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 (POMC). The POMC‐derived peptide alpha MSH (melanocyte‐stimulating hormone) acts on the melanocortin 4 receptor (MC4R) expressed on neurons in the paraventricular nucleus to reduce energy intake and increase energy expenditure. At the same time, leptin inhibits neurons expressing agouti‐related peptide (AGRP), which switches off melanocortin receptors. When these and other key molecules such as BDNF (brain‐derived neurotrophic factor), SIM1 (single minded‐1), and Orthopedia (OTP) are disrupted by inherited mutations, people develop hyperphagia and severe obesity. Rare variants in the Semaphorin 3 ligands and receptors (SEMA3s) affect the development of POMC neurons. The star indicates genes that regulate the transcription of POMC (SRC‐1, PHIP) and in which rare variants are associated with obesity although it is not always fully penetrant in families.
Figure 4.4 Hypothalamic pathways regulating body weight.
Semaphorin 3s are a family of secreted proteins that direct the migration and function of axons during development. Rare variants in the genes encoding ligands, receptors and co‐receptors involved in Semaphorin 3 signaling are enriched in severely obese individuals compared to controls [46]. These variants cause a loss of function through multiple molecular mechanisms, but are not fully penetrant in families. There are parallels with genetic findings in hypogonadotropic hypogonadism, where incomplete penetrance, variable expressivity within and across families and oligogenic inheritance (i.e. more than one gene mutated in the same individual) exists. In mice, Semaphorin 3s acting via the neuropilin‐2 receptor direct the development of the melanocortin circuit formed by Pomc projections extending from the arcuate to the paraventricular nucleus of the hypothalamus [46]. Clinical features include learning difficulties, behavioral abnormalities, and neurological disorders including epilepsy as well as medication‐resistant constipation in childhood.
In the arcuate nucleus of the hypothalamus, leptin binding to its receptor phosphorylates STAT3 which interacts with the transcription factor steroid receptor coactivator (SRC)‐1, which modulates POMC transcription. Disruption of this interaction causes obesity in mice and rare human variants in SRC‐1 identified in severely obese people decrease leptin‐pSTAT3 mediated signaling and Pomc expression in cells [47]. Another gene that directly affects the transcription of POMC is PHIP (pleckstrin homology domain interacting protein). Obesity‐associated PHIP mutants decrease POMC transcription in cells [48]. PHIP deletions and frameshift mutations have been reported in patients with developmental delay, intellectual disability, dysmorphic features, and in some cases, obesity [49]. Some PHIP variant carriers were born with low birth weight, have reduced linear growth in childhood, hyperphagia, insulin resistance, and early type 2 diabetes.
Obesity syndromes associated with neurobehavioral phenotypes
The transcription factors Single‐minded‐homology 1 (SIM1) and Orthopedia (OTP) play a key role in the development of the hypothalamus. Loss of function mutations in SIM1 cause severe obesity with a phenotype that overlaps closely with MC4R deficiency [50, 51]. The transcriptional targets of SIM1 are unknown, but one potential target is the neuropeptide oxytocin. Oxytocin mRNA levels are reduced in mouse models of Sim1 deficiency and oxytocin administration reduces food intake in Sim1‐deficient animals [52]. Reduced number of oxytocin neurons and oxytocin expression are implicated in the hyperphagia and obesity seen in PWS [15, 53], a clinical syndrome caused by lack of expression of a cluster of maternally imprinted snoRNAs on chromosome 15 thought to be involved in alternative mRNA splicing. Both PWS and SIM1 mutation patients exhibit a spectrum of behavioral abnormalities which overlap with autism‐like features and could be related to reduced oxytocinergic signaling [50]. Oxytocin expression is also very low in severely obese mice with a loss of function point mutation in Otp [54]. A small number of severely patients with obesity with mutations in OTP and autistic behaviors have also been reported.
The neurotrophin brain‐derived neurotrophic factor (BDNF) is widely expressed in the brain and signals via the tropomyosin receptor kinase B (TrkB) to regulate neuronal function. Heterozygous deletions and mutations of the BDNF gene [55], and heterozygous loss of function mutations in TrkB have been reported in individuals with speech and language delay, hyperphagia and severe early‐onset obesity as well as hyperactivity, repetitive behaviors often considered to be autistic‐like, fearlessness and in some cases aggression [56].
Src‐homology‐2 (SH2) B‐adaptor protein‐1 (SH2B1) is an intracellular scaffolding protein that mediates signaling through a number of receptor tyrosine kinases and cytokine receptors including the leptin receptor and TrkB. Chromosomal deletion of a region on 16p11.2 which includes SH2B1 [57] and heterozygous mutations in the gene itself [58] are associated with dominantly inherited severe early‐onset obesity and disproportionate insulin resistance. In these studies, we observed that some mutation carriers experience behavioral problems including social isolation and aggressive behavior [58, 59]. Intriguingly, mice with brain‐specific deletion of Sh2b1 gain weight and develop reactive aggression, fatally attacking other males [60]. Brain‐specific restoration of Sh2b1 completely reverses inter‐male aggression.
Conclusions
Whilst individually monogenic obesity disorders are rare, cumulatively, at least 20% of children with severe obesity have rare chromosomal abnormalities and/or highly penetrant genetic mutations that drive their obesity. This figure is likely to increase with wider accessibility to genetic testing and as new genes are identified. A genetic diagnosis can inform management (many such patients are relatively refractory to weight loss through changes in diet and exercise) and can inform clinical decision‐making regarding the use of bariatric surgery. Importantly, some genetic obesity syndromes are treatable [30, 31]. There are a number of drugs in clinical trials targeted specifically at patients with genetic obesity syndromes. Specifically, setmelanotide, an MC4R agonist has been used effectively in phase 2/3 clinical trials of POMC and LEPR deficiencies and is being explored for the treatment of other genetic obesity syndromes affecting the melanocortin pathway (including BBS). Ultimately, understanding how these