in a bio‐assay. These antibodies are the likely cause of refractory periods occurring during therapy. The fluctuating nature of the antibodies probably reflects the complicating factor that leptin deficiency is itself an immunodeficient state and administration of leptin lead to a change from the secretion of predominantly Th2 to Th1 cytokines, which may directly influence antibody production. Thus far, we have been able to regain control of weight loss by increasing the dose of leptin.
Leptin receptor deficiency
Up to 3% of patients with severe obesity have been found to harbor mutations in the leptin receptor gene (LEPR) that are associated with a loss of function in vitro [38]. Whilst heterozygosity for LEP or LEPR mutations is associated with an increase in body weight, severe obesity requires the loss of two alleles due to homozygous or compound heterozygous mutations. Serum leptin levels are not disproportionately elevated in LEPR deficiency, although particular mutations located near the transmembrane domain can result in a truncated extracellular domain that may act as a false binding protein and result in abnormally elevated leptin levels [39, 40]. The clinical phenotype of congenital leptin receptor deficiency is similar to that of leptin deficiency with hyperphagia, severe early‐onset obesity, hypogonadism, and frequent infections.
POMC deficiency
Several unrelated children with obesity with homozygous or compound heterozygous mutations in POMC have been reported [41]. These children were hyperphagic, developing early‐onset obesity as a result of impaired melanocortin signaling in the hypothalamus. They presented in neonatal life with adrenal crisis due to isolated adrenocorticotropic hormone (ACTH) deficiency (POMC is a precursor of ACTH in the pituitary) and had pale skin and red hair due to the lack of MSH function at melanocortin 1 receptors in the skin, although hypopigmentation may be less obvious in children from different ethnic backgrounds. A number of missense mutations that affect POMC‐derived peptides have been described [42].
Prohormone convertase 1 deficiency
Further evidence for the role of the melanocortin system in the regulation of body weight in humans comes from the description of three patients with severe childhood obesity, abnormal glucose homeostasis, very low plasma insulin but elevated levels of proinsulin, hypogonadotropic hypogonadism and hypocortisolemia associated with elevated levels of POMC (Table 4.2). These subjects were found to be compound heterozygote/homozygous for mutations in prohormone convertase 1, which cleaves prohormones at pairs of basic amino acids, leaving C‐terminal basic residues, which are then excised by carboxypeptidase E (CPE) [43]. Although failure to cleave POMC is a likely mechanism for the obesity in these patients, prohormone convertase 1 (PC1) cleaves a number of other neuropeptides in the hypothalamus, such as glucagon‐like peptide 1, which may influence feeding behavior. Intriguingly, the second patient suffered from severe small intestinal absorptive dysfunction as well as the characteristic severe early‐onset obesity, impaired prohormone processing, and hypocortisolemia. We hypothesized that the small intestinal dysfunction seen in this patient, and to a lesser extent in the first patient we described, maybe the result of a failure of maturation of propeptides within the enteroendocrine cells and nerves that express PC1 throughout the gut.
Figure 4.1 Clinical response to leptin therapy in congenital leptin deficiency.
MC4R deficiency
Mutations in MC4R have been reported in up ∼6% of patients with severe early‐onset obesity, and are found at a frequency of approximately 1 in 300 in the general population, making this the most common monogenic form of obesity. While we found a 100% penetrance of early‐onset obesity in heterozygous probands, others have described carriers who were not obese. Given a large number of potential influences on body weight, it is perhaps not surprising that both genetic and environmental modifiers will have important effects on some pedigrees. Taking account of all these observations, co‐dominance, with modulation of expressivity and penetrance of the phenotype, is the most appropriate descriptor for the mode of inheritance.
Figure 4.2 Changes in energy intake and expenditure in two children with congenital leptin deficiency treated with recombinant leptin. (a) Change in ad libitum energy intake in a 3‐year‐old boy (Child B) with congenital leptin deficiency, before and one month after the initiation of leptin therapy. (b) Changes in energy expenditure in Child A (9‐year‐old girl) and Child B (3‐year‐old boy) in response to leptin. BMR, basal metabolic rate; TEE, total energy expenditure expressed per kg lean body weight (LBW).
(Source: Based on Rosenbaum et al. [35].)
Figure 4.3 Leptin therapy is associated with pulsatile gonadotropin secretion at an appropriate developmental age in child (a) (age 11 years) compared to child (b) (age 5 years).
(Source: Modified from Farooqi et al. [30].)
Detailed phenotypic studies of patients with MC4R mutations reveal that this syndrome is characterized by an increase in lean body mass, increased linear growth throughout childhood, hyperphagia, and severe hyperinsulinemia [44]. Of particular note is the finding that the severity of receptor dysfunction seen in in vitro assays can predict the amount of food ingested at a test meal by the subject harboring that particular mutation [44]. An elevated respiratory quotient (ratio of carbohydrate to fat oxidation) in MC4R deficiency is consistent with an impaired ability to mobilize fat seen in MC4R knockout mice. Linear growth of these subjects is striking, with affected children having a height standard deviation score (SDS) of +2 compared to population standards and adults have an increased final height when compared to equally adults with obesity with a normal MC4R genotype. MC4R‐deficient subjects also have higher levels of fasting insulin compared to age‐ and BMI SDS‐matched children.
We have studied in detail the signaling properties of many of these mutant receptors and this information should help to advance the understanding of structure/function relationships and potentially provide in vitro support for the use of MC4R agonists in this group of patients [45].
Genes that affect the development and function of POMC neurons
There are a number of genetic obesity syndromes that are highly but not fully penetrant. Variant carriers are often obese, but not necessarily so. In most cases, there is strong biological evidence supporting the contribution of these variants to the overall clinical features. Several of these genes affect the development or function of the melanocortin neurons in the hypothalamus that regulate body weight (Fig. 4.4).
Neurons in the hypothalamus regulate energy intake and expenditure in response to leptin and other hormones. In the fed state, leptin acting via the leptin receptor (LEPR) stimulates primary neurons in the arcuate nucleus of the hypothalamus that expresses pro‐opiomelanocortin
