Metabolic Syndrome and Obesity in Childhood and Adolescence

W. Kiess, M. Wabitsch, C. Maffeis, A. M. Sharma, W., Kiess, M., Wabitsch, C., Maffeis, A.M., Sharma, Wieland Kiess, Wieland, Kiess

• Publisher: S. Karger
• Year: 2015
• Print ISBN: 9783318027983
• eBook ISBN: 9783318027990
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

Despite the fact that the prevalence of obesity in early childhood has been stable and is no longer increasing in many developed and industrialized countries, the incidence of both obesity and full-blown metabolic syndrome in children and adolescents is still very high. Obesity is a major disease burden in all societies and needs to be prevented early in life. New approaches are eagerly sought and absolutely necessary. This book presents a comprehensive and state-of-the-art summary of current and new knowledge in this critical field. Crucial issues such as nutrition and genetics are described in detail. In addition, new ideas such as e-health and the consequences of urban living conditions are explored. Last but not least, modern treatment concepts and prevention even at an early age are competently discussed. Offering a valuable update on new developments in obesity research and the treatment in children and adolescents, this book is essential reading for all pediatricians and health-care professionals who look after young patients on a regular basis.

Causes

Kiess W, Wabitsch M, Maffeis C, Sharma AM (eds): Metabolic Syndrome and Obesity in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2015, vol 19, pp 31-39 (DOI: 10.1159/000368103)

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Genetics of Obesity in Childhood and Adolescence

Yvonne Böttcher · Peter Kovacs

IFB AdiposityDiseases, Medical Faculty, University of Leipzig, Leipzig, Germany

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Abstract

Obesity is controlled by both genetic and nongenetic factors. Considering BMI as a simple measure of obesity, heritability estimates reach 0.7 for both adults and children. Explaining the heritability of common polygenic obesity remains one of the major challenges in obesity research. Whereas candidate gene and genome-wide linkage studies dominated the search for obesity susceptibility genes over the last two decades, recent advances in genotyping technologies, enabling the high-throughput testing of millions of variants in thousands of individuals, have shown genome-wide association studies (GWASs) to be an efficient tool to identify novel loci associated with obesity. GWASs have revealed that more than 30 polymorphisms are significantly associated with obesity, including those mapping within genes such as FTO, TMEM18, and MC4R. Although many of these genes seem to influence childhood obesity as well, recent GWASs uncovered a strong association of novel loci (OLFM4 and HOXB5) with common early-onset obesity. Future studies need to address the biological role of these novel genes in obesity's complex pathophysiology, as well as its missing heritability, since only a small proportion can be explained so far.

© 2015 S. Karger AG, Basel

Introduction

Obesity is one of the major predictors of common civilization diseases such as type 2 diabetes (T2D), hypertension, cardiovascular diseases, and associated forms of cancer and thus represents a major public health burden [1]. In addition, obesity is strongly linked to psychological disorders, at least in part due to social stigmatism, which leads to further excess weight gain. Considering BMI as a simple measure of obesity, the prevalence of obesity increased rapidly during the last decade. It has been estimated that 1.12 billion adults will become obese (BMI >30) and that more than 2 billion will be overweight (BMI >25) by 2030 [2]. The epidemic proportion of obesity in adults mirrors the situation in children, among whom the incidence has increased dramatically and is expected to reach ~30% in the United States by 2030 [3]. Whereas a small proportion of obesity can clearly be attributed to monogenic forms caused by rare genetic defects, it is well appreciated that common ‘epidemic’ obesity is a complex polygenic disease with both genetic and environmental determinants. In particular, the adoption of a modern lifestyle, manifested by easy access to high-calorie food and accompanied by reduced energy expenditure, represents a major unfavorable environmental component that is contributing to the ongoing epidemic expansion of obesity worldwide [4, reviewed in 5].

Nevertheless, there is no doubt that obesity has genetic components. Major evidence comes from family, twin, and adoption studies, which have provided heritability estimates for BMI as high as 70% in both adults and children [6, 7]. Maternal or paternal obesity is one of the crucial predictors of an increased risk of childhood obesity, with the highest risk occurring when both parents manifest obesity [8]. Nevertheless, as for any other complex polygenic trait, obesity is clearly affected by the environment, which, in a complex interplay with genetics, may result in the disease phenotype.

The search for obesity susceptibility genes has focused on candidate gene and genome-wide strategies. Genome-wide linkage studies represented major approaches for identifying obesity genes over the last two decades. However, advances in genotyping technologies allowed the replacement of these strategies by genome-wide association studies (GWASs). Moreover, admixture mapping based on recent differences in genetic ancestries have revealed a significant relationship between ethnicity and obesity for several genetic regions [9].

This review aims to elaborate the current knowledge of the genetics of obesity.

Polygenic Obesity

Despite the knowledge gained from lessons in monogenic obesity, explaining the heritability of polygenic obesity remains a major challenge in obesity research. This challenge is attributable to the polygenic nature of common obesity as well as to the strong influence of environmental factors. Two major approaches have been used to investigate the components underlying the genetics of obesity: (i) analyses of candidate genes based on their known biological function related to regulation of metabolism and (ii) hypothesis-free genome-wide strategies, both potentially uncovering genes with yet-unknown roles in the pathophysiology of human obesity.

Candidate Gene Approach

The selection of plausible candidate genes for genetic analyses requires a priori knowledge about the pathophysiology of a disease and about the gene's/protein's function. Comprehensive studies on genes regulating energy balance and glucose/insulin metabolism resulted in numerous sequence variants that were significantly associated with obesity and related traits. Despite recent advances in high-throughput genotyping technologies, allowing the performance of large-scale genome-wide screening studies, the candidate gene approach still deserves researchers’ attention. In particular, it provides an efficient tool to verify and/or to finely map the most promising regions from genome-wide efforts and to elucidate the role of rare variants potentially contributing to polygenic obesity. For instance, rare variants in two genes controlling the endocannabinoid system, the fatty acid amide hydrolase gene (FAAH) and the monoglyceride lipase gene (MGLL), were shown to be associated with extreme obesity and metabolite levels [10].

Fatty Acid Synthase Gene

Human fatty acid synthase (FASN) is the major determinant of the de novo synthesis of long-chain fatty acids from acetyl-CoA, malonyl-CoA, and NADPH [11]. Inhibition of the FASN causes a fast decrease in fat stores in mice, suggesting a role for the FASN in energy homeostasis, which makes its gene an attractive candidate for systematic genetic analyses [12]. In addition, FASN represents a strong positional candidate gene since it maps within a linkage region on chromosome 17q25, which was identified in a genome-wide family-based scan for obesity susceptibility genes in Pima Indians from Arizona. In subsequent fine-mapping studies, the contribution of FASN to human body weight and the percentage of body fat was investigated not only in Pima Indians but also in other ethnic populations [13]. A polymorphism predicting the amino acid substitution Val1348Ile has been shown to be associated with the percentage of body fat and the 24-hour substrate oxidation rate in Pima Indians [13]. Moreover, the likely protective effects of this variant against obesity have been supported by data from children and adolescents from Germany [14]. Interestingly, the polymorphism seems to have stronger effects in boys, thus suggesting sexual dimorphism in FASN action. Additionally, studies on mRNA expression that showed correlations of increased FASN mRNA levels in adipose tissue with visceral fat accumulation and impaired insulin sensitivity clearly suggest a role for the FASN in the pathophysiology of obesity [15]. Consistent with this finding, obesity-related FASN genetic variants have been shown to be associated with mRNA expression in visceral and subcutaneous adipose tissue [16].

Genome-Wide Strategies

Linkage Analyses

Family-based genome-wide linkage scans offer a unique tool to assess the co-segregation of highly polymorphic genetic markers with a phenotypic trait/disease. Whereas this strategy turned out to be very efficient for monogenic forms of obesity, less success has been achieved in polygenic obesity. Moreover, the associations of genetic variants with obesity that were identified in linkage studies were not replicated in subsequent efforts, thus suggesting a small increase in the risk of obesity for these common variants.

The ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1), which maps to chromosome 6q, is one of the few representatives identified via genome-wide linkage analysis as linked to childhood obesity and associated traits [17]. The encoded protein ENPP1 binds to the α-subunit of the insulin receptor and inhibits its insulin-mediated conformational changes, autophosphorylation, and tyrosine kinase activity [18]. A nonsynonymous K121Q polymorphism in exon 4 of ENPP1 has been reported to be strongly associated with insulin resistance in healthy, nonobese individuals [19]. Subsequent studies in distinct populations confirmed the associations of the K121Q variant with insulin resistance and T2D [20, 21]. Consistent with this finding, positional cloning within the chromosomal region reve...

Table of contents

• Cover Page
• Front Matter
• Definitions and Clinical Aspects
• Causes
• Consequences
• Societal Aspects and Prevention
• Obesity Management
• Author Index
• Subject Index