Rôle de la génétique et de l’épigénétique dans l’obésité de l’enfant et de l’adolescent

Obesity is a complex, multifactorial disease due to a dysfunction of the hypothalamic control of weight and food intake. The contribution of genetics is constant, but its impact is variable depending on the situations ranging from rare genetic obesities (around 5% of cases) to more frequently polygenic obesity (or common obesity) (95% of cases). Other factors as pre- and post-natal, societal or psychological determinants always interact closely with these genetic factors explaining the high variability of the phenotype and the complex pathophysiology. A true continuum exists between all these situations through the involvement of more or less rare genetic variants located in genes encoding key proteins in the central regulation of food intake. Rare forms of obesity are characterized by their common phenotype including a very early-onset severe obesity (BMI Z score greater than + 3 SD early before the age of 3 years) with resistance to medical treatment, and major eating disorders characterized by difficulties in voluntary control of food intake. Central endocrine abnormalities such as hypogonadotropic hypogonadism or GH deficiency for example, and metabolic abnormalities due to abnormal adipose tissue distribution are also associated with variable degrees (Alström syndrome for example). Neuropsychological abnormalities are also present such as neurodevelopmental disorders (intellectual disability with variable intensity and/or adaptive development disorders which are part of many syndromes such as in Prader-Wili Syndrome; autism spectrum disorders (in SH2B1 or MYT1L deficiency for example), cognitive disorders with difficulties in emotional regulation (eg: Bardet-Biedl Syndrome or specific rare variants located on genes of the melanocortin pathway), behavioral or psychiatric disorders, sleep disorders and major hypothalamic dysfunctions (eg: Prader-Willi Syndrome, Smith Magenis syndrome). This better understanding of the mechanisms has made it possible to better precise the associated phenotypes and, recently, to lead to therapeutic innovations targeting these key genes. This evolution helps to quickly envisage the development of a real personalized medicine in early onset obesity using the combination of drug treatments targeted according to the identified genetic anomaly and/or a multidisciplinary global approach targeting the patient's phenotype or even the bariatric surgery in specific situations.     

Genetics of pediatric obesity

Onset of obesity has been anticipated at earlier ages, and prevalence has dramatically increased worldwide over the past decades. Epidemic obesity is mainly attributable to modern lifestyle, but family studies prove the significant role of genes in the individual's predisposition to obesity. Advances in genotyping technologies have raised great hope and expectations that genetic testing will pave the way to personalized medicine and that complex traits such as obesity will be prevented even before birth. In the presence of the pressing offer of direct-to-consumer genetic testing services from private companies to estimate the individual's risk for complex phenotypes including obesity, the present review offers pediatricians an update of the state of the art on genomics obesity in childhood. Discrepancies with respect to genomics of adult obesity are discussed. After an appraisal of findings from genome-wide association studies in pediatric populations, the rare variant-common disease hypothesis, the theoretical soil for next-generation sequencing techniques, is discussed as opposite to the common disease-common variant hypothesis. Next-generation sequencing techniques are expected to fill the gap of "missing heritability" of obesity, identifying rare variants associated with the trait and clarifying the role of epigenetics in its heritability. Pediatric obesity emerges as a complex phenotype, modulated by unique gene-environment interactions that occur in periods of life and are "permissive" for the programming of adult obesity. With the advent of next-generation sequencing techniques and advances in the field of exposomics, sensitive and specific tools to predict the obesity risk as early as possible are the challenge for the next decade.     

Aetiology of overweight and obesity in children and adolescents

The epidemic diffusion of obesity in industrialised countries has promoted research on the aetiopathogenesis of this disorder. The purpose of this review is to focus mainly on the contribution that European research has made to this field. Available evidence suggests that obesity results from multiple interactions between genes and environment. Parents obesity is the most important risk factor for childhood obesity. Twin, adoption, and family studies indicated that inheritance is able to account for 25% to 40% of inter-individual difference in adiposity. Single gene defects leading to obesity have been discovered in animals and, in some cases, confirmed in humans as congenital leptin deficiency or congenital leptin receptor deficiency. However, in most cases, genes involved in weight gain do not directly cause obesity but they increase the susceptibility to fat gain in subjects exposed to a specific environment. Both genetic and environmental factors promote a positive energy balance which cause obesity. The relative inefficiency of self-adapting energy intake to energy requirements is responsible for fat gain in predisposed individuals. The role of the environment in the development of obesity is suggested by the rapid increase of the prevalence of obesity accompanying the rapid changes in the lifestyle of the population in the second half of this century. Early experiences with food, feeding practices and family food choices affect children's nutritional habits. In particular, the parents are responsible for food availability and accessibility in the home and they affect food preferences of their children. Diet composition, in particular fat intake, influences the development of obesity. The high energy density and palatability of fatty foods as well as their less satiating properties promotes food consumption. TV viewing, an inactivity and food intake promoter, was identified as a relevant risk factor for obesity in children. Sedentarity, i.e. a low physical activity level, is accompanied by a low fat oxidation rate in muscle and a low fat oxidation rate is a risk factor of fat gain or fat re-gain after weight loss. Conclusion Further research is needed to identify new risk factors of childhood obesity, both in the genetic and environmental areas, which may help to develop more effective strategies for the prevention and treatment of obesity.     

Leptin: obesity, diabetes and other peripheral effects--a review

Abstract: There is an increasing epidemic of obesity in the Western and developing world that has not spared children and, hence, is of great concern. Obesity presents numerous physiological and psychosocial problems for the child. Childhood obesity not only increases the risk of obesity in adulthood, it is associated with type 2 diabetes mellitus; is the leading cause of pediatric hypertension; increases the risk of coronary heart disease; and increases stress on the weight-bearing joints. Social and psychological problems are also significant consequences of obesity in children, with lowering of self-esteem and its effects on relationships with peers. Obesity is clearly associated with increased levels of the recently discovered hormone, leptin. Leptin, secreted from adipocytes, is involved in the regulation of food intake, energy expenditure, and energy balance in humans. This review focuses on the hormone, leptin, in an effort to document some of its many local and systemic effects on the body and, specifically, its potential role in obesity-induced diabetes.     

The brain-gut axis in regulation of appetite and obesity

Obesity is the most common metabolic disease globally. It is increasingly a problem of children and individuals in poor countries characterized by food insecurity. This is of great concern as childhood obesity predicts increased future adult obesity. To curb the epidemic of obesity, it is essential to understand the regulation of appetite. Energy stores and nutrient homeostasis are maintained by hypothalamic regulation of energy balance. The hypothalamus receives neural and endocrine signals from the gut, adipose tissue and pancreas in response to food intake. These are integrated, interpreted and directed to other centers in the brain and peripheral organs to orchestrate energy homeostasis. This brain-gut axis is disrupted in obesity. This review discusses the various hormones involved in the regulation of energy balance both at the level of the gut and in the central nervous system.     

An overview of mongenic and syndromic obesities in humans

Obesity is increasing in prevalence in the United States with over 65% of adults considered overweight and 16% of children with BMI > 95 percentile. The heritability of obesity is estimated between 40% and 70%, but the genetics of obesity for most individuals are complex and involve the interaction of multiple genes and environment. There are however several syndromic and non-syndromic forms of obesity that are monogenic and oligogenic that provide insight into the underlying molecular control of food intake and the neural networks that control ingestive behavior and satiety to regulate body weight and which may interact with treatment exposures to produce or exacerbate obesity in childhood cancer survivors.     

The hypothalamic path to obesity

Obesity is a growing public health concern, affecting an estimated 11% of children in Western society. The impact of obesity-related morbidity and mortality on society is significant, with both genetic and environmental factors contributing to its development. In most individuals, food intake and energy expenditure are tightly regulated by a feedback system comprising a number of hormonal and central nervous system pathways. Leptin released from adipocytes acts on hypothalamic neurons to release proopiomelanocortin (POMC), leading to a cascade of neuronal and hormonal events that inhibit feeding behavior. Specific gene mutations in the leptin/POMC pathways account for only 5% of all cases of obesity, and most cases of familial or idiopathic obesity are polygenic in origin. Although further research to identify specific genetic causes of obesity may lead to more tailored therapies, significant changes in societal and individual behavior are needed to stop the obesity epidemic from progressing.     

Methodologic approach to the therapeutic problem of infant and childhood obesity. Review of the literature and personal experience

Notwithstanding the high prevalence and morbidity, current knowledge of obesity is rather rudimentary. Nevertheless recent findings have enabled us to surmount anachronistic nosographic generalizations whereby excess weight was attributed only to inappropriate and excessive food intake and the lack of physical exercise. Various studies indicate that there are complex interactions in determining weight excess: genetic, psychosocial, cultural but also biochemical factors are incriminated and it is now recognised that the aetiology of obesity is multifactorial and that, consequently, there are different types of obesity. However, in most studies concerning the therapeutic approach, it is noted that the same type of treatment is applied to groups of subjects that are probably highly heterogeneous for type of obesity. No easy or final solution to the problem is proposed as for the moment no ideal treatment exists. What is suggested is the need to attempt to identify possible factors linked to weight excess before commencing the therapeutic approach. For each single case, this could permit the use of the most appropriate treatment and make therapeutic results less frustrating.     

肠道微生物与儿童肥胖

肥胖是影响儿童和成人健康的一个严重的公共卫生问题,其病因复杂,是遗传、环境等多种因素共同作用的结果.越来越多的证据显示,肠道微生物参与了体重调控、能量代谢和炎症反应,在肥胖的发生中起了重要作用.自然分娩、母乳喂养和避免生命早期抗生素暴露有益于维持肠道微生物的平衡,可能降低未来发生肥胖的风险.益生元和益生菌可以改变肠道微生物构成,从而影响摄食和体重.探求肠道微生物与肥胖间的关系可为防治儿童肥胖打开新思路.     

Control of food intake

The decisions of an individual about his food intake depend upon a variety of internal and external signals. The present contribution describes the physiological mechanisms controlling food intake to preserve body composition and performance. Centers within the hypothalamus including their connections to higher and lower structures within the central nervous system, especially to the limbic system, are involved in the control a food intake. Neuropeptides and neurotransmitters usually initiate more complex actions including the search for food and satiety phenomena. Their production and release are influenced by food consumption as well as intake of specific nutrients, sensorial perceptions, and a variety of other factors. Vagal reflexes and gastro-intestinal hormones, fat cell size, physical activity, and thermogenesis also influence perceptions of hunger and satiety. A model satisfactorily describing the interactions between all known factors that control food intake is still missing. The path from hunger to satiety could be described as sequences of cascades similar to the various steps in blood clotting. Control of food intake during early life dependably relies on energy requirement, and can be utilized for ad-libitum feeding. Obesity and anorexia nervosa are manifestations of disturbed control over food intake. Neuropharmacology offers several therapeutic approaches to specific conditions. However, by and large abnormalities of food intake control have to be treated by behavioral modification.     

In search of genetic determinants of obesity

Common obesity is a multifactorial trait that lies at the interface between the biology of body energy regulation and the environment. Obesity involves genetic predisposition but also metabolic, hormonal, behavioural, social and cultural aspects. According to some estimates 40 to 70 percent of the variation in obesity-related phenotypes is heritable. Mutations in a single gene cause only about 5% of cases. The number of genes and markers associated or linked with human obesity is more than 200. Interactions between multiple genes, environment and human personality, make the search for obesity-related genes especially challenging.     

Pediatric obesity: etiology and treatment

This article reviews factors that contribute to excessive weight gain in children and outlines current knowledge regarding approaches for treating pediatric obesity. Most of the known genetic causes of obesity primarily increase energy intake. Genes regulating the leptin signaling pathway are particularly important for human energy homeostasis. Obesity is a chronic disorder that requires long-term strategies for management. The foundation for all treatments for pediatric obesity remains restriction of energy intake with lifestyle modification. There are few long-term studies of pharmacotherapeutic interventions for pediatric obesity. Bariatric surgical approaches are the most efficacious treatment but, because of their potential risks, are reserved for those with the most significant complications of obesity.     

Childhood obesity and early food experiences]

Authors insist on the role of early food experiences in the constitution of young child obesity. Obesity often appears precociously within the first two years of life. In many cases, it results from inappropriate feeding behaviors, behaviors of overfeeding deteriorating the mechanisms of energy regulation of the child. The prevention requires a work on the early baby/environment interactions.     

Television and children's consumption patterns. A review of the literature

The recent increase in childhood obesity has, among other things, focused attention on the role that television may play. This paper summarizes results of studies published in peer review journals since 1970 with data pertaining to the relationship between television use and children's food intake. Studies fall into four categories: content analyses; effects of television advertising on children's food behaviors; television and pediatric obesity, with effects on children's dietary intake and physical activity; and television use and children's food consumption patterns. Content analyses have shown that food is the most frequently advertised product category on children's TV. The majority of these ads target highly sweetened products, but more recently, the proportion from fast food meal promotions has been growing. Controlled studies on children's choices have consistently shown that children exposed to advertising choose advertised food products at significantly higher rates than do those not exposed. Purchase request studies have documented associations between number of hours of TV watched and number of requests from the child to the mother for specific food items, as well as the presence of those items in the home. Greater TV use has been associated with higher intakes of energy, fat, sweet and salty snacks, and carbonated beverages and lower intakes of fruit and vegetables. Several large studies have documented associations between number of hours of TV watched and both the prevalence and incidence of obesity. The combination of lifestyle factors that accompany heavy television use appear to place children at risk of obesity and poor nutritional status.     

Paediatric obesities: from childhood to adolescence

Obesity, as in every western country, is currently the most prevalent chronic disease in childhood in Spain. This has led to obesity being one of the most common consultations in general paediatrics and, particularly, in paediatric endocrinology. Furthermore, obesity associated comorbidities are increasing in prevalence in children and adolescents. It is widely accepted that this increase in the prevalence of obesity is derived from an imbalance between energy intake and expenditure, associated to the lifestyle in western countries. However, there is increasing evidence of the role of individual and familial genetic background in the risk of developing obesity. The pathophysiological basis of the mechanisms responsible for the control of appetite and energy expenditure are being discovered on the basis of the increasing known cases of human monogenic, syndromic and endocrine obesity. Thus it is no longer appropriate to talk about obesity but rather about ?obesities?, as their pathophysiological bases differ and they require different diagnostic and management approaches. In 2011, the paediatrician must be aware of this issue and focus the clinical history and physical examination towards these specific clinical sign and symptoms, to better manage the available diagnostic and therapeutic resources when faced with a child with obesity.     

The role of leptin in human obesity

The mechanism involved in body mass regulation in humans includes genetic, environmental, and behavioural factors. Human obesity is usually associated with a positive energy balance. Genetic studies in obese mice have revealed the Ob. gene, its products leptin and the leptin receptor to be important factors in the regulation of both appetite and energy expenditure. Leptin is a 16-kilodaltons adipocyte-derived hormone -which circulates in the serum as the free and bound forms. The leptin serum level reflects the amount of energy stored in adipose tissue. Leptin acts through the leptin receptor, -which belongs to the cytokine - receptor family. In rodents as well as in humans, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia, and reduced energy expenditure. Recent studies have demonstrated that Ob. gene expression is increased in human obesity. However, mutations of Ob. gene present in the mouse are rare in the human population.     

Insulin and human obesity

The prevalence of obesity among modern communities increases dramatically and trends to achieve the characteristics of an epidemic. Obesity is the result of a sedentary life style and increased food intake, which characterises western communities. Obesity is closely related to insulin resistance and hyperinsulinemia and the very frequent combination of obesity and NIDDM is characterised as "Diabesity". The behaviour of man in seeking food and the amount of food consumption is a complicated situation, which is regulated by the CNS and especially in the arcuate nucleus of the hypothalamus. A repertoire of neurohormonal actions, generated in peripheral tissues and integrated in the CNS, encompasses many peptides with orexigenic and anorexigenic actions. Two main hormones, insulin and leptin, accomplish the fine-tuning of these peptides action at the critical level of body weight and energy control. The high prevalence of insulin resistance and hyperinsulinemia in obesity indicates a causative relationship between these two situations. It seems likely that insulin resistance in muscle cells is the prime "defect" which renders individuals vulnerable to obesity. The high prevalence of insulin resistance, about 25%, among otherwise healthy subjects indicates that this genetically determined "defect" may be the result of an evolutionary selection which rendered mankind capable of surviving during long periods of famine, in his long journey from the hunter-gatherer period of his life to the present time of plenty.     

Inadequate leptin level negatively affects body fat loss during a weight reduction programme for childhood obesity

Obesity is a typical example of a complex multifactorial disease arising from behavioural, environmental and genetic factors that may affect individual responses to dietary intake and physical activity. Observational, longitudinal dietary interventional studies in obese patients present contrasting reports on the predictive value of baseline leptin levels. We report on the effect of a weight reduction programme in three different groups of obese children (82 patients in all) assembled on the basis of their baseline leptin levels adjusted for body mass index (BMI), gender and pubertal development. The effectiveness of this programme was decreased in patients with relative hyperleptinaemia or hypoleptinaemia compared to children with baseline leptin levels appropriate to BMI gender and pubertal development.

Conclusion : Information gained from leptin assays could provide predictive insight into an individual's ability to lose body fat and may therefore have important implications for our approach to the treatment and prevention of childhood obesity.     

Neuroendocrine regulation of food intake

Despite a global obesity epidemic suggesting that human physiology is unable to prevent unhealthy gains in body weight, ample evidence indicates that weight can be tightly regulated. Food intake regulation is complex and in this article we will present a basic endocrine feedback loop model of energy homeostasis. Next, integration of long-term regulation with short-term, meal specific regulation and satiety will be discussed. Finally, the role of adiposity signals in modulation of food reward will be highlighted. A basic understanding of the structure-function of these systems will inform the challenges of clinical care for those with disorders of energy balance.     

The inflammatory process of adipose tissue

Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, atherosclerosis, and non-alcoholic fatty liver disease. The evidence that obesity can be regarded as an inflammatory disease comes from numerous studies showing a moderate increase of circulating inflammatory factors in obese patients and the identification of different types of immune cells infiltrating the human adipose tissue. Obesity may induce a pro-inflammatory state, which can cause or worsen insulin resistance in adipose tissue, skeletal muscle, and liver. The causative factors of this inflammation process in obesity are not entirely understood, but adipose tissue seems to play an important role in the relationship between obesity and chronic inflammation. Increased infiltration of adipose tissue with immune cells could cause adipose tissue insulin resistance via autocrine and paracrine cytokine/adipokine signalling, which contributes to systemically decreased insulin sensitivity via endocrine signalling. On the other hand, obesity-induced inflammation could represent a compensatory mechanism for increased adipose tissue turnover in obese states, which might protect obese individuals against deleterious effects of fat accumulation. A better understanding of the mechanisms and molecular components of obesity induced inflammatory response might lead to identifying novel therapeutic targets to prevent obesity-related complications.