Monogenic obesity
Monogenic obesity is excess weight caused by a mutation in a single gene. It differs from syndromic obesity, which involves additional clinical phenotypes such as neurodevelopmental delay or dysmorphic features, and from the more common polygenic obesity, which results from both genetic and environmental risk factors. Monogenetic obesity mostly affects the hypothalamus and leptin–melanocortin system, and accounts for less than 5 percent of severe obesity cases.
Key features that differentiate monogenic obesity from polygenic obesity include hyperphagia, extreme symptoms of obesity and the early onset of obesity. It is a rare, early-onset form of obesity that follows a Mendelian pattern of inheritance. Most cases arise from alterations in a single gene of the leptin-melanocortin pathway, a key regulatory system controlling body weight, hunger, and energy expenditure. Research on monogenic obesity has focused on characterizing its clinical features, establishing diagnostic criteria, and developing therapeutic approaches, with case studies across diverse populations to improve understanding and management of the condition.
Known mutations leading to monogenetic obesity include:
- Leptin deficiency
- Leptin receptor deficiency
- Melanocortin-4 receptor
- Proopiomelanocortin
- Prohormone convertase 1/3
- SIM1
- BDNF
- NTRK2
History of Monogenic Obesity
In 1997, two separate reported cases of monogenic obesity were published, observing a pair of cousins who are the only family members reported to have severe early-onset obesity. Carl Montague and colleagues, as well as Robert Jackson and colleagues at the University of Cambridge, observed severe obesity phenotypes associated with single-gene variants involving the leptin-melanocortin pathway. Montague et al. observed undetectable concentrations of leptin and hyperphagia, and found that both cousins had a homozygous frame-shift variant in the Ob gene. Jackson et al. provided a secondary report that the early-onset obesity phenotypes were associated with single-gene variation in the gene encoding prohormone convertase 1. Their findings established that single genes existed that could directly influence severe human obesity when mutated. Since the discovery, researchers have identified several more genes with variants that can cause monogenic obesity.
A key note is that murine models aid significantly in our current understanding of monogenic human obesity, as most murine genes identified through monogenic variant studies have their corresponding human homologs.
Overview of Leptin-Melanocortin pathway
Leptin, a hormone secreted by adipose tissue and encoded by the Ob gene, is released into the bloodstream during the 'fed state' and crosses the blood brain barrier. Leptin binds to the leptin receptor expressed on the surface of proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus. This activates POMC processing by proprotein convertase 1 into Α-Melanocyte-stimulating hormone. α-MSH is then released and acts on melanocortin 4 receptor in downstream hypothalamic regions, including the paraventricular nucleus. Activation of MC4R neurons initiates a signaling cascade that ultimately reduces food intake and increases energy expenditure.Leptin
WT vs Variants
Adipocytes secrete Leptin, a peptide hormone encoded from the obese gene, also known as the leptin gene. It is a principal regulator of fat mass and is integral in the regulation of fuel stores and energy balance, while signalling the body's nutritional status to peripheral tissues for modulated functions. Studies in mice suggest that leptin commonly regulates many peripheral tissues in humans, such as a mitogenic influence on CD4+ T cells, the circulation of thyrotropin-releasing hormone that regulates metabolism, the regulation of the onset of puberty, and the neuroendocrine restriction responses to food.Homozygosity for loss-of-function variants of LEP attributes to Leptin deficiency. In a case study of a Turkish family with obese family members, the homozygosity for LEP variants results in a C to T substitution at codon 105, leading to an Arg to Trp amino acid change. In another case study, researchers attributed the early-onset obesity in two Pakistani children to a frameshift mutation in LEP that deleted a guanine nucleotide at codon 133. In the case of both families, other family members who were heterozygous for the variation or homozygous for the WT allele did not display any phenotypes associated with obesity.
Phenotypic Effects
Leptin deficiency results in a range of symptoms including increased body mass index, infertility, delayed onset of puberty, cold intolerance, lower energy expenditures and intense hyperphagia. Increased body mass index is observed in mice and the Pakistani and Turkish case studies, where mice grew to three times the size of the wild type and subjects were born at normal weight, then rapidly increased in weight at an early age. Initially, researchers did not observe infertility due to leptin deficiency, as case studies such as the Pakistani family consisted only of young children. However, infertility is now displayed in the Turkish family as the adult subjects present hypothalamic–pituitary hormone insufficiency due to leptin deficiency and have never gone into puberty. Cold intolerance is also observed in both the mice and the Turkish subjects when exposed to cold conditions. Lastly, a consistent symptom of leptin deficiency across mice and subjects in many case studies is intense hyperphagia and lower energy expenditures.Treatment
Subcutaneous recombinant human leptin therapy is a prevalent treatment option for leptin-deficient patients. Researchers observe positive results from the therapy, including an intense loss of fat mass through decreasing food consumption, an increase in basal metabolic activity and lower serum insulin/cholesterol levels. An increase in the proportion of CD4+ T helper cells is also observed. Another study suggests that leptin therapy has the greatest impact on decreased food intake, while other factors, such as energy expenditure, do increase but do not play as much of a role.Leptin Receptor
WT vs Variants
The leptin receptor is a transmembrane protein with an extracellular domain that binds leptin. Its function is mediated by leptin, regulating energy stores, hypothalamic function, and neuroendocrine signaling. Mutational analysis demonstrates that a functional leptin receptor is essential for proper regulation of body weight, sexual maturation, and endocrine hormone secretion.Mutations that produce a secreted, truncated form of the receptor—lacking transmembrane and intracellular domains—are defective in signal transduction but retain the leptin-binding ectodomain Because the mutant leptin receptor is secreted into the bloodstream rather than anchored in the membrane, it binds and sequesters circulating leptin, increasing total serum leptin levels while preventing effective signaling to the brain, thereby contributing to leptin resistance
Phenotypic Effects
In a UK-based study of 300 severely obese, hyperphagic probands, researchers identified LEPR loss-of-function mutations in eight individuals from diverse backgrounds, including Bangladeshi, Turkish, Iranian, Southern European, Norwegian, and White UK descent. All affected individuals exhibited early-onset obesity, hyperphagia, and increased ad libitum energy intake, though there was no major deficit in energy expenditure. Vertical growth and Insulin-like growth factor 1 levels during childhood were normal, but adult height was reduced due to a lack of pubertal growth spurt. Adults exhibited hypogonadism and reduced secondary sex characteristics, along with low sex-steroid levels, Follicle-stimulating hormone, and Luteinizing hormone levels. However, uterine development in adult females was observed, and hormonal levels during the follicular phase were still within the normal range, suggesting that activation of the hypothalamic-pituitary gland was still possible, albeit delayed. Heterozygotes undergo puberty normally and demonstrate normal reproductive functions. Subjects also had reduced CD4+ T cells, but in compensation had higher amounts of B lymphocytes. Surprisingly, the overall clinical phenotype of subjects with leptin receptor deficiency is not as severe as those with leptin deficiency, despite similar phenotypes observed in mice harboring mutations in leptin or its receptor.Melanocortin-4 receptor (MC4R)
WT vs Variants
The melanocortin-4 receptor is a 332-amino acid protein essential for the central regulation of long-term energy. Central regulation consists of regulating food intake and integrating a satiety signal provided to the MC4R from the agonist α-MSH and an orexigenic signal provided by its antagonist agouti-related peptide. MC4R is a G protein-coupled receptor in the paraventricular nucleus of the hypothalamus, and when activated, it transduces a signal to regulate appetite and decrease or increase food intake.Mutations to the MC4R are the most frequent cause of severe monogenic obesity. MC4R mutation can be codominant, and rarer homozygous mutants result in more severe obesity symptoms than heterozygote carriers. There are variations of mutations that can occur and are continuously studied to differentiate between the severity and phenotypes of each mutation. A study of 289 obese Czech children identified a novel missense mutation, Cys84Arg, as well as 5 previously reported variants: Arg7Cys, Ser19fsdelA, Phe51Leu, Ser127Leu, and Gly181Asp. Another study with 300 Chinese children also found novel heterozygous non-synonymous and nonsense mutations in obese Chinese children. Depending on the type of mutation, the effect is either a partial or complete loss of function in MC4R and may also cause intracellular retention of the MC4R. Intracellular retention appears to provide the most severe obesity phenotypes and earlier age onset, even in comparison to complete loss of function mutations.