**8. Treatment options in patients with genetic obesity**

able to narrow down the locus associated with greater accuracy, so this approach took place in the genome‐wide linkage studies for common disease [3]. This new approach has found about 30 loci associated with obesity and high BMI. The strongest association is with FTO gene (the fat‐mass and obesity‐related gene) mutations. Also BDNF, SH2B1 e NEGR1 mutations are associated with obesity and support that obesity is a disorder of hypothalamic function [17].

Since the beginning of the genome‐wide association study (GWAS) era in 2005, a number of large GWASs have been conducted on obesity‐related traits in humans. A large meta‐analysis from 46 studies conducted by the Genetic Investigation of Anthropometric Traits (GIANT) [166] consortium identified 32 SNPs robustly associated with adult BMI. The majority of these SNPs demonstrated directionally consistent effects in age‐ and sex‐adjusted BMI in children and adolescents. However, even in combination, the 32 established SNPs explain <2% of the variation in BMI in either adults or children. The mismatch between the high heritability estimates from twin and other family studies (40–70%) and the small percentage of variation explained through GWAS (<2%) is called the problem of "missing heritability" [167, 168]. A portion of the missing heritability appears to be due to rare genetic variants and some non‐ additive genetic effects that are not found in analyses GWAS that showed only additional effects of common SNPs with minor allele frequencies (MAF) of >5%. Another part of the missing heritability can be explained by the fact that multiple additional common genetic mutations contribute to obesity, but they have a small effect that cannot be found by GWAS

New types of analyses, such as genome‐wide complex trait analysis (GCTA), analysis of uncommon (MAF 0.5–1%) or rare (MAF 0.5%) variants and structural variants not detected by GWAS arrays, epigenetic analysis and gene–gene interactions (epistasis), are helping to fill that gap [167]. The purpose of the novel approach called genome‐wide complex trait analysis (GCTA) is not to identify specific SNPs related to the target phenotype, but rather to estimate the total additive genetic effect of the common SNPs used on currently available DNA arrays

The rare variant—common disease hypothesis—suggests that rare variants contribute signifi‐ cantly to complex traits. Probably, the obese phenotype is the consequence of additive effects and interactions among multiple alleles with varying magnitude of effect. Actually, we know that only 1% of the human genome is transcribed into mRNA and translated into proteins. An additional 0.5% is regulatory regions that control gene expression. Functions of the remaining 98.5% of the genome remain unknown. Rare variants might be identified by massive genotyping or deep sequencing in large families thanks to novel techniques that sequence millions of DNA strands in parallel and at low cost such as next‐generation sequencing techniques [169].

Copy number variants (CNVs) represent another source of the heritability that is missed by GWAS studies. Copy number variants (CNVs) are products of genomic rearrangements, resulting in deletions, duplications, inversions and translocations [167, 170]. The most established CNV in the obesity field is a large, rare chromosomal deletion at 16p11.2; this deletion includes a small number of genes, one of which is *SH2B1*, known to be involved in leptin and insulin signaling. The search for CNVs in the context of obesity has proved fruitful,

analyses [168].

238 Adiposity - Omics and Molecular Understanding

[168].

The use of pharmacologic treatment for obesity is recommended by the American Academy of Pediatrics (AAP) as an adjunct to lifestyle changes when obesity‐related health risks exist and lifestyle changes have not been effective for an individual. In addition, the AAP recom‐ mends pharmacotherapy only for children with BMI ≥99th percentile [171]. On the other hand, the Endocrine Society has suggested limiting pharmacotherapy to patients with a BMI over the 95th percentile who have failed diet and lifestyle intervention, or in limited cases with a BMI over the 85th percentile and severe comorbidities [147]. Overweight children should not be treated with pharmacotherapeutic agents unless significant, severe comorbidities persist despite intensive lifestyle modification. In these children, a strong family history of NIDDM or cardiovascular risk factors strengthens the case for pharmacotherapy [172].

There are currently only a few drugs approved for the treatment of obesity; such drugs belong to different pharmacologic categories with different mechanisms of action. A major class of medications used in weight treatment is appetite suppressants also called anorexigenic agents. These drugs increase hypotalamic levels of norepinephrine, dopamine and serotonin‐promot‐ ing satiety and decreasing hunger [173]. Among the appetite suppressant drugs, sibutramine was used to treat obesity in children until recently. In 2010, sibutramine was withdrawn by the United States Federal Drug Administration (US FDA) and European Medicine Agency (EMA) for increased cardiovascular risk for individuals taking the medication [174]. As well, other drugs of the same class like ephedrine and fenfluramine were withdrawn from the market for their adverse effects [147]. With the withdrawal of sibutramine, orlistat and metformin are now the only available drugs for the treatment of pediatric obesity.

Orlistat, an inhibitor of pancreatic lipases, prevents the breakdown of triglycerides into absorbable fatty acids and monoglycerols. Thus, about one‐third of the dietary intake, triglycerides is not absorbed. It reduces body weight, total cholesterol and LDL cholesterol, and the risk of NIDDM in adults with abnormal carbohydrate metabolism. In USA, orlistat is approved by the FDA in adolescents older than 12 years [175]. It is associated with a significant fall in BMI of 0.7 kg/m2 , but treatment is associated with increased rates of side effects including abdominal discomfort, pain, steatorrhoea and decreased absorption of the fat‐soluble vitamins A, D, E and K. So, it is important to take those fat‐soluble vitamins supplementation 2‐h distance from orlistat administration [147]. Side effects are usually mild to moderate and generally decrease in frequency with continued treatment; this decrease may result from patients learning to consume less dietary fat to avoid these side effects. Typically, doses of 120 mg by mouth three times daily are needed for effectiveness [176, 177].

Although metformin has not been approved by the US FDA for the treatment of obesity, it may be effective as a weight loss agent in addition to its effects as a hypoglycemic agent. Its major site of action is the liver: the drug increases glucose uptake, decreases hepatic gluconeogenesis and reduces hepatic glucose production; also, metformin inhibits lipogenesis and increases insulin sensitivity and may have an effect as an appetite suppressant. The major benefits of the medication are reduction of food intake, weight loss, visceral fat reduction, improvement of the lipid profile and of the carbohydrate intolerance [172, 175, 178]. A systematic assessed five randomized controlled trials all with follow‐up of at least 6 months; compared to placebo, metformin reduced BMI by 1.42 kg/m2 in obese children [179]. Patients treated with metformin report abdominal discomfort, which improves when the drug is taken with food. There is also a risk of vitamin B12 deficiency; therefore, a multivitamin is recommended. The risk of lactic acidosis has been observed in adults but not seen in pediatric patients [147].

Octreotide, a somatostatin analogue, has been investigated as a treatment for hypothalamic obesity. It binds receptors on the beta cells of the pancreas and inhibits insulin release [147]. A study comparing octreotide with placebo has demonstrated statistically significant weight loss and statistically significant mean decreases in BMI among those treated with octreotide for 6  months [180]. Octreotide works better in patients with insulin hypersecretion and insulin resistance. A study has demonstrated that greater weight loss correlated with a greater degree of insulin hypersecretion [181]. The high cost of the drug and the various side effects (gastro‐ intestinal problems, gallstones, GH and TSH suppression, cardiac dysfunction) limit currently use [175].

In the case of monogenic obesity, subcutaneous injection of recombinant human leptin in children and adults with *LEP* mutations resulted in weight loss, mainly of fat mass, with a major effect on reducing food and hyperphagia, induction of puberty (even in adults) and improvement in T‐cell responsiveness [24, 25, 27, 182]. Leptin treatment works in patients with leptin deficiency or with bioinactive leptin, but on the other hand, leptin treatment is useless in LEPR‐deficient subjects, because the receptor mutations make it inactive [24, 183].

In the case of children with PWS, GH therapy can improve growth, body composition, muscle thickness, physical strength and agility, motor performance, fat utilization, and lipid metabo‐ lism [184–186]. The best response to GH in PWS patients is observed in the first 12 months of treatment. Although early treatment is important for the improvement in body composition, generally, in practice, it is possible to start treatment only after 2 years of age. Treatment can be started in a dose of 0.034 mg/kg/day (0.24 mg/kg/week) in infants, and toddlers and IGF‐1 and IGFBP‐3 levels are used to specify the dose of GH therapy. Benefits of continuing GH therapy in adulthood remain unclear although an improvement has been observed in body composition and cognitive functions in patients who received treatment only in adulthood. Contraindications for GH therapy in PWS patients are severe obesity, uncontrolled diabetes mellitus, untreated severe OSA, active cancer and psychosis [108].

A number of the PWS features, such as hyperphagia, obesity and behavioral anomalies, may be due to consequent hypothalamic hyposecretion of oxytocin for the reduction of paraven‐ tricular nucleus neurons. A few studies have investigated the capacity of exogenous oxytocin to improve these PWS features, but other research is necessary [183].

For MC4R‐deficient obese patients, currently, there are no specific treatments. Different MC4R agonists were studied in vivo in animal and human studies, and almost all studies are currently in the preclinical phase. These pharmacological MC4R agonists can restore normal activity in mutated receptors, and in obese animal, models cause decreased food intake, increased total energy expenditure, weight loss and weight‐independent improvement of insulin sensitivity after 8 weeks of treatment [43, 187].

and reduces hepatic glucose production; also, metformin inhibits lipogenesis and increases insulin sensitivity and may have an effect as an appetite suppressant. The major benefits of the medication are reduction of food intake, weight loss, visceral fat reduction, improvement of the lipid profile and of the carbohydrate intolerance [172, 175, 178]. A systematic assessed five randomized controlled trials all with follow‐up of at least 6 months; compared to placebo,

report abdominal discomfort, which improves when the drug is taken with food. There is also a risk of vitamin B12 deficiency; therefore, a multivitamin is recommended. The risk of lactic

Octreotide, a somatostatin analogue, has been investigated as a treatment for hypothalamic obesity. It binds receptors on the beta cells of the pancreas and inhibits insulin release [147]. A study comparing octreotide with placebo has demonstrated statistically significant weight loss and statistically significant mean decreases in BMI among those treated with octreotide for 6  months [180]. Octreotide works better in patients with insulin hypersecretion and insulin resistance. A study has demonstrated that greater weight loss correlated with a greater degree of insulin hypersecretion [181]. The high cost of the drug and the various side effects (gastro‐ intestinal problems, gallstones, GH and TSH suppression, cardiac dysfunction) limit currently

In the case of monogenic obesity, subcutaneous injection of recombinant human leptin in children and adults with *LEP* mutations resulted in weight loss, mainly of fat mass, with a major effect on reducing food and hyperphagia, induction of puberty (even in adults) and improvement in T‐cell responsiveness [24, 25, 27, 182]. Leptin treatment works in patients with leptin deficiency or with bioinactive leptin, but on the other hand, leptin treatment is useless

In the case of children with PWS, GH therapy can improve growth, body composition, muscle thickness, physical strength and agility, motor performance, fat utilization, and lipid metabo‐ lism [184–186]. The best response to GH in PWS patients is observed in the first 12 months of treatment. Although early treatment is important for the improvement in body composition, generally, in practice, it is possible to start treatment only after 2 years of age. Treatment can be started in a dose of 0.034 mg/kg/day (0.24 mg/kg/week) in infants, and toddlers and IGF‐1 and IGFBP‐3 levels are used to specify the dose of GH therapy. Benefits of continuing GH therapy in adulthood remain unclear although an improvement has been observed in body composition and cognitive functions in patients who received treatment only in adulthood. Contraindications for GH therapy in PWS patients are severe obesity, uncontrolled diabetes

A number of the PWS features, such as hyperphagia, obesity and behavioral anomalies, may be due to consequent hypothalamic hyposecretion of oxytocin for the reduction of paraven‐ tricular nucleus neurons. A few studies have investigated the capacity of exogenous oxytocin

For MC4R‐deficient obese patients, currently, there are no specific treatments. Different MC4R agonists were studied in vivo in animal and human studies, and almost all studies are currently

in LEPR‐deficient subjects, because the receptor mutations make it inactive [24, 183].

mellitus, untreated severe OSA, active cancer and psychosis [108].

to improve these PWS features, but other research is necessary [183].

acidosis has been observed in adults but not seen in pediatric patients [147].

in obese children [179]. Patients treated with metformin

metformin reduced BMI by 1.42 kg/m2

240 Adiposity - Omics and Molecular Understanding

use [175].

Finally, most recent studies on the treatment of obesity have focused on the potential role of plants used for obesity and its metabolic disorders treatments, exerting a positive effect on lipid and glucose metabolism, and anti‐inflammatory activity [188]. For example, green tea disclosed anti‐obesity effects in both *in vitro* and *in vivo*, decreasing adipose tissue through the reduction of adipocytes differentiation and proliferation, showing a positive effect in lipid profile, and lipid and carbohydrates metabolisms, and anti‐inflammatory activity [188].

However, in literature, the anti‐obesity properties and the mechanisms of action of some plants such as *Camellia sinensis, Hibiscus sabdariffa, Hypericum perforatum, Persea americana, Phaseolus vulgaris, Capsicum annuum, Rosmarinus officinalis, Ilex paraguariensis, Citrus paradisi, Citrus limon, Punica granatum, Aloe vera, Taraxacum officinale and Arachis hypogea* have been described [188]. However, polysaccharide macromolecules slowing the rate of carbohydrate and fat absorption have been also described reduce insulinemic peaks, enhancing β‐cell function and potentially restoring the insulin secretory reserve in patients with impaired glucose tolerance or NIDDM and genetic obesity history [189].

Another possible therapy for childhood obesity is bariatric surgery. There are 3 types of bariatric procedures: malabsorptive, restrictive and combination procedures. The first proce‐ dures are the jejunoileal bypass and the biliopancreatic diversion with duodenal switch that manage to lose weight by reducing nutrient absorption through the gut anatomical rearrange‐ ments; however, these procedures are not approved in children for their high morbidity and mortality. The Roux‐en‐Y gastric bypass (RYGB) is a combination procedure; it has become the most commonly performed bariatric surgical procedure, and it involves a reduction of stomach size and the reduction of intestinal absorptive capacity via the creation of a gastrojejeunal anastomosis [171, 172, 190]. Laparoscopic adjustable gastric banding (LAGB) is a wholly restrictive procedure, and it has been used more recently. This bariatric procedure is to place a balloon around the esophagogastric junction and inflate it with saline until you get the desired effect of the stomach size reduction. This procedure is recommended in children because it is reversible and does not create permanent intestinal rearrangements [171, 172, 191]. Laparoscopic sleeve gastrectomy (LSG) is a new and attractive option for young patients. It is a new restrictive procedure without the malabsorptive component present in other bariatric procedures. This technique involves the removal of a large portion of the stomach through a vertical resection, and the remaining stomach has a volume drastically reduced, with a capacity of around 100/150 ml. Weight loss outcomes in some study were similar between pediatric and adult patients at all time points, suggesting that LSG is similarly safe and effective in young and adult patients through at least 1 year of follow‐up [192].

The criteria for access to bariatric surgery in childhood are very restrictive: BMI >35 kg/m2 with severe comorbidities or >40 kg/m2 with comorbidities, Tanner stage 4 or 5, to achieve at least 95% of the growth estimate in the case of malabsorptive procedures, the ability to follow the post‐operative diet and exercise, an adequate social support, ability to follow constantly medical indications and treatment and appropriate treatment of psychological problems [190]. Also it is recommended that bariatric surgery be done only in centers that can provide a multidisciplinary pre‐ and post‐operative evaluation and psychological support both before and after the surgery [193].

Currently, data on bariatric surgery in children and adolescents with genetic obesity are limited and still controversial [183]. To date, bariatric surgery experience in treating children and adolescents with monogenic and syndromic forms of obesity is limited, and different bariatric procedures have been used with varying success [194]. Some studies have demonstrated the efficacy of bariatric surgery (in terms of weight loss and reduction of comorbidities such as obstructive sleep apnea, dyslipidemia, hypertension, diabetes mellitus and poor mobility) in patients with monogenic obesity (such as LEPR‐deficient patients and patients with hetero‐ zygous *MC4R* mutations, but not in patients with homozygous *MC4R* mutation [195]) and syndromic obesity (such as PWS, BBS, Alström syndrome) but, due to the limited number of cases, the long‐term efficacy and safety of bariatric surgery in genetic forms of obesity need further evaluation [183].

Even more in the early days are studies that try to correlate specific polymorphisms with response to bariatric surgery: For example, a study tried to find the presence of an association between several polymorphisms (including the *FTO* and *MC4R* genes) with post‐operative weight loss [196]; another study found that a 15q26.1 locus is significantly associated with weight loss after Roux‐en‐Y gastric bypass surgery [197]. Thus, there is some evidence for the use of genomics to identify response to surgical procedures; the identification of genetic contributors could be useful to select those individuals who will obtain a greater benefit from a bariatric surgery. However, these results have yet to be confirmed.
