When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin

Abstract

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.

Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database

“…Certain variants deposited in gnomAD and predicted to be pathogenic were previously associated with congenital leptin deficiency. The non-synonymous mutations p.Asp100Asn (rs724159998, 30), p.Asn103Lys (rs28954113, 6, 31, 32) and the frameshift mutation p.Gly133Val fs Ter15 (rs1307773933, 7) were detected in extremely obese children being homozygous carriers (5). Another study showed that BMI z-scores of carriers of homozygous LEP variants are generally higher than those of the heterozygous or wildtype individuals carrying the same variant (28).…”

“…the α-melanocyte-stimulating hormone. Eventually, the signalling of melanocortin-4-receptor is stimulated and leads to decreased food intake due to satiety signals (1–5).…”

“…Subsequent treatment with recombinant leptin led to a substantial weight loss and a decrease in energy intake (11, 15). Further, besides frameshift mutations, pathogenic nonsense, and non-synonymous variants as well as deletions in LEP have been reported (5). The functional effects of these mutations are diverse.…”

“…the α-melanocyte-stimulating hormone. Eventually, the signalling of melanocortin-4-receptor is stimulated and leads to decreased food intake due to satiety signals (1)(2)(3)(4)(5). Homozygous mutations in the LEP gene cause congenital leptin deficiency disrupting the normal regulation of the body weight.…”

“…Hyperphagia, hypogonadism and impaired immune functions are concomitant symptoms (5,(7)(8)(9)10). This form of monogenic obesity is infrequent, with a prevalence between one and 5% and predominantly affecting individuals with parental consanguinity (5,7,8,(11)(12)(13)(14). In 1997, the first deleterious LEP mutation (p.Gly133Valfs*15) was reported by Montague and colleagues (7).…”