Obesity: Underlying Mechanisms and the Evolving Influence of Diet

Lesli Hingstrup Larsen 0 ) Department of Human Nutrition, Faculty of Science, University of Copenhagen , Rolighedsvej 30, 1958 Frederiksberg C, Denmark Obesity is determined by both genetic and environmental factors. Since 2007, 52 genes have been associated with obesity and obesity-related measurements in genome-wide association studies (GWAS), among these the fat and obesity-associated gene (FTO). Despite the success in identifying genes predisposing to obesity, these GWAS hits only account for approximately about 5 % of the estimated obesity heritability and do not predict who will become obese and who will not. The missing heritability might be accounted for by gene-gene and gene-environment interactions. Most consistently, physical activity has been shown to attenuate the effect of FTO on obesity. Several studies have examined gene-diet interactions in relation to obesity, but only a few suggestive interactions have been identified. This is most probably due to small effect sizes of the interactions and thereby a demand for large samples sizes and accurate measurements of exposures and outcomes. In addition to SNPs, epigenetic changes have been suggested to account for some of the missing heritability, and epigenetic changes have been shown to be induced by dietary intake of mothers, in utero conditions, and early nutrition and can lead to increased risk of developing obesity. Recently, the intestinal microbiome, the collected genome of the bacteria, also has been associated with obesity and with specific dietary profiles. The underlying mechanisms determining the susceptibility to obesity do not only include the genome but also the epigenome and the microbiome that can be modified by diet, and by genotype, adding to the complexity of determining the contributors to obesity. - Obesity is prevalent in westernized countries and has a high incidence in developing countries [1] and with the observed association with an increased overall mortality [2], obesity is a pandemic and a worldwide problem. The increase in the percentage of obese individuals in the population during the past 30 years has been mostly attributed to a change toward a more energy-dense diet and sedentary life, but other factors, including maternal age, infections, and sleep deprivation also have been suggested to contribute to the obesity pandemic [3]. Despite the apparent obesity-promoting environment and a general increase in overweight and obesity on the population level, the individuals response to the environment also is attributable to nonenvironmental factors. Studies of twins and adoptees have shown that monozygotic twins are more concordant for obesity than dizygotic twins, and adoptees are more similar in body mass index (BMI) to their biological, than to their adopted parents [4, 5], making it likely that there is a significant heritable component that determines susceptibility to obesity. The heritability (h2) is estimated to be relatively high by twin studies and low by family studies, but a general estimate of obesity heritability is that it explains approximately 65 % of the variance in BMI [6]. Thus, in addition to the environmental factors giving a high rise in the worldwide prevalence of obesity, genetic predisposition may explain some of the interindividual variance in the given environment. Yet, it has been suggested that the heritability of obesity has been overestimated due to interactions between genes and gene and environment [7 ] and that epigenetic factors, which affect gene transcription without changing the DNA sequence, might explain some of the estimated obesity heritability [8]. Alternatively, the common diseasecommon mutation theory might not apply, and more of the variation in BMI might be explained by relatively rare mutations. Additionally, it has been recently discovered that our other genomethe collected genome of the gut bacteria (microbiome)is associated with obesity [9, 10], suggesting that nonhuman genetic factors also might influence obesity development. Genetic Variation and Obesity Because obesity is a common disease, it has been assumed that the major heritable part of obesity would be common genetic variants, or single nucleotide polymorphisms (SNPs). Still, mutations with a relatively low frequency, and possibly unique for the individual/family, have been shown to lead to severe obesity. Monogenic obesity is mostly caused by mutations in genes in the leptinmelanocortin signaling pathway or genes expressed in hypothalamic nuclei [11]. Mutations reducing the activity or expression of the melanocortin 4 receptor (MC4R) are the most common form of monogenic obesity occurring with a frequency of 26 % in individuals with obesity [1114]. Even with an established link between molecular function (in vitro) of the MC4R mutations and ad libitum food intake [12], there is an age-dependent penetrance of the obese phenotype [14] and environmental factors do still influence MC4R monogenic obesity [15]. A few studies, except for the treatment with recombinant leptin for leptin-deficient children [11], have examined treatment possibilities for individuals with monogenic mutations in the leptin-melanocortin pathway. The studies of lifestyle interventions for individuals with mutations in proopiomelanocortin (POMC) or MC4R show that weight loss on either diet or diet and physical activity was similar to obese individuals without mutations in these genes [1517], but the children with MC4R mutations were not successful in maintaining their weight loss compared with noncarriers [17]. There are indications the MC4R deficiency also might decrease weight loss after bariatric surgery, whereas MC4R haploinsufficiency does not affect weight loss after Rouxen-Y gastric bypass (RYBG) [18, 19]. Before the genome-wide association study (GWAS) era, genome-wide linkage studies that used polymorphic markers to examine the entire genome for co-segregation with obesity in families, and candidate gene studies that used prior knowledge of the gene function to select and identify mutations in relevant genes, identified 52 genomic regions (replicated by at least two studies) and 426 mutations associated with obesity [20]. Compared with genomewide linkage and candidate gene studies, GWAS have had a higher success rate of identifying robust associations between SNPs and obesity due to inclusion of a large number of SNPs covering the genome and a large number of individuals, and using a two-stage design with replication of the initial genome-wide significant SNPs (p < 5 10-8) [21 ]. Since the first GWAS that identified an association between fat mass- and obesity-associated gene (FTO) and BMI for a population of 4,892 British individuals with type 2 diabetes with replication in 38,759 individuals [22] and for an population of 4,741 Sardinian individuals with replication in 3,205 individuals [23], the number of published GWAS has increased greatly. Although with a smaller and smaller (...truncated)