [CCNL1], rs6071166 [SLC32A1], and rs6738627 [COBLL1]) and of sOB-R (rs1137101 [LEPR], rs2767485 [LEPR], and rs1751492 [LEPR]) levels (ng/mL) were obtained from 2 previously reported genome-wide association studies. We obtained associations of leptin and sOB-R levels with AD using inverse variance weighting with fixed effects by combining Wald estimates for each SNP. Sensitivity analyses included using weighted median and MR-Egger methods and repeating the analyses using only SNPs of genome-wide significance. Results: Using inverse variance weighting, genetically predicted circulating leptin levels were not associated with AD, albeit with wide confidence intervals (CIs): odds ratio (OR) 0.99 per log-transformed ng/mL; 95% CI 0.55-1.78. Similarly, the association of sOB-R with AD was null using inverse variance weighting (OR 1.08 per log-transformed ng/mL; 95% CI 0.83-1.41). Results from our sensitivity analyses confirmed our findings. Conclusions: In this first Mendelian randomization study estimating the causal effect of leptin on AD, we did not find an effect of genetically predicted circulating leptin and sOB-R levels on AD. As such, this study suggests that leptin is unlikely to be a major contributor to AD, although the wide CIs preclude a definitive assessment.

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Leptin deficiency andleptingene mutations in obese children from Pakistan

Abstract: The results suggest that leptin deficiency caused by mutations in the leptin gene may frequently be seen in obese Pakistani children from Central Punjab.

Cited by 79 publications

References 24 publications

Biologically Inactive Leptin and Early-Onset Extreme Obesity

Biologically Inactive Leptin and Early-Onset Extreme Obesity

Rapid Improvement of Hepatic Steatosis after Initiation of Leptin Substitution in a Leptin-Deficient Girl

Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study

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