Genes are not “naked” in our genome but are subject to chemical modification regulating gene activities [75,76]. This process includes DNA methylation, RNA-mediated processes, and histone modifications, which are some of the mechanisms included in epigenomics and regulate genomic stability and structure [77]. Some studies identified CpG sites associated with obesity and suggested that variability and methylation could predict obesity [78]. Other CpG sites were associated with BMI and waist circumference [79]. Epigenetic changes can be influenced by environmental factors, such as diet, physical activity, and exposure to toxins. Studies have shown that maternal obesity and gestational diabetes can lead to epigenetic changes in offspring, which can increase the risk of obesity and metabolic disorders later in life [77]. For this reason, it is crucial to identify and classify epigenetic marks on the genome of obese individuals to understand how each susceptibility gene is read to produce a distinct phenotype. This also provides a better explanation of how the environment plays a significant role in influencing how genes are expressed. Since 2013, several association studies have been performed to map the epigenome (EWAS) and understand the various expressions of genes in different tissues. These studies heralded a new era in the study of the genetics of obesity [80,81]. EWAS demonstrated that alteration in DNA methylation is most often a consequence of adiposity [82]. In studies conducted in obese children, genes such as ABCC5, ARID1B, CD247, CHD3, CNTN1, CPNE6, EEFSEC, FAM53B, GABBR1, IGFBP6, KCNQ1, MAD1L1, RPS6KA2, SNO2, SH2B2, SLC43A1, SLCO3A1, STK40, and SYNJ2 are characterized by changes in DNA methylation [83,84]. Interestingly, some studies show how fetal under- and over-nutrition, regulated by maternal diet, are associated with an increased risk of obesity [85]. Individuals prenatally exposed to famine were at higher risk of becoming overweight [86,87]. People exposed to Dutch Hunger Winter have a lower degree of DNA methylation of the imprinted IGF2 gene (Data obtained by comparing unexposed siblings) [86]. Mothers who suffered hunger show alteration in DNA methylation of genes that play a role in metabolic diseases, including INSIGF2, GNASAS1, MEG3, IL10, and LEP [88]. Other studies have detected, in overweight pregnant women, an increase in DNA methylation in four CpG sites (MMP7, KCNK4, TRPM5, and NFKB1) in cord blood DNA [89]. Offspring of obese and underweight mothers show different methylation patterns compared to the offspring of normal-weight mothers [90].

Micro-RNA (miRNA) dysregulation has also been observed in obesity [91]; miRNAs are short non-coding RNA molecules that post-transcriptionally repress gene expression by binding to untranslated regions and encoding target mRNA sequences. It has been demonstrated that miR-27a, miR-103, and miR-143 are upregulated in the adipose tissue of obese individuals. Furthermore, miR-122 has been implicated in the development of non-alcoholic fatty liver disease (NAFLD). Furthermore, several miRNAs are differentially expressed in obese individuals with insulin resistance versus those without insulin resistance [1]. miRNAs could be used as biomarkers of obesity and related disorders, but further validation and qualification research is needed to define them as reliable genomic biomarkers.

The study of the epigenetics of obesity is of particular interest for developing and activating prevention programs at the population level. Indeed, as stated by Danielle Reed, “Epigenetics is sort of like writing in pencil, whereas genetics is really writing in pen” [92]. This means that it is possible to intervene on social determinants and nutritional profiles, for example, to reduce obesity levels.

It is conceivable to foresee that, in the coming years, genetic analysis technologies will identify obesity susceptibility genes, and PRS algorithms will be available on a large scale to identify individuals at high risk of developing obesity and related diseases from birth or before. A child with a predilection toward a genetic form of obesity may be treated with a particular diet, or they may be metabolically “reprogrammed” with the administration of drugs, hormones, and, perhaps, in some rare cases of monogenic obesity, with gene therapy. All this presupposes an accurate medical history and adequate genetic counseling before and after the test. A detailed family history, as well as psychosocial history, diet assessment, and physical activity/exercise are key elements in the diagnostic and therapeutic process of obesity. In fact, only after excluding endocrine causes of obesity and syndromic forms will it be possible to carry out genetic or epigenetic tests to identify adequate and actionable therapeutic targets. Identifying the genetic variants associated with diet-related diseases to study the variability of an individual’s response to diet and nutrition is now considered an interesting and innovative line of research [93]. Studies of the genetics-related effects of nutrition focus on specific gene and SNP variants and how they interact with dietary habits (nutrigenomics). Not only what we eat, but also when it becomes important for some individuals, is important. In fact, eating late has been linked to less weight loss in the AA genotype of PLIN1 14995 A > T carriers [94]. Another example is shown by how the best results of a low-fat diet were found in overweight and obese subjects with the IRS1 rs2943641 CC genotype [95]. Another study indicated that overweight and obese individuals with the T allele of PPM1K rs1440581 have greater weight loss on a low-carbohydrate diet [96]. Additionally, a genetic variant in the FGF21 region improves the risk of developing obesity, determining the preference for carbohydrate intake [97]. These studies demonstrate that there is an interaction between diet and genes that supports precision nutrition interventions that consider interindividual variability [98].

It is indisputable that food has a huge impact on mental and physical health. Genetic and biochemical knowledge today make the time ripe for clinical trials of specific approaches to the prevention or treatment of diseases, such as obesity, using food as medicine [99].

The Food and Drug Administration (FDA, Silver Spring, MD, USA) has approved two drugs intended for patients with genetic causes of obesity: metreleptin and setmelanotide. The other drugs, such as semaglutide, liraglutide, phentermine–topiramate, and naltrexone–bupropion is approved for weight loss in the general population and can be used to treat patients with genetic obesity. Metreleptin is a leptin analog used to treat patients with congenital generalized lipodystrophy in leptin-deficient patients with mutations in the leptin gene. However, metreleptin cannot be used in patients with leptin receptor mutations or mutations downstream of the leptin signaling pathway. The use of this drug is monitored by the FDA’s Risk Evaluation and Mitigation Strategies (REMS) Panel. Setmelanotide is a MC4R agonist used in obese patients with genetic mutations in the POMC, PCSK1, or LEPR genes and Bardet Biedl syndrome. The advantage of this drug is that it acts directly on the MC4R receptor, bypassing multiple targets, which may be mutated in the leptin pathway.

From what has been described above, it is, therefore, possible to state that distinct interventions of a nutritional or pharmacological type can modify the epigenome of the body for the benefit of patients with obesity. However, in some cases, it is a necessary recourse to resort to bariatric surgery. This, too, can determine epigenomic changes, such as the pattern of exosomal micro-RNAs of adipocytes, and it can cause epigenetic changes in differential methylated regions in HOXB1, PRKCZ, SLC38A10, and SECTM1 genes [100].

Regarding surgical treatment, according to some studies, outcomes are worse in patients with Prader-Willi syndrome than in patients with common obesity [101]. According to other studies, the results obtained in patients undergoing gastrectomy and mini gastric bypass were the same in PWS patient and in the control group [101]. There are some studies on patients with monogenic obesity associated with alteration of the leptin/melanocortin pathway; the outcome of surgery in a patient with a homozygous variant in the LEPR gene showed that there is an initial weight loss maintained for six years, and then the patient returned to the obese form [102]. A large study was carried out by a Dutch group on patients, including 30 of whom who had mutations in genes such as POMC and PCSK1, with results not significantly different from noncarrier patients of these mutations [103]. An additional Chinese study analyzing patients carrying variants in the LEP, LEPR, SIM1 and PCSK1 genes demonstrated significantly less weight loss at six years than patients without the variant [104]. Concerning MC4R variants, studies show how there is an identical weight loss at one year for patients with the MC4R variants and the control group [105] or without significant differences after one and two years after RYGB (Roux-en-Y Gastric Bypass) [105]. Cooiman et al., after revisional RYGB after one and two years of follow-up, observed that MC4R patients have insufficient weight loss [103].

Even regular exercise can be considered an “environmental therapy”, as it can cause widespread changes in DNA methylation in the RUNX1, NDUFC2, THADA, MEF2A, and PRKAA2 genes. Indeed, it has been shown that, in patients who lose weight, their methylation profiles of the RYR1, TUBA3C, and BDNF genes resemble those of lean individuals [77,85,100].