Obesity (Obesity) - Genes NR0B2, POMC, GHRL, UCP1, CARTPT, ADRB2, ENPP1 (? PC1), ADRB3, AGRP, LEP, LEPR, PPARG, SIM1, UCP3, MC4R, SDC3, and PPARGC1B.

Obesity is a multifactorial process that arises from the interaction between a genetic predisposition and the presence of certain external factors. This process is characterized by an increase in body weight beyond the needs of skeletal physical structure as a result of excessive accumulation of body fat. The relationship between the incemento the rate of obesity, and the risk of morbidity and implied to him mortality, such as dyslipidemia, hepatic steatosis ovarian syndrome and hypogonadism, orthopedic problems, cholecystitis, cardiovascular disease, diabetes, cerebral pseudotumor, and certain types cancers, cause the obesity is considered a major health problem.

They were detected many loci associated with susceptibility to obesity and thinness. Some key autonomic mutations (heterocogóticas), as melanocortin receptor-4 alone can cause obesity. Also we found some autosomal disorders related recessive as leptin deficiency, deficiency leptin receptor, convertase-1 prohormone and proopiomelanocortin. These alterations are associated with hypogonadotrophic hypogonadism, hypoadrenalism statures.

There syndromes in which obesity is a reliable sign Cohen's syndrome, among others (see descriptions of these syndromes) occurs in Prader-Willi syndrome, Bardet-Biedl, and.

Many studies have tried to compare groups of homogeneous populations of different ages, obese and lean, the differences in both. In these groups has been studied, among others, power consumption, microbiota (microbioma) intestinal, the number of adipocytes, and various genetic markers. From these studies, it has shown that energy consumption is lower in children who acquire overweight compared to other thin children. The intestinal microbial flora (microbiome) contains less obese compared to lean Bacteroides, suggesting that obesity also have a microbial component, in which case the microbiome of obese have greater capacity to save energy diet. The number of existing adipocytes of adults, is acquired in childhood and adolescence, whereas in children remains constant in both obese and thin, even when they lose weight, changing in childhood and adolescence, and remaining constant in adulthood. At this stage of life, or destroyed to decrease or increase.

In maintaining body mass they have been considered very important few factors: leptin produced in adipose tissue and its receptor located in the hypothalamus, stimulating hormone melanocytes produced POMC neurons, and release of orexigenic peptides stimulants appetite. Also described many other genes that somehow contribute to the development of obesity, sometimes found in predisposition to obesity, in cases of early obesity, or in cases of late obesity, or in cases of severe obesity (morbid).

They could consider several ways to expose genes that have impicaso in the development of obesity. Consider most appropriate expose depending on the relationship that has been established, in some cases, as have found their involvement in cases of early onset, predisposition to it, late - onset, severe obesity (morbid), or varied, However, as other classifications, it has its limitations, and uncertainties.

Genes involved in early - onset obesity

The NR0B2 gene, located on the short arm of chromosome 1 (1p36.1), encodes a protein that interacts with retinoid and thyroid hormone receptor, inhibiting its ligand - dependent transcriptional activation. In addition, their interaction with estrogen receptor has been shown to inhibit its function. Studies suggest that the protein represses the transactivation mediated by nuclear hormone receptor through two separate stages: competition with coactivators and outcomes of its transcriptional repressor function. They have identified 18 variations NR0B2 gene.

The POMC located on the short arm of chromosome 2 (2p23.3) encodes the precursor of ACTH (corticotropin serum) in the hypophysis. POMC (Pro-opiomelanocortin) neurons produce ?-MSH anorectic peptide (melanocyte stimulating hormone) and another called CART. Activating them decreases food intake and increases energy expenditure. Another group, the orexigenic neuropeptide expressed (appetite stimulant) NPY and AGRP, whose activation increases food intake and decreased energy expenditure. Both populations signals from the hypothalamus project to other brain areas containing second - order neurons, involved in energy homeostasis. Particularly, the lateral hypothalamus, which induces the expression of the melanin concentrating hormone (MCH) and the paraventricular nucleus, which does the same with hormones TRH (thyrotropin releasing hormone) and CRH (corticotropin releasing hormone) .The deficiency POMC generates hyperphagia and morbid obesity due to loss of melanocortin signaling in melanocortin receptor-4 (MC4R) and secondary to hypocortisolemia ACTH deficiency, leading to hypoglycemia. Typically, the phenotypes resulting from mutations in the gene have red hair and POMC pale skin due to dispigmentation.

Genes associated with predisposition to obesity

The GHRL gene, located on the short arm of chromosome 3 (3p26-p25) encoding ghrelin-obestatin preproprotein that is cleaved to yield two peptides, ghrelin and obestatin. Ghrelin is a powerful stimulant of appetite and plays an important role in energy homeostasis. It is believed that ghrelin regulates multiple activities, including hunger, reward perception through the mesolimbic pathway, gastric acid secretion, gastrointestinal motility and secretion of glucose - stimulated insulin. Meanwhile, obestatin, regulates adipocyte function and glucose metabolism. 4 mutations have been identified, including 3 meaningless in GHRL gene that increase the predisposition to obesity.

The UCP1 gene, located on the long arm of chromosome 4 (4q28-q31), and UCP3, located on the long arm of chromosome 11 (11q13.4), encoding proteins of mitochondrial uncoupling, member of the family of transport proteins mitochondrial anions (MACP). UCPs are mitochondrial carrier proteins that create leaks protons through the inner mitochondrial membrane, thereby decompose the oxidative phosphorylation of ATP synthesis. As a result, the energy is dissipated as heat. 7 described in the UCP1 gene mutations and 9 UCP3 gene mutations. These changes are associated with increased susceptibility to obesity, early onset generally.

The CARTPT gene, located on the long arm of chromosome 5 (5q13.2), encoding a satiety factor closely associated with the actions of leptin and neuropeptide Y. This anorexigenic peptide inhibits hunger induced and completely blocks the feeding response induced neuropeptide Y regulated by leptin in the hypothalamus. It also promotes neuronal survival and development in vitro. They have identified two mutations in the gene CARTPT. Mutations in this gene are associated with increased predisposition to obesity, early onset generally.

The ADRB2 gene, located on the long arm of chromosome 5 (5q31-q32), encoding the beta-2 adrenergic receptor that is a member of the superfamily of G protein - coupled receptors This receptor is directly associated with one of its end effectors, the C class of calcium channel L - type Ca (V) 1.2. This receptor-channel complex also contains a G, a adenylate cyclase, cAMP - dependent kinase and protein phosphatase PP2A. The assembly of complex signaling provides a mechanism that ensures the specific and rapid signaling this coupled receptor protein G have been described six mutations ADRB2 gene. These mutations are associated with increased susceptibility to obesity, early onset generally.

The ENPP1 gene (? PC1), located on the long arm of chromosome 6 (6q22-q23), encodes a protein called ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1). ENPP1 protein helps break down adenosine triphosphate (ATP), especially when located outside the cell. The extracellular ATP is rapidly degraded to adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate is important in preventing calcification in the body. The ENPP1 protein also plays a role in the control of cell signaling in response to the hormone insulin, through the interaction between a portion of the ENPP1 protein, called the domain SMB2, and the insulin receptor. They have identified 54 variations in the ENPP1 gene. Variations in this gene are associated with increased predisposition to obesity, early onset generally.

The ADRB3 gene, located on the short arm of chromosome 8 (8p12), encodes a protein belonging to the family of receptor beta adrenergic, which mediate activation - induced catecholamine adenylate cyclase through the action of proteins G . This receptor is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis. They described two missense mutations in the ADRB3 gene. These changes are associated with increased predisposition to obesity, early onset generally.

Genes implicated in late - onset obesity

The AGRP gene, located on the long arm of chromosome 16 (16q22), encodes a receptor antagonist melanocortin-3 and melanocortin-4 appears to regulate the hypothalamic control of feeding behavior through melanocortin receptor and / or regulation intracellular calcium, and therefore plays a role in the homeostasis of body weight. 5 described mutations in the gene AGRP. Variations in this gene are associated with late onset obesity.

Genes involved in severe obesity (morbid)

The LEP gene, located on chromosome 7 (7q31.3), encoding leptin, a hormone secreted mainly in white adipose tissue, 167 amino acid, which circulates in blood in proportion to the fat content to regulate the amount of tissue adipose and body mass by interacting with specific neuronal receptors that affect appetite and energy homeostasis. To do this, leptin receptors are highly expressed in hypothalamic neurons that act as primary sensors alterations in energy reserves, controlling food intake and energy expenditure. Thus, leptin regulates reciprocally these two neuronal populations, contributing to the regulation of appetite and energy homeostasis. In addition, leptin is expressed in male and female reproductive organs, mammary glands and the immune system. Homozygous mutations can generate a truncated with no detectable serum concentrations protein, resulting in severe early onset obesity. Symptoms are heterogeneous, but generally have in common severe obesity and hyperphagia early onset and often also hyperinsulinemia. In this gene they have been described 6 missense mutations, one mutation cutting / splicing (splicing), two regulatory mutations and 3 deletions small.

The LEPR gene, located on chromosome 1 (1p31), encodes the leptin receptor, a protein homologous membrane receptor family cytokine class 1 A 3% of those affected by obesity have homozygous mutations in this gene, causing loss of all isoforms of the leptin receptor. In addition, heterozygous mutations are also associated with increased weight, but for the development of morbid obesity loss two aelelos, either as a result of a homozygous mutation heterozygous mutations or compound is required. Certain mutations affecting nearby regions to the transmembrane domain of the leptin receptor may result in a truncated extracellular domain which could act as a protein binding spuriously resulting elevated leptin levels. However, the genetic alterations located in other areas of the LEPR gene usually not generate large accumulations of leptin. In this gene they have been described 11 missense mutations, one mutation cutting / splicing, 1 small insert, 1 insert major / duplication, and one variation of repetition.

Overall, the results of leptin deficiency and deficiency of leptin receptor are similar. In both cases, affected individuals experience rapid weight gain during the first months of life, with excessive accumulations of subcutaneous fat deposited in the trunk and extremities. In line with the severity of obesity hyperinsulinemia and observed some adults develop diabetes mellitus type 2 during the third or fourth decade of life. All cases are characterized by severe hyperphagia and may be associated with hypogonadotropic hypogonadism.

The PPARG gene, located on the short arm of chromosome 3 (3p25), encoding PPAR-gamma protein, a regulator of adipocyte differentiation and glucose homeostasis. It acts as a critical regulator of homeostasis by suppressing intestinal proinflammatory-kappa-? responses mediated by NF. Likewise, it plays a role in regulating cardiovascular circadian rhythms by regulating transcription arntl / BMAL1 in blood vessels. 20 described mutations, 2 deletions and 1 insertion / deletion in the PPARG gene. Variations in this gene are associated with severe obesity.

The SIM1 gene, located on the long arm of chromosome 6 (6q16.3) encodes a transcription factor that can have pleiotropic effects during embryogenesis and in the adult. It has identified a deletion and a complex rearrangement in the SIM1 gene associated with severe obesity.

The UCP3 gene, located on the long arm of chromosome 11 (11q13.4), encoding mitochondrial uncoupling proteins, family member of the mitochondrial carrier proteins anions (MACP). UCPs are mitochondrial carrier proteins that create leaks protons through the inner mitochondrial membrane, thus uncoupling oxidative phosphorylation of ATP synthesis. As a result, the energy is dissipated as heat. 9 described in the UCP3 gene mutations.

Other genes involved in obesity

The MC4R gene belongs to the superfamily of G protein - coupled receptors (GPCR). Neuropeptides that act as ligands bind to the central cavity causing a conformational change induced activation. Genetic abnormalities in the MC4R gene, located on the long arm of chromosome 18 (18q22), are the most common genetic alterations in obese individuals. Mutations in the receptor gene melanocortin-4 (MC4R) result in obesity as an isolated trait. 137 described in the MC4R gene variations that cause disturbances in ligand binding and alter affinity receptor agonists versus antagonists, preventing the coupling of the ligand and subsequent signal transduction. This gene is involved in autosomal dominant obesity.

The SDC3 gene, located on the short arm of chromosome 1 (1p35.2), encodes a protein belonging to the family of proteoglycans "syndicated". This protein may play a role in the organization of cell shape to affect the actin cytoskeleton, possibly to transfer signals from the cell surface in a mechanism dependent carbohydrate. They described two missense mutations in the gene SDC3. Allelic variants of this gene have been associated with obesity.

The PPARGC1B gene, located on the long arm of chromosome 5 (5q32), encoding a protein that stimulates the activity of several transcription factors and nuclear receptors, including estrogen receptor alpha, nuclear respiratory factor 1, and receiver glucocorticoids. The encoded protein may be involved in the oxidation of fats, non - oxidative glucose metabolism and the regulation of energy expenditure. 3 have been identified mutations in the gene PPARGC1B. Variations in this gene are associated with significant obesity.

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with obesity, by complete PCR amplification of the exons of NR0B2 genes, POMC, GHRL, UCP1, CARTPT, ADRB2, ENPP1 (? PC1), ADRB3, AGRP, LEP, LEPR, PPARG, SIM1, UCP3, MC4R, SDC3, and PPARGC1B, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).