Genetics and Obesity

Function

Genetic and epigenetic variations contribute to obesity by influencing the function of metabolic pathways in the body and regulating neural pathways and appetite centers. Subsequently, these variations influence insulin resistance, dyslipidemia, inflammation, hypertension, and ectopic fat deposition-especially in the liver, which are the markers of obesity.[2] Genetic mutations can be inherited in an autosomal dominant or autosomal recessive manner and are influenced by genetic mechanisms of deletion, genetic imprinting, and translocation. However, epigenetic modifications are more complex and occur at any given time and can be passed on from generation to generation to cause obesity. Geneticists have identified some crucial periods when epigenetic changes occur, especially during the growth of the fetus. Factors influencing these epigenetic changes include:

1. Maternal nutrition-both maternal over and undernutrition give rise to epigenetic changes that can affect the fetus and have intergenerational and transgenerational effects. Maternal undernutrition and intrauterine growth retardation are known to be risk factors for permanent changes in fetal insulin metabolism. Although this is a survival adaptation mechanism in fetal life, when these children are born and exposed to a nutrient-rich environment, it predisposes them to develop obesity and type 2 diabetes. This concept is widely known as the thrifty phenotype hypothesis, which was put forth by Hales and Barker 1992, published in the Journal Diabetologia. The new terminology for this concept is the "Developmental Origins of Health and Disease hypothesis."[9] 

Human studies that elaborated this concept include-the Dutch Hunger Winter study of victims of the Dutch famine of 1944-1945, which looked at the changes in the IGF2 gene, the Chinese famine study, the Kiang West longitudinal population study in the Gambia, which looked at differences in populations born in the wet and dry season with special focus on the POMC gene. Maternal overnutrition, on the other hand, including low protein and high-fiber diets, have been studied to cause fetal obesity. The effect of maternal diet on fetal health is widely known as the theory of fetal programming.[7][10][11] The rising prevalence of obesity and type 2 diabetes in developing countries like India and sub-Saharan Africa confounded epidemiologists for the longest time and is now known to have its origins explained by the theory of fetal programming.[9]

2.  Maternal exposure to toxins like organochlorides, polycyclic aromatic hydrocarbons, arsenic [which can cause gestational diabetes mellitus and thus fetal metabolic syndrome], and cigarette smoking can cause epigenetic modifications. An example of this is- changes in the GF11 gene seen in mothers who smoke >15 cigarettes a day. Researchers are now terming these factors as "obesogens" or "endocrine-disrupting chemicals."[10][11]

3. Maternal stress has been associated with diet-induced obesity in rat models. The Quebec Ice Storm Study in humans implied the association between type 2 diabetes and children born to pregnant mothers experiencing grief after the storm.[10]

4. Maternal diabetes, younger maternal age, low pre-pregnancy weight have been studied in association with fetal metabolic derangements and later childhood obesity.[12][13][14]

5. Nutritional disturbances in the postnatal environments and early childhood nutrition in twin studies have been linked to childhood obesity and metabolic abnormalities in early adulthood.[7]

6. Altered gut microbial flora with antibiotic use in the first year of life and even in adulthood is linked to obesity and non-alcoholic fatty liver disease (NAFLD).[10] Microbial metabolites can cause epigenetic modifications, change gene expression profiles, and cause genome reprogramming.[15]

7. Paternal nutrition-overnutrition, prediabetes, and low protein diets are linked to epigenetic modifications associated with fetal obesity. There is a new interest in this field of "Paternal Origins of Health and Disease."[7][10]

8. A high intake of sugary beverages, fried foods, high saturated fats, sleep disturbances, and a sedentary lifestyle in adulthood has been linked to epigenetic modifications, e.g., DNA methylation of PGC1 alpha encoded by PPARGC1A.[10][5]

In the laboratory, the mammals used to study epigenetics include sheep, pigs, mice, rats, macaques, and drosophila. The tissues used in human epigenetic studies include peripheral blood-leukocytes and CD4+ T cells, cord blood, liver, pancreas, skeletal muscle, subcutaneous adipose tissue from the abdomen and buttock.[7]

Issues of Concern

Genetic Obesity Can Be Classified as Monogenic and Polygenic Obesity [included under nonsyndromic obesity] or Syndromic Obesity

1. Syndromic obesity: This can be further classified as obesity caused by chromosomal rearrangements like Prader-Willi syndrome, WAGR syndrome, SIM1 syndrome, and pleiotropic syndromes, including Bardet-Biedl syndrome, Fragile X syndrome, Cohen syndrome, etc.

Prader-Willi syndrome (PWS) is caused by the deletion of paternal 15q.11-13-the Prader-Willi Critical Region (PWCR) in most cases or by maternal uniparental disomy in 20 to 30% of cases. The PWCR on the maternal chromosome is normally genetically imprinted; hence the loss of the paternal PWCR causes Prader-Willi syndrome. PWS characterized by mental retardation, dysmorphic facies, hypotonia, short stature, and hormonal deficiencies in addition to obesity. It is associated with severe hyperphagia and food compulsivity in childhood. The genes in the PWCR that are lost include NPAP1, MAGEL2, SNURF-SNRPN, MKRN3, and NDN, which leads to lower expression of proconvertase-1 in the hypothalamus, contributing to obesity.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disease seen more in families with a history of consanguinity. It is characterized by problems in the BBSome, which is a unit of motility for cilia. Sixteen genes have been implicated in various forms of BBS. Children affected by this disorder present with learning disabilities, dyslexia, progressive rod-cone dystrophy, hypogonadism, type 2 diabetes, labile behavior, renal abnormalities, and polydactyly.

Other causes of syndromic obesity include 5p13 microdeletion syndrome, 16p11.2 deletion, Albright hereditary osteodystrophy associated with GNAS mutation, Alstrom syndrome-ALMS1 mutation, CHOPS syndrome-AFF4 mutation, Carpenter syndrome-RAB23 mutation, Cohen syndrome-VPS13B/COH1 mutation, Rubinstein Tayabi syndrome-CREBBP mutation, OBHD syndrome-NTRK2 mutation, Kleefstra syndrome- EHMT1 mutation, etc.[11][3][16]

2. Monogenic obesity: Monogenic obesity can be further classified into autosomal dominant or autosomal recessively inherited forms of genetic obesity. Monogenic obesity generally involves mutations in the leptin signaling pathway leading to suppression of anorexigenic and activation of orexigenic pathways. To understand the many forms of monogenic obesity, it is crucial to understand the intricate functioning of the leptin signaling pathway. Normally, leptin acts on the leptin receptor [LEPR], which increases the levels of proopiomelanocortin [POMC] and cocaine and amphetamine-regulated transcript [CART]. POMC, in turn, increases the levels of proprotein convertase 1/3, which increases the formation of alpha melanocyte stimulating hormone [alpha-MSH]. Alpha-MSH then acts on the melanocortin 4 receptor [MC4R] in the hypothalamus to initiate the feeling of satiety. Also, leptin normally suppresses the neuropeptide Y (NPY)-agouti-related peptide (AgRP)-Y1R orexigenic pathway.[16]

• Autosomal recessive inheritance: Mutations in the leptin gene located on chromosome 7, leptin receptor located on chromosome 1, PCSK 1 located on chromosome 5, and POMC located on chromosome 2 are examples of mutated genes that have an autosomal recessive inheritance. Homozygous mutations in the leptin gene are generally seen in consanguineous families and can be treated with metreleptin. Mutations in leptin receptors are frameshift, missense, or nonsense mutations that cannot be treated with metreleptin. POMC generates both alpha MSH and Adrenocorticotropic hormone (ACTH). Patients with POMC mutations develop central adrenal insufficiency and skin hyperpigmentation. Mutations of POMC can be inactivating or nonsense mutations, and patients can be treated with setmelanotide and hydrocortisone.[16]
• Autosomal dominant inheritance: Mutations in genes SH2B1 located on chromosome 16, MRAP2 located on chromosome 6, and LPR2 located on chromosome 2 are examples of mutated genes with an autosomal dominant inheritance. Mutations in genes-BDNF located on chromosome 11, SIM1 located on chromosome 6, NTRK2 located on chromosome 9 give rise to abnormal proteins involved in hypothalamic neuronal differentiation leading to the development of severe obesity and cognitive impairment. Mutations in MC4R have codominant inheritance and constitute the commonest cause of monogenic obesity, with a prevalence of 0.5% to 6% in different populations. Setmelanotide cannot be used in these cases of impaired or loss of function of MC4R because its action depends on the normal downstream signaling of MC4R.[16][11][17]
• Other gene mutations that can cause obesity include NPY gene mutations, ghrelin receptor mutations, MC3R gene mutations, and FTO mutations (the most significant gene mutations contributing to obesity in adults and children).[3]

3. Polygenic obesity: Sixty percent of inherited obesity is polygenic. Polygenic obesity is associated with mutations in CYP27A1, TFAP2B, PARK2, IFNGR1, as well as UCP2 & UCP3-which code for uncoupling proteins in skeletal and brown adipose tissue, ADRB1-3 which code for the beta-adrenergic receptors affecting energy utilization and lipolysis, and SLC6A14-which regulates tryptophan accessibility for serotonin synthesis which affects appetite control and energy balance.[3][16][2]

Epigenetic Modifications Linked to Obesity

• DNA methylation/demethylation-the most common mechanism of epigenetic modifications seen throughout the genome. Methylation is governed by the action of DNA methyltransferase 1 (DNMT1), and demethylation is carried out by ten-eleven-translocation (TET) enzymes. Variations in the methylation of CpGs in the genome constitute the "Differentially Methylated Regions" (DMRs).
• Histamine modification by acetylation and methylation. Histone modification regulates five essential adipogenesis genes, including Pref-1, c/EBP beta, C/EBP alpha, PPAR gamma, and aP2.
• Histone variants: Histone macroH2A1.2 inhibits adipogenesis and increases leanness while promoting metabolic health. 
• ATP-dependent chromatin remodeling complexes' involvement leads to further acetylation, phosphorylation, or methylation of genes.
• The addition of micro-RNAs, long non-coding RNAs, piRNAs, or siRNAs leads to pre and post-transcriptional variations in RNA.[10][7][11]

Cross-sectional and longitudinal studies have identified differential methylation sites in CPT1A, ABCG1, and SREBF1 genes in the blood, associated with BMI variation. Differential methylation of LY86 in blood leukocytes is seen between obese and lean people. Variation in the waist to hip ratios varies with ADRB3 methylation in blood. Other significant epigenetic changes causing variations in BMI have been seen in PGC1A, HIF3A, FTO, TCF7L2, FASN, CCRL2, ELOVL2 genes.[7] 

In prenatal famine, differential methylation in CDH23, SMAD7, INSR, CPT1A, KLF13, RFTN1 genes has been studied from adult whole blood samples. In intrauterine growth retardation, pancreatic islet failure and insulin resistance are linked to decreased acetylation of histones 3 and 4. Maternal high-fat diets have been linked to adipose tissue hyperplasia by reduced methylation of promoter Scd1. Maternal obesity has been associated with hypermethylation of POMC in the fetal brain and hypomethylation of dopamine reuptake transporter promoting fat and sugar cravings in children.[10] The gut flora in adult life changes based on diet and can induce epigenetic modifications like histone deacetylation and lower levels of methylation of FFAR3 and TLR. Thus epigenetic variations need to be studied in specific tissues due to the differential expression of genes in body tissues.[15]

Clinical Significance

When diagnosing genetic causes of obesity, good history taking, and physical exam skills are extremely important. A detailed history includes personal history, family history, medication history, psychosocial history, diet and activity/exercise history, and history of weight gain. Endocrine causes of obesity like hypothyroidism, growth hormone deficiency, hypothalamic obesity, and Cushing's disease must be ruled out early with history, physical examination, and lab work. Syndromic obesity can sometimes be distinctly diagnosed based on the presence of physical features, like in Prader-Willi syndrome or Albright's hereditary osteodystrophy. After basic lab work is done, including a complete blood count, comprehensive metabolic panel, growth hormone, thyroid-stimulating hormone, and dexamethasone suppression test, physicians can check leptin, insulin, and proinsulin levels. If all the above blood work is negative genetic testing can be carried out.

These genetic tests are expensive and done in limited centers across the United States. They include linkage analysis to look for familial aggregation of Mendelian traits, Sanger sequencing, chromosomal microarrays, next-generation sequencing with whole genome and whole exome sequencing, as well as rare variant association tests.[16]

The Food and Drug Administration (FDA) has approved two drugs that target patients with genetic causes of obesity-metreleptin and setmelanotide. The other drugs like semaglutide, liraglutide, phentermine-topiramate, and naltrexone-bupropion are approved for weight loss in the general population and may be used to treat patients with genetic obesity.

1. Metreleptin is a leptin analog used to treat patients with congenital generalized lipodystrophy in leptin-deficient patients with mutations in the leptin gene. However, metreleptin cannot be used in patients with leptin receptor mutations or mutations downstream in the leptin signally pathway. The use of this drug is monitored by the Risk Evaluation and Mitigation Strategies (REMS) group of the FDA. The dose is generally 0.06 mg/kg/dose once daily for patients with weight <40kg and 2.5 to 5 mg a day for weight >40 kg or adult patients.[18]
2. Setmelanotide is an MC4R agonist used in obese patients with genetic mutations in POMC, PCSK1, or LEPR genes and Bardet Biedl syndrome. The advantage of this drug is that it acts directly on the MC4R receptor bypassing multiple targets, which could be mutated in the leptin pathway. It is generally administered as a 2 mg daily subcutaneous dose.[19]

Other drugs studied in Prader-Willi syndrome include beloranib-a MetAP2 inhibitor and nasal oxytocin, but these are not FDA approved.[11] Bariatric surgery with Roux en Y gastric bypass, sleeve gastrectomy, and laparoscopic gastric banding has been shown to benefit patients with genetic causes of obesity. The only exception is in patients with complete loss of MC4R function where bariatric surgery was not found to be effective.[16]

It is now well studied that distinct interventions can modify the epigenome of the body to benefit patients with obesity. Examples of this are:

• Bariatric surgery can cause changes in adipocyte-derived exosomal micro-RNA and cause epigenetic changes in differential methylated regions in HOXB1, PRKCZ, SLC38A10, SECTM1 genes.[11][7]
• Regular exercise can cause widespread changes in DNA methylation in the RUNX1, NDUFC2, THADA, MEF2A, PRKAA2 genes. For patients who maintain their weight loss, the DNA methylation profiles resemble lean individuals, as seen in RYR1, TUBA3C, and BDNF genes.[10][6][7]
• Fasting can cause changes in DNA methylation of genes-LEP (leptin) and ADIPOQ (adiponectin).[10]
• The use of probiotics, prebiotics, and fecal transplant can restore gut flora and cause positive epigenetic modifications in patients with obesity.[15]

Other Issues

In genome-wide association studies done so far, most subjects have European ancestry. However, 47% or the vast majority of patients grappling with the burden of obesity in the United States are of African-American and Hispanic/Latino descent. The African Ancestry Anthropometry Genetics Consortium (AAAGC) and the Hispanic and Latino Consortium (HISLA) were created to study specific alleles related to obesity in these populations. The Population Architecture using Genomics and Epidemiology (PAGE) study performed large-scale genotyping involving 54,000 participants of African-American, Hispanic/Latino, East Asian, Native Hawaiian, and Native American descent to study specific genetic variants associated with obesity.[20]

The future of genetic and epigenetics is promising, especially in the area of obesity and metabolic disease. Epigenetic studies form the basis of precision medicine with distinct targets for gene modulation. The reversible nature of epigenetic marks gives geneticists and clinicians a chance to suggest changes in lifestyle with dietary modification and exercise and avoidance of tobacco, alcohol, and potential obesogens before patients and their offspring suffer the consequences. The use of histone deacetylators is now being suggested beyond the boundaries of Hematology/Oncology for its use in lifestyle medicine, and research in this field is ongoing. Methylation Quantitative Trait Locus (meQTL) studies are now being used to further epigenetic studies. New Nutri-pharmacogenomic studies are expanding our understanding of how nutrition affects genetics.[10][11][6]

Enhancing Healthcare Team Outcomes

With the help of GWAS and EWAS, we now understand how genetics and epigenetics play an important role in obesity. Diagnosing, managing, and supporting patients with genetically predisposed obesity requires a dedicated team of health care professionals experienced in their various fields with good teamwork. Since the origins of obesity are directly associated with maternal health, a team of obstetricians, pediatricians, nutritionists, geneticists, psychologists can help mitigate risk factors associated with maternal and childhood obesity.

Pediatric endocrinologists play a significant role in diagnosing early childhood obesity. In contrast, adult endocrinologists can help treat and control diabetes and other cardiometabolic parameters that cause epigenome changes passed on from generation to generation. Early lifestyle interventions, bariatric surgery, and medications form the basis of the treatment of genetically predisposed obesity.