New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

Abstract

Historically, some genetic syndromes and monogenic forms of obesity have been identified by clinical features and by sequencing candidate genes in patients with severe obesity. The phenotypic expression of genetic factors involved in obesity is variable, thereby allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. Many of the findings emerged from studying families who displayed a classical Mendelian pattern of inheritance. On the contrary, patients with syndromic obesity show a various degree of intellectual disability, different dysmorphic features, and organ-specific abnormalities. But to date, not all involved genes have been identified so far. New diagnostic tools, such as genome-wide studies, array CGH, and whole-exome sequencing, have highlighted more complex models of inheritance, and even more candidate genes were identified. This increase of knowledge may provide insights into the mechanisms involved in the regulation of body weight and finally lead to specific treatments. In these patients, hyperphagia is often a primary phenotypic component. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present today with a lack of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. We have evaluated retrospectively the literature data on weight, body mass index (BMI), clinical features, treatments, and treatment response in pediatric patients with forms of genetic obesity. However, this chapter provides an updated picture of emerging knowledge outlined by the more comprehensive genetic approaches, trying to outline more candidate genes for these forms of genetic obesity. Relevant papers will be identified through systematic searches of the PubMed, EMBASE and Cochrane databases. All published studies in the English language concerning these disorders will be evaluated. Keywords in the

Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus

“…In this study, we showed that APOC3 rs2854116 C-allele carrier patients have a six-fold higher risk of developing MAFLD in a dominant model. Our findings are also consistent with previous reports that the APOC3 rs2854116 genetic variant leads to increased plasma concentrations of apolipoprotein C3, resulting in hepatic insulin resistance and MAFLD in multiethnic populations[ 23 , 45 , 46 ].…”

“…The polymorphism in the promotor region of the APOC3 rs2854116 (-455T>C) gene has been extensively studied and has been found to be related with insulin resistance at the transcriptional level. Consequently, the overexpression of APOC3 , which functions to inhibit lipoprotein lipase and the cellular uptake of triglyceride-rich lipoprotein particles, may result in hypertriglyceridemia, as has been confirmed by in vivo and clinical studies[ 23 , 24 , 42 - 44 ]. In this study, we showed that APOC3 rs2854116 C-allele carrier patients have a six-fold higher risk of developing MAFLD in a dominant model.…”

“…Additionally, other studies indicate that genes involved in the lipid metabolism pathway, such as APOC3, APOB, APOA5, and LIPC , are associated with MAFLD[ 15 - 22 ]. Moreover, GHRL and LEP also exhibit an association with MAFLD pathogenesis[ 23 - 25 ]. In a previous study, it was shown that the APOC3 rs2854116 is associated with elevated serum levels of triglycerides, while this genotype did not affect the incidence of lipoatrophy after adjusting for gender and stavudine (d4T)-containing regimens in Thai people living with HIV[ 26 ].…”

Impact of Genetic Variations and Epigenetic Mechanisms on the Risk of Obesity

“…Syndromic obesity includes Bardet-Biedl, Prader-Willi, Alstrom, and Smith-Magenis syndromes, characterized by obesity as the predominant phenotype and associated with disorders such as mental retardation, congenital defects in organs, dysmorphism of the limbs, or endocrine and facial dysfunction. Although numerous studies have revealed the genes or chromosomal regions involved in the etiology of many of these syndromes, their relationship with the development of obesity is still unknown [10,20,55]. Bardet-Biedel syndrome (BBS) is a rare autosomal recessive ciliopathy, characterized by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, mental retardation, and hypogonadism.…”