Читать книгу Clinical Obesity in Adults and Children - Группа авторов - Страница 86

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.