**4. Pathophysiology of comorbidities of pediatric obesity**

Complications of pediatric obesity occur during childhood and adolescence and increased the risk for morbidity and mortality into adulthood.

Obesity, particularly abdominal, has been shown to be an important risk factor for a number of chronic diseases in adults. Associated with obesity in childhood is a wide range of health serious complications and increased risk of premature onset year of illnesses. The most important organic complications are dyslipidemia, arterial hypertension, type 2 diabetes mellitus, nonalcoholic fatty liver disease, polycystic ovaries syndrome, orthopedic and respiratory complications. The metabolic syndrome (central obesity, hypertension, glucose intolerance and hyperlipidemia) increases risk for cardiovascular morbidity and mortality. The most frequent psychological complications are disorders concerning body image, eating habits and depression [4, 19].

Insulin resistance is defined as a decreased response of tissue to the action of insulin, and due to lowering of the capacity of insulin to stimulate glucose utilization by muscle cells and fat cells and to suppress hepatic glucose production, and insulin resistance in the protein and lipid metabolism. The association of obesity with insulin resistance is well-known: the factors and the mechanism by which the insulin resistance compensation is produced by beta islet cells and those that lead to the "failure" of the pancreatic beta cells in obese patients. It seems that microvascular changes associated with diabetes begin early stages still hyperinsulinemia with normal glycaemia or impaired oral glucose tolerance test. A central role in regulating central nervous system appears to have fat in the body's glucose metabolism by integrating information neural hormonal and nutritional. Insulin via the insulin receptor in the central nervous system regulates food intake and energy homeostasis. Adipose tissue seems to play a role in insulin resistance by metabolites, hormones and adipocytokines influencing different stages of insulin action. Fat distribution is an important determinant of insulin resistance, abdominal fat tissue lipolysis is easier and is less sensitive to insulin anti-lipolysis than subcutaneous adipose tissue. Total fat in children correlates well with the visceral and the relationship of visceral adipose tissue and the cardiovascular risk factors demonstrated in adults appears to differ [4, 31].

#### **4.1. Dyslipidemia**

Other epidemiologic studies highlight the possibility that obesity could be triggered or exacerbated by exposure to environmental endocrine disrupting chemicals (dichlorodiphenyltrichloroethane—DDT and bisphenol A—BPA). Some studies in adults and children establish an association between urinary BPA levels and obesity or obesity related diseases, as well as

Endocrine disruptors can disturb every level of the endocrine system. They can interrupt the action of enzymes involved in steroidogenesis. The endocrine disruptors inducing obesity are called obesogens and have been revealed to target transcription regulators that function to control intracellular lipid homeostasis as well as proliferation and differentiation of adipocytes. The main group of regulators that are targeted represent a group of nuclear hormone receptors recognized as peroxisome proliferator-activated receptors (PPARα, δ and γ). PPARγ is considered to be the master regulator of adipogenesis and plays key roles in nearly all aspects of adipocyte biology. Other endocrine disruptors are known to promote adipogenesis, but probably do not act through PPARγ, these include BPA, organophosphate pesticides

Hormonal disorders associated with childhood obesity include growth hormone deficiency, growth hormone resistance, hypothyroidism, leptin deficiency or resistance to leptin action, glucocorticoid excess (Cushing syndrome), precocious puberty, polycystic ovary syndrome (PCOS), prolactin-secreting tumors. Furthermore, in obese individuals, dysfunction in the gut-brain hypothalamic axis and ghrelin/leptin hormonal pathway has been proposed to have

Specific syndromes and single gene defects that are linked to obesity in children have been identified. These are very rarely causes of obesity, Generally, monogenic forms of childhood obesity are very rare, accounting for <1% in children. Mutations in only a few genes are known to cause the development of severe obesity in early childhood. Single gene disorders that can cause obesity include deficiency in leptin or its receptor, mutation in leptin gene, deficiency of proopiomelanocortin (POMC), haploinsufficiency receptor 4 and accessory protein receptor 2 of melanocortin, also disorders of protein convertase 1 [4, 18]. The leptin/leptin receptor system regulate food intake through reduce feeding and increased energy expenditure. Some forms of monogenic obesity like congenital leptin deficiency benefits from leptin substitution

Moreover, children with genetic syndromes associated with obesity typically have early onset obesity and characteristic signs on physical examination, including dysmorphic features, developmental delay, short stature or intellectual disability, retinal changes or deafness. The Prader Willi syndrome is the most common among obesity syndromes and is characterized by hypotonia and feeding difficulties during infancy, hyperphagia and obesity developing during early childhood and developmental delay. Other syndromes associated with childhood obesity are Pseudohypoparathyroidism, Laurence Moon Biedl (Bardet Biedl) syndrome,

a role in excess energy intake and abnormal appetite control [28].

therapy that leads to significant decrease in weight [29].

Cohen syndrome, Down syndrome and Turner syndrome [30].

diabetes and cardiovascular disease [18].

102 Adiposity - Epidemiology and Treatment Modalities

and monosodium glutamate [27].

**3.1. Genetic factors**

Research on elucidating the relationship between obesity and atherogenic dyslipidemia appears to show a close relationship with insulin resistance. Three major events are based on atherogenic dyslipidemia of obesity with insulin resistance: excessive production of very low density lipoprotein-cholesterol, lipoprotein catabolism and defective catabolism of high density lipoprotein-cholesterol. Visceral fat is associated with impaired insulin-glucose homeostasis, the plasma lipoprotein, in particular increased triglycerides and decreased high density lipoprotein-cholesterol [4].

Arterial hypertension is recognized as an important component of metabolic syndrome in adults, but in children, its role is not very clear. While some studies hypertension is considered the direct effect of obesity, insulin resistance in others, it is considered a predictor of hypertension, independent of BMI. Arterial hypertension in the pathogenesis of obesity and insulin resistance may play a role in which leptin resistance physiological actions of insulin that leptin central nervous system vessels and kidneys should be changed. Studies suggest the involvement of oxidative stress in the pathogenesis and hypertension by stimulating reactive oxygen species by the renin–angiotensin–aldosterone system [32].
