**5. Epigenetics and obesity**

ring in a subset of patients with WAGR (Wilms tumor, aniridia, genitourinary malformations

Oligogenic obesity or common obesity is the result of the set of behavioral, environmental and genetic factors that may influence individual responses to diet and physical activity [131]

**Figure 4.** Gene–environment interactions in common obesity. Adapted with permission from Mutch and Clément

The obesogenic changes of our environment in recent decades, especially the unlimited supply of cheap food with high palatability and high energy density, associated with genetic suscept‐

The recent rapid rise in prevalence of childhood obesity suggests that, probably, environmental factors have a large impact on body weight in patients with common obesity although individual responses to these environmental factors are influenced by genetic factors called

Any of a group of alleles, at distinct gene loci that collectively control the inheritance of a quantitative phenotype or modify the expression of a qualitative character, are termed "polygenic" variants. A polygenic variant by itself has a small effect on the phenotype; only in combination with other predisposing variants does a sizeable phenotypic effect arise. Potentially, many such polygenic variants play a role in body weight regulation. It is estimated that the total number of genes with a small effect most likely exceeds [133]. These genes are involved in a variety of biological functions such as the regulation of food intake, energy expenditure, carbohydrate and lipid metabolism and adipose tissue development [131].

ibility are the causes of the current obesity epidemic [132].

and retardation) syndrome [62].

232 Adiposity - Omics and Molecular Understanding

**4.4. Oligogenic obesity**

(**Figure 4**).

[131].

susceptibility genes [3].

Heritability estimates of BMI from twin studies range from 50 to 90% [143], so it plays a fundamental role in determining body weight. However, this latest figure appears in con‐ tradiction to the evidence of an epidemic increase in pediatric obesity over the last 20 years, time totally inadequate to record permanent changes in the genome. Only the reprogram‐ ming of gene expression through epigenetic modifications resulting from relevant environ‐ mental changes that have taken place mostly in the early periods of life may partially justify this phenomenon [11]. Epigenetic regulation of gene expression emerged in the last few years as a potential factor that might explain individual differences in obesity risk [144]. Epigenetics can be defined as heritable changes that are mitotically stable (and poten‐ tially meiotically) and affect gene function but do not involve changes in the DNA se‐ quence [145].

Currently, there is a growing interest in the study of the relationship between genetic variation, epigenetic variation and disease simultaneously. The two main mechanisms that lead to epigenetic changes are DNA methylation, and the alterations to histone proteins that alter the likelihood that specific genes are transcribed [146, 147].

Interindividual variations in epigenetic changes like CpG methylation can potentially alter gene function and predispose to obesity. The variation in the degree of methylation, in fact, is able to modulate the expression of genes involved in controlling hypothalamic appetite [148]. Using a genome‐wide approach, obesity has been related to changes in DNA methylation status in peripheral blood leukocytes of lean and obese adolescents for two genes: in the *UBASH3A* (*ubiquitin‐associated and SH3 domain‐containing protein A*, OMIM \*605736, 21q22.3) gene, a CpG site showed higher methylation levels in obese cases, and one CpG site in the promoter region *TRIM3* (*tripartite motif‐containing protein 3*, OMIM \*605493, 11p15.4) gene, showed lower methylation levels in the obese cases [149]. Also the obesity risk allele of *FTO* has been associated with higher methylation of sites within the first intron of the *FTO* gene, suggesting an interaction between genetic and epigenetic factors [150]. In addition, the obesity risk allele of *FTO* affects the methylation status of sites related to other genes (*KARS* [16q23.1; OMIM \*601421], *TERF2IP* [16q23.1; OMIM \*605061], *MSI1* [12q24.31; OMIM \*603328], *STON1* [2p16.3; OMIM \*605357] and *BCAS3* [OMIM \*607470]), showing that the *FTO* gene may influence the methylation level of other genes [151]. Finally, a recent work has demonstrated that hypermethylation of the *POMC* gene plays an important role in preparing to obesity by reducing the expression of the gene itself [148].

Epigenetic changes usually occur during prenatal development or the early post‐natal period. Already *in utero*, in fact, there may be a switch of energy balance resulting from exposure to specific environmental factors, resulting in epigenetic changes that can affect the potential of the fat mass of offspring. For example in a recent work, the methylation status of CpG from five candidate genes in umbilical cord tissue DNA from healthy neonates was measured, and it was found that higher methylation levels within promoter region of *RXRA* (*retinoid X receptor, alpha*, OMIM \*180245, 9q34.2) gene, measured at birth, were strongly correlated with greater adiposity in later childhood [152]. Maternal nutrition is a major factor leading to epigenetic changes. Thus, the levels of vitamins consumed in pregnancy such as folate, methionine and vitamin B12, which affect methylation, become very important [147]. One study showed that prenatal exposure to malnutrition can determine abnormal DNA methylation resulting in epigenetic modifications that remain for the whole existence and that predispose to obesity and metabolic and cardiovascular risk in later life [153]. On the other hand also glycemic status during pregnancy is an important factor; in fact, hyperglycemia, as well as having a strong impact on the child's weight, can increase the risk of developing insulin resistance and obesity [147].
