Genetics of Obesity

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With rapidly rising urbanization, economic development, and standard of living across the globe, the transition to a first world nation is accompanied by a growing epidemic: Obesity. Ample inexpensive junk food overloaded with sodium, trans and saturated fats, and sucrose abound on every store shelf and attempt to enamor consumers in through advertisements. This preys upon the weaknesses of many individuals, yet there is much more to the story than mere gluttony and insufficient willpower. Some of the upstream causes of insatiable consumption are due to neurological alterations and dysregulation[1]. This includes the hypothalamus (housing the arcuate, paraventricular, and ventromedial nuclei that play a role in food intake regulation), the dopamine (DA) reward system, and the enteric nervous system (with hormonal and neural feedback to the CNS)[1][2]. A multitude of factors can disrupt the homeostasis of the milieu intérieur, thus impacting the metabolic rate and drive to eat. This subtopic is primarily concerned with the genetic causes and epigenetic modifications that initiate and maintain considerable weight gain. Diet-induced downregulation or upregulation of specific genes leads to neuroanatomical changes in the hypothalamic and dopamine systems (which control satiety and reward, respectively)[1][2]. Monogenetic causes of obesity will be explored, as well as the potential remedies through behaviour (e.g. exercise) and genetic engineering.

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1.1 Dopamine-related genes


It has been shown that food consumption is regulated by two main areas of the brain: the hypothalamus and the reward circuitry (which includes the nucleus accumbens (NAcc), the ventral tegmental area (VTA), and the prefrontal cortex (PFC))[1]. The function of these neuroanatomical regions becomes dysregulated with the consumption of foods high in fat and/or sugar[1]. This dysregulation is quite particular in that it culminates in producing obesity and hyperphagia[1].

Since dopamine is one of the critical neurotransmitters for modulating consumption, a number of genes can be affected to produce some neuroanatomical dysfunction which manifests itself by promoting weight gain[1]. Epigenetic mechanisms act to either suppress or bolster the expression of particular genes via a multitude of methods including methylation and demethylation[1][3]. If more DA is released in the hypothalamus, it will promote increased consumption[1]. On the other hand, less DA in the reward circuitry means less pleasure is derived from consuming the same food, so this also increases food intake[1].

1.1a) Tyrosine Hydroxylase (TH)

In one study[1], mice were either fed a high fat (HF) diet or control diet. The researchers used quantitative real-time polymerase chain reaction (RT-PCR) to evaluate the level of expression of particular genes. When the hypothalami of HF-fed rats were compared to controls, the expression of TH, the enzyme that synthesizes DA, increased 2.5-fold[1]. In contrast, the VTA saw a 60% reduction in expression[1]. The authors used a methylated DNA immunoprecipitation (MeDIP) assay to assess the degree of methylation present on specific genes. Given that increased methylation elicits gene repression and demethylation promotes enhanced expression[1][3], the findings of the assay reinforce the RT-PCR analysis results[1]. The promoter region methylation of the TH gene was diminished in the hypothalamus and augmented in the VTA[1].


1.1b) Dopamine Transporter (DAT)

In the same study elucidated above in the TH section[1], the authors also determined the expression and methylation of the DAT gene. DAT is the protein that removes synaptic DA[1]. In the hypothalami of the HF-fed rats, there was roughly a 3.25-fold increase in DAT mRNA[1]. The VTA saw roughly a 65–70% decline in expression[1]. Similar to the TH gene, methylation was reduced in the hypothalamus but accentuated in the VTA[1].

Another study (addressed in the subsequent section) also found that OP rats fed diets high in fat and sugar saw a statistically significant increase in VTA DAT gene expression[4].

1.1c) D1 Receptor

In the Vucetic et al. study, D1 receptors significantly decreased in the aforementioned 3 regions of the reward circuitry[1].

Another experiment examined dopamine receptor expression in the NAcc of rats fed diets high in fat and sugar. After the animals had gained a certain amount of weight, they were separated into two groups: an Obesity-Prone (OP) and an Obesity-Resistant (OR) group. The OP group had significantly reduced expression of the D1 receptor in the NAcc[4].

1.1d) D2 Receptor

Also in the Vucetic et al. study, D2 receptors decreased significantly in the VTA only[1].

In the Johnson and Kenny study, they used three groups of rats to examine (1) how different diets and access to those diets affect weight, (2) how those diets affect the reward threshold, and (3) the amount of striatal D2 receptor expression. With unrestricted access to energy-laden food, those rats' reward thresholds progressively increased above the established baseline[5]. The authors found that body weight had an negative relationship with striatal D2 receptor expression[5]. The authors suggest that chronic consumption of HF food (similar to an addiction) downregulates D2 receptors, thus fueling compulsive intake to achieve the necessary level of reward[5].

BMI ranges
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Using PET scans and a D2 receptor radioligand, Wang et al. were able to quantify the level of striatal D2 receptor expression. Compared to those of normal weight, obese individuals—thus, with high BMI—show significant reduction in striatal D2 receptors[6]. BMI was inversely yet linearly correlated with the receptor expression in the striatum[6]. Over-stimulation of the reward system leads to a compensatory reduction in the number of receptors in the region, thus fostering a compulsive consumption to mitigate the reduced excitation[6].

Having even one A1 allele—as opposed to the A2 allele—of the TaqIA predisposes a person to obesity; this is because there is diminished dopamine signalling in the striatum associated with that genotype[7].

1.2 Lipoprotein Lipase

LPL is an enzyme that both hydrolyzes triglycerides (TGs) and promotes the uptake of lipoproteins through its action on lipoprotein receptors[8]. Obese individuals have high levels of LPL in adipocytes; however, it is not responsive to either insulin or food consumption[8]. A lack of the LPL enzyme results from an autosomal recessive genotype[8]. A lack of functioning LPL in humans results in hypertriglyceridemia[8]. Over-expression of LPL in mice dramatically lowers plasma TG levels[8].

The tissue in which there is over- or under-expression of LPL plays an important role in preventing or furthering fat mass accumulation[9]. If LPL is selectively over-expressed in skeletal muscle, this actually promotes more muscular fatty acid (FA) uptake for oxidation and, consequently, less is stored in adipocytes[9][10]. Moreover, under-expression of LPL in adipocytes mitigates unnecessary FA storage[9][11].

1.3 Apolipoproteins

1.3a) Apo A-IV


A comprehensive study conducted using rats demonstrated that a HF diet leads to reduced levels of hypothalamic apo A-IV[12]. Apo A-IV is deemed to be a lipid-induced satiety signal, and as such, the expression in the hypothalamus can be reduced via fasting and enhanced via lipid consumption[12]. However, the chronic effects of HF food intake on apo A-IV was unknown. The researchers found that of the 5 groups of rats, those on a HF diet weighed significantly more than the others[12]. There was a temporal-dependent effect of lipid consumption on hypothalamic apo A-IV mRNA expression[12]. With time, the HF-fed rats saw a gradual decline in the amount of apo A-IV expressed in the hypothalamus, and at week 10, the reduction was significant[12]. When lipids were given to fasted rats, all groups except the HF rats saw an increase in hypothalamic apo A-IV expression; this implies a diminished response to lipids[12]. Interestingly, apo A-IV infusion into the intracerebroventicular region inhibits consumption[12].

1.3b) ApoA-V

Transgenic mice made to express APOAV, normally found in humans, saw a two-thirds decline in triglycerides (TG) circulating in the plasma[9][13]. However, a knockout (KO) of the gene elicits a 4-fold increase in plasma TG levels[9][13].

1.3c) ApoC-I

ApoC-I has been shown to inhibit LPL, and thus, transgenic mice expressing human ApoC-I demonstrate reduced hydrolysis and removal of TG from the plasma[9][14].

Also notable is the effect of APOC1 over-expression in monogenetic models of obesity. When APOC1 was over-expressed in mice with leptin gene deficiency (i.e. ob/ob mice), those mice were protected from becoming obese[9][15]. Insulin sensitivity improved while plasma glucose decreased[15]. Compared to ob/ob mice, APOC1-expressing mice weighed significantly less and had reduced adipocyte size[15].

However, apoC1 KO mice do not show significantly diminished plasma lipid levels; instead, they remain normal when given standard chow diets[16].

1.3d) ApoC-III

ApoCIII is another inhibitor of LPL[9][16][17]; a deficiency in this apolipoprotein results in lowered plasma TG levels since LPL-mediated hydrolysis increases[16].

Apoc3 KO mice were created to test the consequences of removing this LPL inhibitor. Since the deficiency results in increased TG hydrolysis and deposition of fatty acids into adipose tissue, these mice were significantly more obese than control mice also given HF diets[18].

1.3e) ApoE

When plasma ApoE levels of mice were increased by 50%, they saw a 3-fold increase in the plasma TG levels[19]. If increased by 80%, there was 4-fold augmentation[19].

Comparing ApoE KO and ApoE mice, those lacking ApoE exhibited higher plasma TG levels and reduced FA deposition into adipocytes[20]. When both groups were fed the control diet, KO mice had lower levels of glucose and insulin[20]. This implies that the KO mice are more sensitive to insulin[20].

ApoE is the VLDL receptor ligand[21]. Obese mice lacking both the leptin gene (i.e. ob/ob) and ApoE (i.e. apoE–/–) did not become as obese as ob/ob mice when both groups were on a diet high in fat and cholesterol[21].

1.4 Leptin, leptin receptors and the ob gene


Leptin is a hormone made from the ob gene that regulates food consumption and metabolism[22]. There are two main leptin receptors types: the short form (OB-Ra) and the long form (OB-Rb)[22]. Although the short form's role in signalling has not yet been elucidated, it aids in transporting leptin across the blood-brain barrier (BBB) and is also involved in degrading leptin[22]. The long form is found in particular hypothalamic nuclei, and it can activate the JAK-STAT and MAPK signal transduction pathways[22][23].

The authors state that the most likely origin for obesity, as far as leptin is concerned, is due to leptin insensitivity that is acquired through time, and not due to mutations in the ob gene[22]. This study examined the genetic expression of the two types of receptors in the hypothalamus and liver in relation to serum leptin[22]. Rats were given HF diets in order to mimic the types of changes that manifest as a result of energy-dense food consumption[22].


The rats that became obese, by virtue of their HF diets, demonstrated a statistically significant negative correlation between receptor expression and serum [leptin][22]. In the obese rats, both the hypothalamus and the liver showed reduced leptin receptor expression compared to controls[22]. The results suggest that a diet which increases serum leptin is one of the means of acquiring leptin insensitivity[22].

1.5 Melanocortin

The melanocortin pathways of the hypothalamus are known to regulate feeding and metabolism[24][25].

1.5a) Melanocortin 3 Receptor (MC3R)

Melanocortin 3 receptor (MC3R) KO mice have been shown to become obese but via pathophysiological changes that are different from those of MC4R KO mice[26]. MC3R KO mice actually become hypophagic instead of hyperphagic like the MC4R KO mice[26]. Like their MC4R KO counterparts, they also have a normal metabolic rate; however, MC3R KO mice have a greater ratio of weight gain per quantity of food consumed[26][27].

Pathophysiology of obesity during childhood
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1.5b) Melanocortin 4 Receptor (MC4R)


A KO of this gene is known to lead to obesity[24]. A study was conducted using mice to examine the efficacy of preventing the obese phenotype through voluntary exercise. It adequately demonstrated that long-term exercise from an early age is essential in combating the obesity that would result from MC4R KO[24]. The efficacy, however, of counteracting the obese phenotype through exercise decreases with age[24].

1.6 POMC gene

So far, only the hypothalamic arcuate nucleus and the nucleus tractus solitarius (NTS) are known to have POMC neurons[25]. One of a number of proteins derived from the POMC polypeptide is α-melanocyte-stimulating hormone (α-MSH)[25]. Normally, it acts upon the MC3R and MC4R to attenuate consumption and promote energy loss[25]. However, there is desensitization with recurrent administration[25]. It was shown that POMC over-expression in either of the two aforementioned regions of the brain leads to significant and maintained weight reduction[25].

Derivatives from the POMC polypeptide
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Using rats, the authors transfected both the arcuate nucleus and the NTS simultaneously with the POMC gene using the recombinant adeno-associated virus (rAAV)[25]. Before the viral vector was delivered, all rats weighed roughly the same[25]. However, POMC rats demonstrated was a statistically significant drop in food intake by day 5, and by day 6 it was 58% lower than controls[25]. Weight loss was both significant and maintained in POMC rats[25]. POMC over-expression also bolstered the amount of voluntary exercise (they ran double the distance compared to controls)[25]. Overall, lipolysis increased, as did the sensitivity to insulin[25].

1.7 c-Jun NH2-Terminal Kinase 1 (JNK1) gene

In obesity, the levels of active JNK are substantially increased, whereas a JNK1 deficiency decreases adiposity and enhances the body's response to insulin[28]. Whether it be a dietary or a genetic model of obesity, JNK1 activity in hepatocytes, adipocytes, and myocytes is significantly higher than that of controls[28]. JNK1 KO mice show reductions in adipocyte size and seem to be protected from insulin resistance acquired through obesity[28].

1.8 FTO gene

A genetic analysis study has uncovered a particular single nucleotide polymorphism (SNP) in an intron of a fat mass and obesity associated (FTO) allele that is strongly associated with high BMI and type 2 diabetes[29].

Schematic of factors that contribute to developing type 2 diabetes
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The protein derived from the FTO gene is a nucleic acid demethylase that is dependent on the presence of 2-oxoglutarate[30]. Since it is thought to be involved in energy regulation, it was found to be present in specific nuclei of the hypothalamus[30]. Mice that were fasted for 2 days, when compared to the freely fed mice, demonstrated a 60% decline in FTO mRNA in arcuate nucleus; this was not due to the fasting-induced decreased levels of leptin[30].

Rats given HF diets, compared to those given regular chow, see arcuate Fto mRNA expression increase 2.5-fold[31]. Over-expression of arcuate Fto mRNA caused a reduction in consumption, whereas under-expression increased it[31]. However, there were no significant differences in weight or fat mass between the different groups of rats even though changes in gene expression affected food intake[31].

Contribution of different genes towards obesity
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Increase in obesity throughout the U.S. over the years
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1. Vucetic, Z., Carlin, J. L., Totoki, K., & Reyes, T. M. (2012). Epigenetic dysregulation of the dopamine system in diet-induced obesity. Journal of Neurochemistry, 120, 891-898. doi: 10.1111/j.1471-4159.2012.07649.x
2. MacKay, W. A. (2010). NEURO 101: Neurophysiology without tears . Toronto: Sefalotek Ltd.
3. Samaranayake, J. K. K. M., & Pradhan, S. (2009). Epigenetic mechanisms in mammals. Cellular and Molecular Life Sciences, 66, 596-612. doi: 10.1007/s00018-008-8432-4
4. ALSIÖ, J., OLSZEWSKI, P. K., NORBÄCK, A. H., GUNNARSSON, Z. E. A., LEVINE, A. S., PICKERING, C., & SCHIÖTH, H. B. (2010). Dopamine d1 receptor gene expression decreases in the nucleus accumbens upon long-term exposure to palatable food and differs depending on diet-induced obesity phenotype in rats. Neuroscience, 171, 779-787. doi: 10.1016/j.neuroscience.2010.09.046
5. Johnson, P. M., & Kenny, P. J. (2010). Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nature Neuroscience, 13, 635-641. doi: 10.1038/nn.2519
6. Wang, G., Volkow, N. D., Logan, J., Pappas, N. R., Wong, C. T., Zhu, W., … Fowler, J. S. (2001). Brain dopamine and obesity. Lancet, 357, 354-357.
7. Stice, E., Spoor, S., Bohon, C., & Small, D. M. (2008). Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science, 322, 449-452. doi: 10.1126/science.1161550
8. Wang, H., & Eckel, R. H. (2009). Lipoprotein lipase: From gene to obesity. American Journal of Physiology - Endocrinology and Metabolism, 297, E271-E288. doi: 10.1152/ajpendo.90920.2008
9. Voshol, P. J., Rensen, P. C. N., van Dijk, K. W., Romijn, J. A., & Havekes, L. M. (2009). Effect of plasma triglyceride metabolism on lipid storage in adipose tissue: Studies using genetically engineered mouse models. Biochimica Et Biophysica Acta, 1791, 479-485. doi: 10.1016/j.bbalip.2008.12.015
10. Jensen, D. R., Schlaepfer, I. R., Morin, C. L., Pennington, D. S., Marcell, T., Ammon, S. M., … Eckel, R. H. (1997). Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle lipoprotein lipase. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 273, R683-R689.
11. Weinstock, P. H., Levak-Frank, S., Hudgins, L. C., Radner, H., Friedman, J. M., Zechner, R., & Breslow, J. L. (1997). Lipoprotein lipase controls fatty acid entry into adipose tissue, but fat mass is preserved by endogenous synthesis in mice deficient in adipose tissue lipoprotein lipase. Proceedings of the National Academy of Sciences, 94, 10261-10266.
12. Liu, M., Shen, L., Liu, Y., Woods, S. C., Seeley, R. J., D'Alessio, D., & Tso, P. (2004). Obesity induced by a high-fat diet downregulates apolipoprotein A-IV gene expression in rat hypothalamus. American Journal of Physiology - Endocrinology and Metabolism, 287, E366-E370. doi: 10.1152/ajpendo.00448.2003
13. Pennacchio, L. A., Olivier, M., Hubacek, J. A., Cohen, J. C., Cox, D. R., Fruchart, J., … Rubin, E. M. (2001). An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science, 294, 169-173. doi: 10.1126/science.1064852
14. Berbée, J. F. P., van der Hoogt, Caroline C., Sundararaman, D., Havekes, L. M., & Rensen, P. C. N. (2005). Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL. Journal of Lipid Research, 46, 297-306. doi: 10.1194/jlr.M400301-JLR200
15. Jong, M. C., Voshol, P. J., Muurling, M., Dahlmans, V. E. H., Romijn, J. A., Pijl, H., & Havekes, L. M. (2001). Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1. Diabetes, 50, 2779-2785.
16. Jong, M. C., Rensen, P. C. N., Dahlmans, V. E. H., van der Boom, H., van Berkel, Theo J. C., & Havekes, L. M. (2001). Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice. Journal of Lipid Research, 42, 1578-1585.
17. van Dijk, K. W., Rensen, P. C. N., Voshol, P. J., & Havekes, L. M. (2004). The role and mode of action of apolipoproteins CIII and AV: Synergistic actors in triglyceride metabolism? Current Opinion in Lipidology, 15, 239-246. doi: 10.1097/01.mol.0000130096.77252.1f
18. Duivenvoorden, I., Teusink, B., Rensen, P. C., Romijn, J. A., Havekes, L. M., & Voshol, P. J. (2005). Apolipoprotein C3 deficiency results in diet-induced obesity and aggravated insulin resistance in mice. Diabetes, 54, 664-671.
19. Huang, Y., Liu, X. Q., Rall Jr., S. C., Taylor, J. M., von Eckardstein, A., Assmann, G., & Mahley, R. W. (1998). Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. The Journal of Biological Chemistry, 273(October 9), 26388-26393.
20. Hofmann, S. M., Perez-Tilve, D., Greer, T. M., Coburn, B. A., Grant, E., Basford, J. E., … Hui, D. Y. (2008). Defective lipid delivery modulates glucose tolerance and metabolic response to diet in apolipoprotein E–Deficient mice. Diabetes, 57, 5-12. doi: 10.2337/db07-0403
21. Chiba, T., Nakazawa, T., Yui, K., Kaneko, E., & Shimokado, K. (2003). VLDL induces adipocyte differentiation in ApoE-dependent manner. Arteriosclerosis Thrombosis and Vascular Biology, 23, 1423-1429. doi: 10.1161/01.ATV.0000085040.58340.36
22. Liu, Z. -J., Bian, J., Liu, J., & Endoh, A. (2007). Obesity reduced the gene expressions of leptin receptors in hypothalamus and liver. Hormone and Metabolic Research, 39, 489-494. doi: 10.1055/s-2007-981680
23. Malendowicz, W., Rucinski, M., Macchi, C., Spinazzi, R., Ziolkowska, A., Nussdorfer, G. G., & Kwias, Z. (2006). Leptin and leptin receptors in the prostate and seminal vesicles of the adult rat. International Journal of Molecular Medicine, 18, 615-618.
24. Irani, B. G., Xiang, Z., Moore, M. C., Mandel, R. J., & Haskell-Luevano, C. (2005). Voluntary exercise delays monogenetic obesity and overcomes reproductive dysfunction of the melanocortin-4 receptor knockout mouse. Biochemical and Biophysical Research Communications, 326, 638-644. doi: 10.1016/j.bbrc.2004.11.084
25. Zhang, Y., Rodrigues, E., Li, G., Gao, Y., King, M., Carter, C. S., … Scarpace, P. J. (2011). Simultaneous POMC gene transfer to hypothalamus and brainstem increases physical activity, lipolysis and reduces adult-onset obesity. European Journal of Neuroscience, 33, 1541-1550. doi: 10.1111/j.1460-9568.2011.07633.x
26. Mencarelli, M., Walker, G. E., Maestrini, S., Alberti, L., Verti, B., Brunani, A., … Di Blasio, A. M. (2008). Sporadic mutations in melanocortin receptor 3 in morbid obese individuals. European Journal of Human Genetics, 16, 581-586. doi: 10.1038/sj.ejhg.5202005
27. Chen, A. S., Marsh, D. J., Trumbauer, M. E., Frazier, E. G., Guan, X., Yu, H., … Van der Ploeg, Lex H.T. (2000). Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nature Genetics, 26, 97-102.
28. Hirosumi, J., Tuncman, G., Chang, L., Gorgun, C. Z., Uysal, K. T., Maeda, K., … Hotamisligil, G. S. (2002). A central role for JNK in obesity and insulin resistance. Nature, 420, 333-336. doi: 10.1038/nature01137
29. Frayling, T. M., Timpson, N. J., Weedon, M. N., Zeggini, E., Freathy, R. M., Lindgren, C. M., … McCarthy, M. I. (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science, 316, 889-894. doi: 10.1126/science.1141634
30. Gerken, T., Girard, C. A., Tung, Y. L., Webby, C. J., Saudek, V., Hewitson, K. S., … Schofield, C. J. (2007). The obesity-associated FTO gene encodes a 2-Oxoglutarate–Dependent nucleic acid demethylase. Science, 318, 1469-1472. doi: 10.1126/science.1151710
31. Tung, Y. L., Ayuso, E., Shan, X., Bosch, F., O'Rahilly, S., Coll, A. P., & Yeo, G. S. H. (2010). Hypothalamic-specific manipulation of fto, the ortholog of the human obesity gene FTO, affects food intake in rats. Plos One, 5(1), 1-8. doi: 10.1371/journal.pone.0008771

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