Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.

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BackgroundThe melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the melanocortin 4 receptor (MC4R) gene resulting in partial or complete loss of function have been described with autosomal co-dominant inheritance. These mutations are the most common cause of non-syndromic monogenic obesity. In this context, this study aimed to sequence the MC4R gene in a Brazilian cohort of adults with severe obesity.MethodsThis study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m2, stratified into three groups, according to the period of obesity onset. From the total sample, 25 patients were enrolled in the childhood-onset group (0–11 years), 19 patients in the adolescence/youth-onset group (12–21 years), and 119 patients in the adult-onset group (>21 years). Blood pressure, anthropometric and biochemical characteristics were obtained, and the MC4R coding region of each subject’s DNA was assessed using automated Sanger sequencing.ResultsSignificant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity.ConclusionThis study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic MC4R variant in a Brazilian patient with severe and adulthood-onset obesity.

Introduction: Silicosis is a fibrotic lung disease resulting from the inhalation of crystalline silica and can be classified as simple or complicated according to the International Labour Organization criteria. Furthermore, individuals exposed to crystalline silica also have a higher risk for the development of tuberculosis (Tb).The contribution of inflammatory cytokines to the risk of silicosis and Tb in different populations has previously been reported. Since genetic background might be related to susceptibility to silicosis and Tb, the study of polymorphisms within IL-1α, IL-1β, and tumor necrosis factor protein-coding genes may contribute to elucidating the genetic basis of these diseases.Methods: Single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction using restriction fragment length polymorphism or by Taqman methodology, in a sample of 102 silica-exposed patients from Brazil.Results: No significant associations were observed between the SNPs studied and the severity of silicosis. However, significant associations were found between Tb and the C allele (odds ratio [OR] = 1.93, 95% confidence interval [CI], 1.01-3.73) and the CC genotype (OR = 2.34, 95% CI, 1.04-5.31) of IL1A −899C>T. The IL1B +3954C>T polymorphism also showed an association with Tb (T allele dominant model OR = 2.38, 95% CI, 1.04-5.41). Conclusion:These preliminary results demonstrate that the IL1A and IL1B gene variations may contribute to some extent to susceptibility to Tb, but not silicosis.However, additional studies are still needed to confirm these results.