Читать книгу Clinical Obesity in Adults and Children - Группа авторов - Страница 87

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.