POLSKI
Inheritance
For a couple of decades, we have faced the pandemic of obesity, both in children and adults. Recent statistics have revealed that 39 million of children younger than 5 years and 340 million older children are affected by excessive weight. Moreover, a disturbing trend in BMI is observed, with the index increasing by 0.32 kg/m2 per decade. Observational follow-up studies reveal that childhood obesity is associated with a 5.8-fold higher risk of obesity in adulthood compared to normal body weight in childhood [1]. Fifty-five per cent of children who have obesity in childhood remain obese in their teens, and 70% are obese after the age of 30 years. Among teenagers, the statistics are even more serious. As many as 80% of teenagers with obesity retain obesity as adults [2]. Those persons are at risk of comorbidities and complications of obesity. Not only is cardiometabolic risk significantly higher, but also, among others, the incidence of cancer, infertility, emotional and depressive disorders are increased. And this is not the end of the story because obesity increases the risk of excessive weight gain and metabolic complications in the offspring.
It is well known that children with obesity often have parents with obesity, and obesity often ‘runs in’ these families. The risk of obesity in a child is almost two-fold higher if the parents are obese or overweight [3]. It looks even worse if both parents are obese (OR: 12.0) or severely obese (OR: 22.3) [4]. Usually, in each family, there are several reasons for obesity „heritability”. Non-modifiable factors related to obesity persistence in families are mutations in obesity-related genes. It is estimated that 40–75% of BMI and abdominal adiposity are attributable to independent genetic influences [5]. Very rare causes of multigenerational obesity are autosomal-dominant pathogenic mutations in some genes where obese phenotype in observed in heterozygous patients. The mutations in the melanocortin-4 receptor (MC4R), detected in 3–5% of severely obese patients, are the most common form of genetic obesity; what is more, their inheritance is autosomal-dominant [6]. Most of the monogenic and syndromic forms of obesity are inherited in autosomal-recessive manner and the family history of obesity is not characteristic. Polygenic heritability of obesity is much more common, determined by the cumulative effect of risk variants in multiple genes related to hunger/satiety pathways, adipogenesis, metabolism and many others. Independently, each gene polymorphism has a small to moderate effect on the phenotype, but together, their effect is significant [7]. Locke et al., based on a GWAS of 340,000 people, identified 97 loci associated with BMI and estimated that these loci account for 2.7% of the variation in BMI. What is interesting is that the loci are ethnic-related, with different variants in different genes in various populations. Which translates into various obesity risks in particular populations depending on the historical background [7]. Our European population has been raised for the last 300 years in a stable food supply, which resulted in the elimination of 30 genes from our genotype as related to high cardiometabolic risk [7]. It was estimated that if genome-wide variation was taken into account, the effect on BMI could be as high as 21% [8]. Modifiable family-related obesity risk factors are well known: cultural, emotional, and parenthood style aspects of the lifestyle and diet. It is a reason for the necessity of involving the whole family in the process of therapy of the obese child.
However, parental obesity has not only environmental and genetic influence on the health of the offspring. Transgenerational inheritance of obesity is related also to epigenetic modifications of DNA. These modifications are related to methylation of CpG (cytosine prior guanine), histone and non-coding RNA modifications [9]. Methylation of cytosine located before guanine takes place usually at so called CpG island. The islands are located very often at the transcription start sites, which means that their methylation leads to silencing of the gene expression. Methylation within the gene’s body usually leads to gene expression. The negative association was shown between BMI in subjects with obesity and methylation at the leptin gene promoter and positive association for methylation status of members of the insulin signaling pathway [10]. Also, the modification of the histones (methylation and acetylation) can be related to the silencing of the genes expression through changes in chromatin structure – from euchromatin to heterochromatin. Histone modifications were found to regulate gene expression related to adipogenesis and appetite control [10]. Short and long non-coding RNA particles’ epigenetic modification is also a possible mechanism which can influence gene expression and have both been implicated in the pathogenesis of obesity.
Epigenetic modifications, as an effect of gene-environmental interaction, are related to dietary factors (amount of calories, micro- and macronutrients, compositions), gut microbiota, chemicals, and many other factors. Epigenetic programming can take place in germline cells (oocytes, sperm), during fetal life, in early postnatal development, and also throughout the lifespan. Some modifications are passed to the next generations, influencing the offspring’s phenotype. Moreover, it seems that epigenetic reprogramming is possible. It was shown that in rodents paternal obesity, modulates sperm microRNA content and germ cell methylation status, increasing the risk of excessive weight and insulin resistance in offspring even if they were on a normal-calorie diet [11]. What is important is that the paternal inheritance of obesity and metabolic disorders faded in severity with each generation. Maternal obesity, by its influence during pregnancy, can shape fetal body weight and metabolism. Wang et al. showed that obesity in mother can impair fetal mitochondriogenesis and brown adipose tissue development via upregulation of special miRNA - miR-204-5p [12]. Periconceptional BMI is a well-known risk factor of a child’s obesity. It is observed that children born from mothers who reduce body weight after bariatric surgery prior to conception have lower birth weight and risk of obesity than siblings born before weight reduction [13]. Conversely, when the offspring stays in an unhealthy environment or has unhealthy habits (e.g. a high-calorie diet), the epigenetic modification can increase, intensifying the severity of metabolic disturbances and obesity. An intervention of diet and physical activity in pregnancy was found to be associated with slight changes in the epigenome in fetal tissues. The intervention had an impact on the offspring’s body composition and DNA methylation in areas related to obesity, diabetes, adiposity, and birth weight [14].
Studying the changes of a phenotype related to epigenetic modifications and the expanding knowledge about transgenerational inheritance opens many possibilities for diagnostic algorithm elaborations, treatment interventions, and personalized approaches to children with obesity and their families. The treatment and prevention of childhood obesity is not only important for the present generation – to maintain a long life in good quality, but what is even more important, for the health of the future generations. Because a healthy, normal-weight future mother means healthy generations of offspring with low obesity and metabolic risk.
Treatment
Currently, there is no doubt that regardless of the primary cause or causes leading to the development of obesity, it is a disease that requires interdisciplinary diagnosis of its consequences and complications as well as multi-specialist, multifactorial treatment. To make the treatment of childhood obesity effective, the therapeutic process should be properly planned with the analysis of individual conditions. First of all, the causes of obesity disease should be taken into consideration (including genetic, iatrogenic, psychological, cultural, etc.). It is very important to determine the patient’s and family’s readiness to start treatment, including awareness of obesity as a chronic disease and belief in the possibility of its treatment. Modern obesity treatment is not only focused on reducing body weight, but above all on introducing changes that will restore the body’s energy and metabolic balance. Therefore, the treatment process can be long, expensive, and require the involvement of various methods and specialists in various fields. Regardless of the choice of the leading treatment method, the basis of therapy is always the introduction of permanent changes in diet habits and lifestyle, and the patient and his family must be ready and determined to make these changes. The readiness to change refers to a patient’s interest in changing a behavior and their belief that they can bring about this change [15].
Factors that can significantly influence this readiness and motivation are as follows: perceptions of weight status, health challenges, nutrition habits, and access to physical activity are influenced by familial, cultural, and socioeconomic factors [15, 16]. The latest recommendations of the American Academy of Pediatrics emphasize the role of Intensive Health Behavior and Lifestyle Treatment (IHBLT) as the foundation for treating childhood obesity. This method is based on an intensive, specialist-supervised, systematic introduction of changes to the lifestyle of the entire family. Experts recommend that children > 6 years of age be enrolled in such a program, but it can also be considered for children aged 2–5 years. The IHBLT is the most effective when it occurs face-to-face, engages the whole family, and delivers at least 26 hours of nutrition, physical activity, and behavior change lessons over 3 to 12 months. This method, however, should not be treated as the only, definitive form of treatment, but only as an introduction and a basis for further actions. It should be foundational to continuous obesity treatment and should continue longitudinally. It should be also provided in conjunction with pharmacotherapy and metabolic and bariatric surgery if these treatments are indicated in selected cases. That method may be available in the form of a defined program and may be offered in pediatrician, general practitioner or specialist. It can be introduced by individual medical centres, it may be part of healthcare systems, or it can be carried out in partnership with community organisations [15]. The psychological and social context is extremely important throughout the treatment process. Diagnosis of the psychological functioning of a child with obesity is an important element of a comprehensive diagnosis in the context of designing a scheme of cooperation with a child with obesity and their environment. Its implementation is intended to serve both a better understanding of the child and their immediate environment from the initial stages of treatment, as well as to adapt therapeutic activities so that they bring the best possible effect [16]. The individual predispositions and capabilities of patients and their families should be taken into account when implementing the recommendations using the “small steps” method. It is very important to set realistic, measurable goals of the treatment. These obviously cannot just be goals and targets related to the child’s weight. In recent years, medical methods – pharmacotherapy and surgery – have been gaining increasing importance in the treatment of childhood obesity, especially the significant severe obesity and obesity with complications. It is currently believed that they should not be introduced as a “last form of help” when everything has failed, but should be taken into account at every, even early stage of treatment, depending on the individual needs of the patient [16]. Among the wide range of drugs already available for the treatment of childhood obesity, two analogues of glucagon-like peptide 1 (GLP-1 agonists, liraglutide and semaglutide) can be used. Both can be used regardless of the cause of obesity as a complementary therapy to dietary changes and increased physical activity. Their use should be considered in patients in whom an intensive lifestyle modification program has not limited weight gain or has not been effective in treating obesity complications. Both drugs can be used in adolescents aged ≥ 12 years with a BMI corresponding to ≥ 30 kg/m2 in adults. The action of both drugs is related to their incretin activity, which mimics the impaired secretion of intestinal peptides in response to food stimuli in obesity. Administration of a GLP-1 agonists to obese patients leads to an increase in postprandial insulin concentration (depending on the glucose delivered with the meal), reduces glucagon secretion, delays gastric emptying and causes weight loss by reducing appetite and the volume of food intake. In children and in adults, both drugs have been shown to have a beneficial effect on the cardiometabolic profile. The main adverse effects of the drugs include gastrointestinal symptoms (nausea, vomiting, diarrhea). Rapid loss of adipose tissue is also a risk factor for the development of gallstones, which should be remembered and the patient should be informed about this [17, 18]. It is also worth paying attention to recent reports regarding the possible negative impact on the mental state of the treated [19].
In the secondary obesity, of genetic origin, there are alternative forms of pharmacotherapy. For years, it has been known that recombinant human growth hormone is effective as a complementary treatment to a comprehensive care plan for patients with Prader-Willi syndrome [20]. In genetically determined leptin deficiency, effective causal treatment is possible by administering recombinant methionyl human leptin to patients. The results of studies have shown its beneficial effect on reducing appetite, reducing adipose tissue mass and improving metabolic parameters. Importantly, treatment with recombinant leptin has a beneficial effect on the functions of the gonadal axis, restoring the correct rhythm of gonadotropin secretion and normalizing the course of puberty. In addition, during treatment, the rhythm of cortisol secretion is normalized, the function of the thyroid axis and the functioning of the immune system are improved [21]. The newest drug introduced for the treatment of monogenic obesity in children is setmelanotide. It is an agonist of the MC4R receptor, registered as a first-line drug in children > 6 years of age with morbid obesity caused by mutations in the POMC, PCSK-1 and leptin receptor genes. In patients with these diseases, a beneficial effect of the drug on reducing body weight and appetite has been demonstrated. Currently, studies are underway to assess the efficacy of setmelanotide in other forms of genetic obesity, including Bardet-Biedl, Alström, Smith-Magenis syndromes and obesity associated with mutations in the MC4R, SH2B1, SRC1 or SIM1 genes [22]. In the treatment of obesity caused by the KSR2 mutation, which is associated with severe insulin resistance, bradycardia and reduced basal metabolic rate, metformin is used [23]. However, these observations are supported only by individual case reports and studies on an animal model. Interestingly, the importance of metformin as a supportive treatment for obesity complications has recently been emphasized in the AAP recommendations. Although this drug is not dedicated to the treatment of childhood obesity, its use may be beneficial in enhancing the effectiveness of dietary interventions and physical activity in those patients who have polycystic ovary syndrome or clinically significant insulin resistance or metabolic fatty liver disease [15]. Surgical treatment of obesity is the most radical method, but at the same time the most effective in terms of rapid weight loss, lowering blood pressure, improving lipid and carbohydrate metabolism and reducing the severity of obstructive sleep apnea. With all these advantages, it should be borne in mind that this is an irreversible method, requiring the patient to adapt to the requirements of postoperative treatment throughout their life after the procedure. Therefore, it cannot be treated as a treatment method replacing lifestyle modification. The decision on qualification for treatment should be made after ≥ 12 months of treatment, including dietary modification and increased physical activity, and in selected cases, pharmacotherapy. A necessary condition for bariatric surgery is obtaining informed consent from the patient and their parents, confirming full understanding of the nature of the procedure, its risks and benefits. Indications for surgical treatment in children with obesity include BMI > 40 kg/m2 or BMI > 35 kg/m2 with concomitant diabetes, prediabetes, arterial hypertension, obstructive sleep apnea syndrome, dyslipidemia (especially hypertriglyceridemia), symptoms of intracranial hypertension (pseudotumor cerebri), MAFLD, severe skeletal abnormalities and urinary incontinence. Additional indications include significant deterioration of the quality of life and limitation of daily activity of the patient [15, 16].
Recent years have brought many new discoveries that allow for a better understanding of the pathophysiology of obesity, which can no longer be perceived solely as a pathological accumulation of fat. Thanks to a better understanding of the mechanisms leading to the development of obesity, we have gained the opportunity to develop increasingly effective methods of treatment. However, the scale of the problem resulting from ignoring obesity as a disease for decades is so large that the question arises: will we still have time...?
