Cauzele genetice ale obezitatii review

Autor : Ivascu Alina NicoletaCoordonator : dr. Radu Ioan UrsuNOTE personaleLucrarea trebuie sa aiba cam de cuvinte - aproximativ 4 pagini. Structura de tip review : 1. introducere (descrierea domeniului, situatia actuala si motivatia articolului)2. corp (contine analiza domeniului) 3. concluzii.Introducere

Some WHO global estimates from 2008 follow. More than 1.4 billion adults, 20 and older, were overweight. Of these overweight adults, over 200 million men and nearly 300 million women were obese. Overall, more than 10% of the worlds adult population was obese.In 2011, more than 40 million children under the age of five were overweight. Once considered a high-income country problem, overweight and obesity are now on the rise in low- and middle-income countries, particularly in urban settings. More than 30 million overweight children are living in developing countries and 10 million in developed countries.[footnoteRef:1] [1: http://www.who.int/mediacentre/factsheets/fs311/en/]

Obesity is a major contributor to morbidity and mortality, and its prevalence has increased markedly in the last 30 years. This is thought to have occurred due to the increased availability of energy-dense foods and the reduced requirement for physical exertion during work and domestic life. But there is also a genetic component to obesity. Heritability (the chance that offspring will inherit a trait) for BMI is 50%-70%, while heritability for total body fat is as high as 80%. These numbers, along with twin studies, have demonstrated that obesity is partially genetically regulated. Several methods for finding genes controlling obesity have been employed, with some being more successful than others. Below is a brief summary of what is currently known about the genetics of obesity.[footnoteRef:2] [2: Genetics of obesity- American Medical Association.]

Obesity is a critical public health problem that affects many lives, many communities and many nations. We are all familiar with the facts. There are over 1.5 billion overweight people in the world today with around a third - 500 million of them - obese. Obesity has also reached epidemic proportions here in Europe. Between 30% and 80% of adults are overweight in this part of the world. And overweight causes 1 million deaths each year in the region. Even in countries with traditionally low rates of obesity - such as France, the Netherlands and Norway - the situation is worsening.[footnoteRef:3] [3: 16th European Congress on Obseity, ADG Speech ]

The genetic causes of human obesity are diverse and may produce different types of obesity. At present, there are 38 genetic markers found to be correlated with a high body mass index (BMI) and possibly leading to monogenic obesity syndromes, while over 60 regions have been identified throughout the whole human genome which seem to have a role in the adipose tissue distribution and mass, in the energetic ballance of the organism and in the regulation of satiety hormones (leptin and insulin) and causing polygenic or common obesity. At the same time, a number of over 30 complex pleiotropic genetic syndromes with obesity as a main clinical feature are described. Twins and family studies state that obesity is a heritable disorder, today being a well-known fact that the family history of obesity is a high risk predictor for the early onset of this disease in children.[footnoteRef:4] [4: Obesity, a gene review, dr. Radu Ioan URSU.]

Human genes involved in the ethiopathogenesis of obesity

The etiology of obesity is multifactorial, involving a complex interaction among genetics, hormones and the environment. Though multiple candidate genes have been implicated in the pathogenesis of obesity, these findings are inconsistent. These genes include the fat mass and obesity associated gene (FTO), the beta-3-adrenergic receptor gene (ADRB3), leptin (LEP) and leptin receptors (LEP-R), melanocortin-4 receptor gene (MC4R) and other genetic polymorphisms.Alterations in these genes expression due to mutations or abnormal variants (polymorphisms) are known of being the cause of several monogenic obesity syndromes and also of being involved in the common, polygenic obesity.FTO : This gene is a nuclear protein of the AlkB related non-haem iron and 2-oxoglutarate-dependent oxygenase superfamily but the exact physiological function of this gene is not known. Other non-heme iron enzymes function to reverse alkylated DNA and RNA damage by oxidative demethylation. Studies have shown that the FTO is strongly correlated with body mass index, obesity risk, and type 2 diabetes, at the same time playing a role in nervous and cardiovascular systems and a strong association with.It is estimated that about 70% of the obese individuals reveal mutations within the FTO gene. It is associated with abnormal BMI and obesity that increases towards adulthood.[footnoteRef:5] [5: http://ghr.nlm.nih.gov/gene/FTO]

Location : 16q12.2PRL (prolactin) : The PRL gene, with its cytogenetic location 6p22.3 and coding for the pituitary prolactin hormone, which mainly has its role on the mammary gland in lactation, is associated with obesity more particularly in adults.Genome wide associated studies (GWAS) also found among the common genetic variants contributing to the increase in the susceptibility for obesity a SNP, rs4712652, in the very vicinity of the PRL gene.[footnoteRef:6] [6: Obesity, a gene review, Radu Ioan Ursu. ]

TUB : The tubby homolog gene, found on chromosome 11p15, encodes for one of the members of the Tubby family transcription factors. The TUB gene is highly expressed in the hypothalamus, its main functions being in signal transduction and transcription regulation. Mutations in this gene will cause obesity and insulin resistance in mice. Three SNPs have also been discovered in human to being linked to obesity rs1528133, rs2272382 and rs2272383.[footnoteRef:7] [7: Obesity, a gene review, Radu Ioan Ursu.]

Visfatin : is a recently discovered adipokine on chromosome 7q22.3, corresponding actually to the PBEF1 gene Visfatin is mainly expressed in human in the visceral adipose tissue and is involved in insulin expression by activating the insulin receptor, being at the same time correlated with inflammation visfatin is considered to be a proinflammatory cytokine a link between inflammation and obesity and apoptosis. Studies suggest that visfatin is associated with obesity, insulin resistance, type 2 diabetes, metabolic syndrome and cardiovascular disease, its possible use as a predictor of this conditions being taken under consideration.[footnoteRef:8] [8: Obesity, a gene review, Radu Ioan Ursu.]

NPC1 : Mutations in the Niemann Pick disease type C1 gene (18q11.2), an intracellular cholesterol transporter found in the endosome/lysosome limiting membrane, lead to Niemann Pick type C disease, an autosomal recessive disorder. Studies indicate that the NPC1 gene expression levels in the white adipose tissues` adipocytes are high in obese persons and decrease with the body mass index. About 10% of the obese children and 14% of the obese adults are caused by mutations in the NPC1 gene.ENPP1 : Another obesity-associated gene is the ectonucleotide pyrophosphatase/ phosphodiesterase 1 gene, a member of the ENPP genes family, found on chromosome 6q23.2 . The function of the protein expressed by this gene is to hydrolyze different types of bonds, including nucleotides` phosphodiester and pyrophosphate bonds, possibly regulating insulin sensitivity. Mutations in this gene cause insulin resistance, infantile arterial calcification and the ossification of the posterior longitudinal ligament of the spine. Until now there is only one SNP of the ENPP1 gene, K121Q, found to play a role in the BMI and obesity, and in other metabolic disorders as well.MAF : The V-maf musculoaponeurotic fibrosarcoma oncogene homolog (chromosome 16q23.2) regulates the insulin and glucagon expression. MAF gene, a member of the MAF gene family, is a transcription factor modulating cell differentiation and gene transcription in humans. About 6% of the cases of childhoodobesity and 16% of all the obese adults have revealed the involvement of the MAF gene. A SNP of the gene, rs1424233, is correlated with weight gain in tested individuals.NEGR1, INSIG 2, CETP : NEGR1 gene, mapped to chromosome 1p31.1, is apparently implicated in cell adhesion. Variants of this gene are associated with obesity [19]. The INSIG2 gene is located on chromosome 2q14.2 and is thought of being correlated with extreme cases of obesity.The CETP gene on chromosome 16q13 codes for the cholesteryl ester transfer protein, which has the role of transporting cholesteryl esters between lipoproteins. The Tag1B gene polymorphism plays a role in obesity, being a HDL-cholesterol modulating factor. Certain SNPs near the TMEM18, GNPDA2, KCTD15, BDNF, ETV5, SEC16B, SH2B1, and MTCH2 genes show an important implication in the regulation of body mass.Multiple hormones are involved in the regulation and pathophysiology of obesity, including adipokines and others. Ghrelin is a circulating peptide hormone derived from the stomach. It is the only known peripherally acting orexigenic hormone and is responsible for stimulating appetite. Peptide YY (PYY) is found throughout the intestine at progressively higher levels distally, with the highest levels in the colon and rectum. PYY is released postprandially, and signals to the hypothalamus, resulting in delayed gastric emptying, thus reducing gastric secretion. Administration of PYY before meals results in decreased food consumption.Cholecystokinin (CCK), produced in the gallbladder, pancreas and stomach, and concentrated in the small intestine, is released in response to dietary fat. It regulates gallbladder contraction, pancreatic exocrine secretion, gastric emptying and gut motility. CCK also acts centrally by increasing satiety and decreasing appetite and acts on the satiety signal via subtype CCK-A receptors on the afferent vagal fibres to the brain, causing termination of appetite.Several hormones, collectively referred to as adipokines, are produced by the adipocytes. The key secretory products are tumour necrosis factor-alpha (TNF-), interleukin-6 (IL-6), leptin and adiponectin (AdipoQ). The role of TNF- in obesity has been linked to insulin resistance through the liberation of free fatty acids, reduction in adiponectin synthesis and impairment of insulin signalling. TNF- also activates nuclear factor-kappa B, leading to a series of inflammatory changes in vascular tissue. TNF- is a proinflammatory cytokine produced by several types of cells, but mostly by the macrophages and monocytes. The gene, found on chromosome 6 (6p21.3), has various functions in coagulation, endothelial disfunction and lipid metabolism. It also activates the NFkB proinflammatory pathway, producing insulin resistance, an increase in the circulating TNF- levels being identified in obese individuals. During the past years, the TNF- gene and its receptors have become interesting treatment targets for obesity, insulin resistance and type 2 diabetes.IL-6 is a pleiotropic circulating cytokine resulting in inflammation, impairment of host defenses and tissue injury. It is secreted by many cell types, including immune and endothelial cells, fibroblasts and adipocytes. It acts by inhibiting insulin receptor signal transduction in hepatocytes, increasing circulating free fatty acids from adipose tissue and reducing adiponectin secretion.Interleukin-6 is a cytokine with the cytogenetic location 7p21 produced equally in a number of tissues, including the adipocytes and with a variety of functions. It plays a role in inflammation, triggers the acute phase response, is implicated in lymphocyte and monocyte maturation, functions as a myokine, induces the protein C synthesis within the liver, etc. High levels of IL-6 are correlated with insulin resistance play a role in obesity related diabetes and insulin resistance. Leptin acts as a dominant long-term signal responsible for informing the brain of adipose energy reserves. Leptin is transported across the blood-brain barrier and binds to specific receptors on appetite-modulating neurons and the arcuate nucleus in the hypothalamus, inhibiting appetite. Leptin-deficient mice that lack leptin receptors have been shown to be hyperphagic and obese. Furthermore, leptin deficiency reduces energy expenditure. True leptin deficiency in humans is rare; however, obese humans are, in part, leptin-resistant.Adiponectin is an adipokine derived from plasma protein. It is insulin sensitizing, anti-inflammatory and antiatherogenic. In contrast to other adipokines, adiponectin messenger RNA (mRNA) levels are reduced in adipose tissue in obese and diabetic individuals, and adiponectin levels are restored to normal levels after weight loss. The 3q27.3 AdipoQ gene encodes, exclusively within the adipocyte, for the protein adiponectin, an adipokine with multiple and important actions and functions. It plays a role in the lipid and glucid metabolisms, is an insulin sensitizing factor, functions in the skeletal muscles and liver by stimulating AMP kinase activation, negatively mediates TNF-gene expression, takes part in processes such as angiogenesis and cell growth, etc. Low levels of adiponectin are correlated with insulin resistance, type 2 diabetes and coronary artery disease, while high levels of this hormone are associated with a decrease in the risk of cardiovascular disease. Studies point out that adiponectin possesses important anti-diabetic, anti-atherogenic and anti-inflammatory characteristics. Certain SNPs in the AdipoQ gene have been described to being associated with an increased risk of developing obesity, metabolic syndrome and type 2 diabetes. Increased visceral fat results in increased levels of IL-6, TNF- and C-reactive protein, and reduced levels of adiponectin and interleukin-10, resulting in a proinflammatory milieu that leads to both insulin resistance and endothelial dysfunction, and culminating in the metabolic syndrome, diabetes and atherosclerosis. Visceral adiposity modulates these key regulators of inflammation, and has a proinflammatory potential equivalent to or greater than that of macrophages.[footnoteRef:9] [9: Obesity : A review of pathogenesis and management strategies, Brinderjit Kaila & Maitreyi Raman]

Genes causing monogenic syndromes

The hormonal and neural networks that regulate adiposity are complex, making the dissection of genetic control difficult. Clues have come from monogenic (variations in one gene) obesity. While this type of obesity is rare, it provides a genetic starting point. The most common obesity single gene disorders are produced by mutations in the LEP, LEP-R, MC4R, POMC, PCSK1 genes, but leptin deficiency was the first cause of monogenic obesity to be demonstrated in a human patient.Leptin : chromosome 7q32.1- was the first adipokine to have been discovered in and is almost exclusively expressed by the white adipose tissue adipocytes. The most important function of the LEP gene is in modulating the body mass by transmitting the satiety signal to the hypothalamus in order to stop or decrease the food intake. Leptin plays major roles within the human organism, such as its roles in immunity, reproduction, angiogenesis, inflammation, hematopoiesis etc. Leptin levels are high in obese individuals and are proportionally correlated with BMI. Mutations in this gene lead to severe obesity, type 2 diabetes, morbid obesity associated with hypogonadism, the diminishing of the normal expression of LEP gene causing obesity-related monogenic disorders such as the congenital leptin deficiency or partial leptin deficiency (in heterozygote carriers).

The congenital leptin deficiency is an autosomal recessive disorder caused by the frameshift 133G mutation and is the first single gene disorder associated with obesity. The clinical features of this disease are the early onset of obesity, hypogonadotropic hypogonadism, hyperinsulemia and anomalies in the hypothalamo-pituitary-thyroidal axis, hyperphagis, etc. The disorder is treatable through leptin administration.LEP-R The leptin receptor gene has its locus on chromosome 1p31.3. The roles of the leptin receptor gene are in the lipid metabolism and in gene transcription regulation. Possible connections of LEP-R with the reproduction process have been described. Mutations within the leptin receptor gene are linked to obesity and abnormal pituitary function. The decrease of the LEP-R gene synthesis leads to the leptin receptor deficiency autosomal recessive mendelian disorder. The patients suffering from this disease have a normal birthwieght but then develop postnatal hyperphagia, severe obesity, hypogonadotropic hypogonadism, hypothyroidism, increased growth hormone (GH) expression and low levels of insulin-like growth factor 1 (IGF-1) and insulin growth factor binding protein 3.POMCThe pro-opiomelanocortin gene (2p23.3) expresses a polypeptide hormone precursor. The precursor can be cleaved in 10 different peptides (lipotropins, adrenocorticotrophin, melanotropins, endorphins) with distinct functions depending on the tissue where the gene is secreted. A number of eight cleavage sites can be found on the polypeptide precursor, the protein synthesis being produced mainly in the corticotroph cells of the anterior pituitary gland. Mutations in the POMC gene cause obesity, red hair and adrenal disfunction and as the same time generate monogenic obesiy syndromes in human. The POMC deficiency is an autosomal recessive disorder numbering adrenocorticotropic hormone deficiency, hyperphagia and early onset obesity as main signs and symptoms.Obesity reflects the lack of POMC-derived peptides as ligands at the melanocortin MC4 and MC3 receptors, which are expressed in the hypothalamic leptin-melanocortin pathway of body weight regulation. Hypocortisolism and alteration of pigmentation are caused by the lack of POMC-derived peptides at the adrenal MC2 receptor and the skin MC1 receptor, respectively.[footnoteRef:10] [10: Obesity due to proopiomelanocortin deficiency, J. Clin]

MC4R The MC4R gene, found on the 18q21.32 chromosome, belongs to the melanocortin receptor gene family and seems to be strongly correlated with the regulation of the energy balance of the organism. Mutations in the MC4R gene lead to an autosomal dominant single gene disorder called MC4R deficiency, the most common obesity-related mendelian disease in humans. Its clinical features include hyperphagia, early onset hyperinsulinemia and obesity.PCSK1 The PCSK1 gene (5q15 chromosome) is part of the subtilisin-like proprotein convertase family and plays a role in the hypothalamic processing of POMC and of other neuropeptides. Mutations in the PCSK1 gene cause the autosomal recessive protein deficiency characterized by severe childhood obesity, hypoglicemia, hypoadrenalism and neuroendocrine affection.Additionally, mutations in three genes (SIM1, BDNF, and NTRK2) involved in neural development have been shown to cause rare monogenic obesity. These genes partially control the function of the hypothalamus; inactivation of the genes results in hyperphagia and a sense that the body needs to increase its energy intake.SIM1 : haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includesSIM1, were reported in obese children with a Prader-Willilike syndrome; however,SIM1involvement in obesity has never been conclusively demonstrated.BDNF - A recent study provides new insights into the central control of energy balance and obesity, showing that feeding behavior in mice can be modulated by local dendritic translation of a key protein in neuronal plasticity brain-derived neurotrophic factor.NTRK2 - This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation. Mutations in this gene have been associated with obesity and mood disorders. Alternate transcriptional splice variants encoding different isoforms have been found for this gene.Genes causing polygenic obesity syndromes

Most of the obesity cases are caused by more than one gene (over 90% of all obese individuals). Genome-wide studies indicate chromosomes 2p, 3q, 5p, 6p, 7q, 10p, 20q as sites for candidate genes for polygenic obesity. The 2p21 chromosome location is one of the strongest sites associated with obesity, as it contains the POMC gene. A number of over 70 genes having some correlation with obesity have been found, but their involvement in the ethiopathogenesis of this disorder is not yet fully understood.In contrast to rare monogenic obesity, common obesity appears to be polygenic with no simple inheritance pattern and significant contribution from environmental factors.Two genes, FTO and INSIG2, have been identified by linkage studies to be associated with common obesity. Variants in FTO are associated with BMI and increased risk for obesity. Studies demonstrate that FTOvariations are associated with modestly increased food intake and satiety, and also with decreased lipolytic activity in adipocytes. INSIG2encodes a protein thought to regulate the proteins responsible for fatty acid synthesis and adipogenesis. An INSIG2 variant is associated with increased BMI. Interestingly, variations in the melanocortin 4 receptorand in BDNF, both identified as causative of monogenic obesity, seem to account for a measurable number of common obesity cases as well.FTOINSIG2

Pleiotropic obesity

Over 30 genetic syndromes have been described of including obesity among their main clinical features. These are complex disorders, each having its distinct clinical characteristics, evolution, onset of symptoms, pathogeny, inheritance, etc. Some of the main genetic syndromes with obesity are: Prader-Willi syndromeAlbright hereditary osteodistrophy Ulnar-mammary syndrome Bardet-Biedl syndrome Alstrom syndrome Cohen syndrome fragile X syndrome Borjeson-Forssman-Lehman syndrome MEHMO syndromeWilson-Turner syndrome WAGRO syndromePRADERWILLI SYNDROMEPrader-Willi syndrome is a complex genetic condition that affects many parts of the body. In infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes mellitus (the most common form of diabetes).People with Prader-Willi syndrome typically have mild to moderate intellectual impairment and learning disabilities. Behavioral problems are common, including temper outbursts, stubbornness, and compulsive behavior such as picking at the skin. Many affected individuals also have sleep abnormalities. Additional features of this condition include distinctive facial features (such as a narrow forehead, almond-shaped eyes, and a triangular mouth), short stature, and small hands and feet. Some people with Prader-Willi syndrome have unusually fair skin and light-colored hair. Both affected males and affected females have underdeveloped genitals. Puberty is delayed or incomplete, and most affected individuals are unable to have children (infertile).The PraderWilli syndrome (PWS) is an autosomal dominant disorder characterized by hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism and hyperphagia and obesity. Sporadic deletion of the paternal chromosomal segment 15q11.2q12 or loss of the entire paternal chromosome 15 with presence of two maternal homologues (uniparental maternal disomy) results in PWS (Amos-Landgrafet al. 1999). There is a lack of expression of paternally imprinted genes within the 4.5Mb PWS region and several candidate genes have been studied and their expression shown to be absent in the brains of PWS patients (Swaabet al. 1995). Recently, Wevrick and colleagues have showed that Necdin and Magel2 bind to and prevent proteasomal degradation of FEZ1, a protein implicated in axonal outgrowth and kinesin mediated transport and also bind to the BardetBiedl syndrome (BBS) protein BBS4in vitro(Leeet al. 2005). Interactions among these molecules occur at or near centrosomes, and centrosomal dysfunction has been implicated in BBS and may be relevant to the common phenotypic features of learning disabilities, hypogonadism and obesity in these patients. However, the precise role of these genes and the mechanisms by which they lead to a pleiotropic obesity syndrome remain elusive.There has been interest recently in the role of the enteric hormone ghrelin. Several groups have shown that children and adults with PWS have fasting plasma ghrelin levels that are 4.5 fold higher than equally obese controls. As ghrelin is implicated in the regulation of meal-time hunger in rodents and humans, these observations may implicate ghrelin in the pathogenesis of hyperphagia in these patients (Cummingset al. 2002;Haqqet al. 2003).Go to:BARDETBIEDL SYNDROMEBardet-Biedl syndrome is a disorder that affects many parts of the body. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.Vision loss is one of the major features of Bardet-Biedl syndrome. Loss of vision occurs as the light-sensing tissue at the back of the eye (the retina) gradually deteriorates. Problems with night vision become apparent by mid-childhood, followed by blind spots that develop in the side (peripheral) vision. Over time, these blind spots enlarge and merge to produce tunnel vision. Most people with Bardet-Biedl syndrome also develop blurred central vision (poor visual acuity) and become legally blind by adolescence or early adulthood.Obesity is another characteristic feature of Bardet-Biedl syndrome. Abnormal weight gain typically begins in early childhood and continues to be an issue throughout life. Complications of obesity can include type 2 diabetes, high blood pressure (hypertension), and abnormally high cholesterol levels (hypercholesterolemia).Other major signs and symptoms of Bardet-Biedl syndrome include the presence of extra fingers and/or toes (polydactyly), intellectual disability or learning problems, and abnormalities of the genitalia. Most affected males produce reduced amounts of sex hormones (hypogonadism), and they are usually unable to father biological children (infertile). Many people with Bardet-Biedl syndrome also have kidney abnormalities, which can be serious or life-threatening.Additional features of Bardet-Biedl syndrome can include impaired speech, delayed development of motor skills such as standing and walking, behavioral problems such as emotional immaturity and inappropriate outbursts, and clumsiness or poor coordination. Distinctive facial features, dental abnormalities, unusually short or fused fingers and/or toes, and a partial or complete loss of the sense of smell (anosmia) have also been reported in some people with Bardet-Biedl syndrome. Additionally, this condition can affect the heart, liver, and digestive system. BBS is a rare (prevalence less than 1/100000), autosomal recessive disease characterized by obesity, mental retardation, dysphormic extremities (syndactyly, brachydactyly or polydactyly), retinal dystrophy or pigmentary retinopathy, hypogonadism and structural abnormalities of the kidney or functional renal impairment (Katsaniset al. 2001a,b). BBS is a genetically heterogeneous disorder that is now known to map to at least eight loci: 11q13 (BBS1;Mykytynet al. 2002), 16q21 (BBS2;Nishimuraet al. 2001), 3p13p12 (BBS3;Sheffieldet al. 1994), 15q22.3q23 (BBS4;Mykytynet al. 2001), 2q31 (BBS5;Younget al. 1999), 20p12 (BBS6;Slavotineket al. 2000), 4q27 (BBS7;Badanoet al. 2003) and 14q32.11 (BBS8;Ansleyet al. 2003). Although BBS is usually transmitted as a recessive disorder, some families have exhibited so called tri-allelic inheritance where the clinical manifestation of the syndrome requires two mutations in one BBS gene plus an additional mutation in a second, unlinked BBS gene (Katsaniset al. 2001a,b).The recent discovery of the novel BBS3, 5, 7 and 8 genes by phylogenetic/genomic approaches has led to progress in the understanding of the mechanisms underlying the pleiotropic features of BBS (Beales 2005). These proteins are all involved in basal body and centrosomal function and impact on ciliary development and transport (Mykytyn & Sheffield 2004). BBS1, 2, 6 and 4 are all involved in intracellular trafficking (Nishimuraet al. 2004) and mice lacking the Bbs4 protein recapitulate the major components of the human phenotype, including obesity and retinal degeneration (Mykytynet al. 2004). It remains to be seen what role these proteins and organelles play in energy balance, cognitive impairment and renal development. Alstrm syndrome Is a rare condition that affects many body systems. Many of the signs and symptoms of this condition begin in infancy or early childhood, although some appear later in life.Alstrm syndrome is characterized by a progressive loss of vision and hearing, a form of heart disease that enlarges and weakens the heart muscle (dilated cardiomyopathy), obesity, type 2 diabetes mellitus (the most common form of diabetes), and short stature. This disorder can also cause serious or life-threatening medical problems involving the liver, kidneys, bladder, and lungs. Some individuals with Alstrm syndrome have a skin condition called acanthosis nigricans, which causes the skin in body folds and creases to become thick, dark, and velvety. The signs and symptoms of Alstrm syndrome vary in severity, and not all affected individuals have all of the characteristic features of the disorder.

Cohen syndrome Is an inherited disorder that affects many parts of the body and is characterized by developmental delay, intellectual disability, small head size (microcephaly), and weak muscle tone (hypotonia). Other features include progressive nearsightedness (myopia), degeneration of the light-sensitive tissue at the back of the eye (retinal dystrophy), an unusually large range of joint movement (hypermobility), and distinctive facial features. Characteristic facial features include thick hair and eyebrows, long eyelashes, unusually-shaped eyes (down-slanting and wave-shaped), a bulbous nasal tip, a smooth or shortened area between the nose and the upper lip (philtrum), and prominent upper central teeth. The combination of the last two facial features results in an open-mouth appearance.The features of Cohen syndrome vary widely among affected individuals. Additional signs and symptoms in some individuals with this disorder include low levels of white blood cells (neutropenia), overly friendly behavior, and obesity that develops in late childhood or adolescence. When obesity is present, it typically develops around the torso, with the arms and legs remaining slender. Individuals with Cohen syndrome may also have narrow hands and feet, and slender fingers.Fragile X syndromeIs a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behavior such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorders that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.Most males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty.

Wilson Turner syndromeWTS is an X-linked neurologic disorder characterized by severe intellectual disability, dysmorphic facial features, hypogonadism, short stature, and truncal obesity. Affected females have a milder phenotype than affected males.

Epigenetics & Obesity

Phenotype associated with variations in both FTO and INSIG2is dependent on environmental factors as well. Among homozygous carriers of the variant of FTO associated with increased BMI, those who were physically active showed a BMI almost 2 points lower than those who were inactive. In a small study of INSIG2 variants, physical activity seemed to modify the effects of the genetic variation on BMI.

Ourgenomecontains all the information to make us who we are, but many of the details of our behavior and appearance are actually determined bygeneregulation. A striking example of the power ofgene regulationis seen in agouti mice, in which geneticallyidentical twinscan look entirely different in both color and size. For example, one mouse may be small and brown, but her twin sister may be obese and yellow. Another genetically identical sister may have a mottled look with both fur colors present and fall in the middle of the weight range. The genome of each of these mice is the same, but thegene expressionobviously differs (Figure 1; Duhlet al., 1994).

In these mice, the epigenome is what makes the difference. Picture a network of molecules that are intimately intertwined with nuclearDNAand that have the power to silencegenes. The behavior of this entourage of molecules can be altered by theenvironment(or "nurture," to use the terminology of the classic "nature versus nurture" debate) and can have a profound effect on an individual'sphenotype.For instance, in normal, healthy mice, the agouti genes are kept in the "off" position by the epigenome, which attaches methyl groups to the corresponding regions of DNA, resulting in the DNA's compaction to preventtranscription. In yellow and/or obese mice, however, the same genes are not methylated; thus, these genes are expressed or "turned on." The turning on of this single gene results in an apparent freak of nature. Mice whose agouti gene is "on" are also more likely to suffer from diabetes andcanceras adults.Environmental Triggers

A number of environmental triggers have been shown to affect the behavior of anorganism's epigenome, tipping the balance betweenmethylationor lack thereof, and thus between genes that are "off" and those that are "on." One suspected trigger is a chemical found in many plastic drink bottles, including baby bottles, called bisphenol A. In one particularly notable study, scientist Randy Jirtle and his group of researchers exposed pregnant mice to bisphenol A and watched as more of their genetically identicalprogenydeveloped into yellow, obese mice than would normally be expected (Dolinoyet al., 2007). In Jirtle's experiment,DNA methylationat the agouti gene sites was decreased by 31%. (DNA methylation was reduced on other genes as well.) These results supported the hypothesis that bisphenol A alters the action of organisms' epigenomes by removing methyl groups from DNA.The implications of this discovery are staggering. With the rise of obesity in Americans coinciding with the widespread use of bisphenol A in everything from water bottles to dental sealants, one can't help wondering whether there is a causal connection. Yet, Jirtle himself is the first person to say that such an association cannot be definitively demonstrated until evidence shows that bisphenol A indeed affects the expression of the human genes involved in obesity.So, how does the agouti gene cause such disparate effects in mice? It was first discovered that the agoutiproteinbinds to a melanocortin receptor located on a mouse's skin cells, which blocks those cells from making black pigment (Luet al., 1994). Thus, because the agouti gene is constantly turned "on" inmutantmice, the melanocortin receptor is always blocked, and the animals are yellow. Roger Cone speculated that the same type of receptor might also be present in a mouse's brain. In the same 1994 paper, he reported finding melanocortin receptors in an area of the mouse brain known to be involved in feeding behavior and body weight set point. Thus, the agouti protein appears responsible for both phenotypic differences in mouse twins: coat color and body weight.But exactly how does exposure to bisphenol A affect both skin cells and brain cells? Through careful study, Jirtle found that the amount of DNA methylation was fairly consistent through an individual mouse's body. This result suggested that the demethylation that led to yellowness and obesity occurred in earlydevelopment. Despite this suggestion, not all the mice pups that Jirtleobservedgrew to be unhealthy. In other words, bisphenol exposure didn't guarantee obesity in mice; rather, it simply increased the risk of developing obesity.Environmental ProtectionWhen gene expression goes awry during development, as in bisphenol-exposed mouse pups, the consequences can cause changes in adult mice that were not seen at birth. This phenomenon, called fetal programming, may play a role in many health conditions, including heartdisease, diabetes, obesity, and cancer. The yellow agouti mouse has been a great animalmodelwith which to studyepigeneticsand fetal programming. Recently, it has also been used to show that dietary factors can prevent the agouti gene from being turned on.More specifically, not only did Jirtle's group find an increased risk of disease with maternal chemical exposure in mice, but they also noted that certain nutrients were protective. In particular, supplementing the mothers' diets with methyl-donating substances, such as folic acid and vitamin B12, was shown to counteract the reduction in DNA methylation caused by bisphenol A. In addition, a constituent of soy products called genistein prevented an increased number of unhealthyoffspring. Whether a similar diet might reverse epigenetic effects once they appear, however, is unknown and awaits experimental testing. Despite such uncertainties, this epigenetic mechanism clearly demonstrates how profoundly environment can affect gene expression and phenotype in a long-lasting way.

ConclusionsBody mass index is a highly heritable human trait. Despite legitimate concerns about the environmental forces responsible for recent secular changes in its prevalence, this fact has not altered. Our knowledge of the molecules involved in the control of human body fat mass has increased dramatically, largely from the study of humans who become severely obese from a young age. Notably, in the vast majority of cases described to date, the causative mutation disrupts the function of hypothalamic integrative centres and results in increased food intake. Progress has been slower in identifying common genetic variants that underlie susceptibility/resistance to obesity in the general population. However, it is highly likely that such variants will affect similar pathways to those revealed by the rare monogenic defects. If that is the case, then it might eventually be necessary to reclassify obesity from a metabolic disorder to a neuro-behavioural one.[footnoteRef:11] [11: Genetics of Obesity, Stephen O'Rahilly.]

Population-wide prevention and treatment efforts aimed at reducing obesity are usually costly and difficult to conduct. Therefore, efforts to prevent obesity at the public health level can be focused on identification and counseling of susceptible individuals. This situation emphasizes the need for greater understanding of the ways in which interactions between diet/lifestyle and genes may help distinguish who will and who will not respond to dietary interventions. Such knowledge will provide a strong scientific rationale for tailoring diet/ lifestyle interventions from a one-size-fits-all approach to a personalized approach. Attempts to integrate the emerging knowledge into personalized health practices are still in the very early stages.[footnoteRef:12] [12: Gene-environment interaction and obesity, Lu QiandYoung Ae Cho]