This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison
Genetics and obesity
Obesity is defined as a weight that is greater than what is generally considered healthy for a given height. [1] In 1986, Stunkard, et al. provided some of the first evidence that genetic influences are a significant determinant of obesity by comparing adopted children to both their biological and adoptive parents. Surprisingly, the adopted children's Body Mass Index (BMI) and weight class showed a strong correlation to their biological parents but no correlation to their adopted parents.[2] More recent adoption studies have also found that genetics has a large influence on an individual's susceptibility to obesity. [3,4,5]
Obesity Quick Facts
- An adult who has a BMI of 30 or higher is considered obese [1]
- Over 1/3 of US Adults (35.7%) are obese [6]
- Obesity-related conditions include heart disease, stroke, type 2 diabetes and certain types of cancer [6]
- The estimated annual medical cost of obesity in the U.S. was $147 billion in 2008 [6]
- The medical costs for people who are obese are $1,429 higher than those of normal weight[6]
- Non-Hispanic blacks have the highest age-adjusted rates of obesity at 49.5% followed by Mexican Americans at 40.4%, all Hispanics at 39.1%, and non-Hispanic whites at 34.3% [7]
The tub gene
The Tub gene, located on human chromosome 11p15.4 was first discovered in tubby mice. [8] These mice develop severe adult-onset obesity (ultimately reaching twice the weight of their wild-type litter-mates) and insulin resistance without hyperglycemia. [9] The autosomal recessive tubby mutation has also been found to cause hearing and vision deficiencies. [10]
A spontaneous G to T transversion at a donor splice site is responsible for the tubby phenotype. This transversion abolishes the donor splice site resulting in a 398bp intron being included in the final transcript between exons 11 and 12, disrupting the protein secondary structure in the "tubby domain". [11,12] This transversion was shown to be a loss of function mutation as a knockout of the Tub gene results in the same phenotype. [13]
The Tub gene is highly expressed in the retina, cochlea, and brain (including the hippocampus and paraventricular, ventromedial, and arcuate nuclei of the hypothalamus). [11] The high level of Tub expression in the hypothalamus (a brain region that is involved in systematic energy regulation) indicates that the phenotype may be due to defects in neuroendocrine control of metabolism, although the actual mechanism of the tubby mutation and its link to obesity remains unknown. [14]
The human obesity syndromes described by Bardet, Biedl, and Alstrom share similarities with the tubby phenotype. Bardet-Biedl syndrome is characterized by pigmentary retinopathy, obesity, mental retardation, hypogenitalism, and polysyndactyly, but is genetically heterogeneous. Alstrom syndrome is characterized by retinitis pigmentosa, deafness, obesity, and diabetes mellitus. [15]
A spontaneous G to T transversion at a donor splice site is responsible for the tubby phenotype. This transversion abolishes the donor splice site resulting in a 398bp intron being included in the final transcript between exons 11 and 12, disrupting the protein secondary structure in the "tubby domain". [11,12] This transversion was shown to be a loss of function mutation as a knockout of the Tub gene results in the same phenotype. [13]
The Tub gene is highly expressed in the retina, cochlea, and brain (including the hippocampus and paraventricular, ventromedial, and arcuate nuclei of the hypothalamus). [11] The high level of Tub expression in the hypothalamus (a brain region that is involved in systematic energy regulation) indicates that the phenotype may be due to defects in neuroendocrine control of metabolism, although the actual mechanism of the tubby mutation and its link to obesity remains unknown. [14]
The human obesity syndromes described by Bardet, Biedl, and Alstrom share similarities with the tubby phenotype. Bardet-Biedl syndrome is characterized by pigmentary retinopathy, obesity, mental retardation, hypogenitalism, and polysyndactyly, but is genetically heterogeneous. Alstrom syndrome is characterized by retinitis pigmentosa, deafness, obesity, and diabetes mellitus. [15]
the tub protein
The TUB protein is the founding member of the Tubby-like protein family (TULPs) which all contain a unique 260 amino acid "tubby domain" at their carboxyl terminus that forms a unique helix-filled barrel structure. This structure is disrupted due to the tubby splice site mutation that results in the last 44 amino acids of the carboxyl terminus being replaced by 20 different amino acids. [11] This nonsense mutation prevents the protein's proper folding, and therefore, function. [14] The "tubby domain" is highly conserved in both plants and animals. The amino terminal is not nearly as conserved but is thought to contain a transcription factor activation domain. [16]
TUB has also been shown to respond to signals from heterotrimeric G-proteins that result in the translocation of TUB from the plasma membrane to the nucleus where it can regulate gene expression. [12] The upstream signal proteins and downstream target genes remain unclear, although the stimulation of the serotonin receptor 5HT2C [12], insulin receptor tyrosine kinase (IRTK) [17,18,19], and leptin receptor (LEPR) [19] have been shown to affect TUB nuclear translocation.
TUB has also been shown to respond to signals from heterotrimeric G-proteins that result in the translocation of TUB from the plasma membrane to the nucleus where it can regulate gene expression. [12] The upstream signal proteins and downstream target genes remain unclear, although the stimulation of the serotonin receptor 5HT2C [12], insulin receptor tyrosine kinase (IRTK) [17,18,19], and leptin receptor (LEPR) [19] have been shown to affect TUB nuclear translocation.
Treatments for obesity
Most cases of obesity are currently treated through lifestyle changes including reducing the number of calories consumed per day and increasing the number of calories burned through physical activity. Along with reducing calories, the amount of saturated fats and trans fats consumed should also be reduced. Through these changes, an individual who is obese can often lose 5-10% of their current body weight within six months. [20]
Medicines such as Orlistat (Xenical® and Alli®), Lorcaserin Hydrochloride (Belviq®), and Qsymia™ may also be prescribed by physicians for patients suffering from obesity that cannot be successfully managed through lifestyle changes alone. [20]
Weight loss surgery may also be an option for people with severe obesity (BMI greater than 40) or obesity in combination with other life-threatening conditions. Gastric bypass surgery creates a small stomach pouch that bypasses part of the small intestine where most of the calories you eat are absorbed. This operation limits food intake and also the amount of calories your body can absorb. In a gastroplasty, a band or staples are used to create a small pouch at the top of the stomach, thereby limiting the amount of food and liquids the stomach can hold. Both of these surgeries can have life-long side effects, and therefore, are used as a last resort for treating obesity. [20]
Medicines such as Orlistat (Xenical® and Alli®), Lorcaserin Hydrochloride (Belviq®), and Qsymia™ may also be prescribed by physicians for patients suffering from obesity that cannot be successfully managed through lifestyle changes alone. [20]
Weight loss surgery may also be an option for people with severe obesity (BMI greater than 40) or obesity in combination with other life-threatening conditions. Gastric bypass surgery creates a small stomach pouch that bypasses part of the small intestine where most of the calories you eat are absorbed. This operation limits food intake and also the amount of calories your body can absorb. In a gastroplasty, a band or staples are used to create a small pouch at the top of the stomach, thereby limiting the amount of food and liquids the stomach can hold. Both of these surgeries can have life-long side effects, and therefore, are used as a last resort for treating obesity. [20]
References
Cover Photo Credit
[1] Centers for Disease Control and Prevention: Defining Overweight and Obesity
[2] Stunkard, A, et al. (1986). An Adoption Study of Human Obesity. The New England Journal of Medicine, 314(4). doi: 10.1056/NEJM198601233140401
[3] Stunkard, A.J., Harris, J.R., Pedersen, N.L., & McClearn, G.E. (1990). The Body-Mass Index of Twins Who Have Been Reared Apart. The New England Journal of Medicine, 322(21), 1483. doi: 10.1056/NEJM199005243222102
[4] Allison, D.B., Kaprio, J., Korkeila, M., Koskenvuo, M., Neale, M.C., & Hayakawa, K. (1996). The heritability of body mass index among an international sample of monozygotic twins reared apart. Int. J. Obes. Relat. Metab. Disord., 20(6), 501-506.
[5] Maes, H.H.M., Neale, M.C., & Eaves, L.J. (1997). Genetic and Environmental Factors in Relative Body Weight and Human Adiposity. Behavior Genetics, 27(4), 325. doi: 10.1023/a:1025635913927
[6] Centers for Disease Control and Prevention: Adult Obesity Facts
[7] Flegal, K.M., Carroll, M.D., Kit, B.K., & Ogden, C.L. (2012). Prevalence of Obesity and Trends in the Distribution of Body Mass Index Among U.S. Adults, 1999-2010. The Journal of the American Medical Association, 307(5), doi:10.1001/jama.2012.39.
[8] North, M.A., Naggert, J.K., Yan, Y., Noben-Trauth, K., & Nishina, P.M. (1997). Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. PNAS, 94(7), 3128.
[9] Coleman, D.L. & Eicher, E.M. (1990). Fat (fat) and Tubby (tub): Two Autosomal Recessive Mutations Causing Obesity Syndromes in the Mouse. Journal of Heredity, 81(1): 424-427.
[10] Ohlemiller, K.K., Hughes, R.M., Mosinger-Ogilvie, J., Speck, J.D., Grosof, D.H., & Silverman, M.S. (1995). Cochlear and retinal degeneration in the tubby mouse. Neuroreport, 6(6): 845-849.
[11] Kleyn, P.W., Fan, W., Kovats, S. G., et al. (1996). Identification and Characterization of the Mouse Obesity Gene tubby: A Member of a Novel Gene Family. Cell, 85(2), doi:10.1016/S0092-8674(00)81104-6.
[12] Santagata, S., Boggon, T.J., Baird, C.L., Gomex, C.A., Zhao, J., Shan, S., Myszka, D.G., & Shapiro, L. (2001). G-Protein Signaling Through Tubby Proteins. Science, 292(5524).
[13] Stubdal, H., Lynch, C.A., Moriarty, A., et al. (2000). Targeted Deletion of the tub Mouse Obesity Gene Reveals that tubby is a Loss-of-Function Mutation. Molecular and Cellular Biology, 20(3).
[14] Carroll, K., Gomez, C., & Shapiro, L. (2004). Tubby Proteins: The Plot Thickens. Molecular Cell Biology,
5(1), doi:10.1038/nrm1278.
[15] OMIM. Tubby, Mouse, Homolog of; TUB.
[16] Boggon, T.J., Shan. W.S., Santagata, S., Myers, S.C., & Shapiro, L. (1999). Implication of tubby proteins as transcription factors by structure-based functional analysis. Science, 286(5447) doi: 10.1126/science.286.5447.2119
[17] Kapeller, R., Moriarty, A., Strauss, A., Stubdal, H., Theriault, K., Siebert, E., Chickering, T., Morgenstern, J.P., Tartaglia, L.A., & Lillie, J. (1999). Tyrosine Phosphorylation of Tub and Its Association with Src Homology 2 Domain-containing Proteins Implicate Tub in Intracellular Signaling by Insulin. The Journal of Biological Chemistry, 274(35), 24980, doi:10.1074/jbc.274.35.24980.
[18] Stretton, C., Litherland, G.J., Moynihan, A., Hajduch, E., & Hundal, H.S. (2009). Expression and modulation of TUB by insulin and thyroid hormone in primary rat and murine 3T3-L1 adipocytes, Biochemical and Biophysical Research Communications, 390(4), 1328, doi: 10.1016/j.bbrc.2009.10.147.
[19] Prada, P.O., Quaresma, P.G.F., Caricilli, A.M., et al. (2013). Tub Has a Key Role in Insulin and Leptin Signaling and Action in Vivo in Hypothalamic Nuclei. Diabetes, 62(1),137, doi: 10.2337/db11-1388.
[20] National Institutes of Health. How are Overweight and Obesity Treated?
[1] Centers for Disease Control and Prevention: Defining Overweight and Obesity
[2] Stunkard, A, et al. (1986). An Adoption Study of Human Obesity. The New England Journal of Medicine, 314(4). doi: 10.1056/NEJM198601233140401
[3] Stunkard, A.J., Harris, J.R., Pedersen, N.L., & McClearn, G.E. (1990). The Body-Mass Index of Twins Who Have Been Reared Apart. The New England Journal of Medicine, 322(21), 1483. doi: 10.1056/NEJM199005243222102
[4] Allison, D.B., Kaprio, J., Korkeila, M., Koskenvuo, M., Neale, M.C., & Hayakawa, K. (1996). The heritability of body mass index among an international sample of monozygotic twins reared apart. Int. J. Obes. Relat. Metab. Disord., 20(6), 501-506.
[5] Maes, H.H.M., Neale, M.C., & Eaves, L.J. (1997). Genetic and Environmental Factors in Relative Body Weight and Human Adiposity. Behavior Genetics, 27(4), 325. doi: 10.1023/a:1025635913927
[6] Centers for Disease Control and Prevention: Adult Obesity Facts
[7] Flegal, K.M., Carroll, M.D., Kit, B.K., & Ogden, C.L. (2012). Prevalence of Obesity and Trends in the Distribution of Body Mass Index Among U.S. Adults, 1999-2010. The Journal of the American Medical Association, 307(5), doi:10.1001/jama.2012.39.
[8] North, M.A., Naggert, J.K., Yan, Y., Noben-Trauth, K., & Nishina, P.M. (1997). Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. PNAS, 94(7), 3128.
[9] Coleman, D.L. & Eicher, E.M. (1990). Fat (fat) and Tubby (tub): Two Autosomal Recessive Mutations Causing Obesity Syndromes in the Mouse. Journal of Heredity, 81(1): 424-427.
[10] Ohlemiller, K.K., Hughes, R.M., Mosinger-Ogilvie, J., Speck, J.D., Grosof, D.H., & Silverman, M.S. (1995). Cochlear and retinal degeneration in the tubby mouse. Neuroreport, 6(6): 845-849.
[11] Kleyn, P.W., Fan, W., Kovats, S. G., et al. (1996). Identification and Characterization of the Mouse Obesity Gene tubby: A Member of a Novel Gene Family. Cell, 85(2), doi:10.1016/S0092-8674(00)81104-6.
[12] Santagata, S., Boggon, T.J., Baird, C.L., Gomex, C.A., Zhao, J., Shan, S., Myszka, D.G., & Shapiro, L. (2001). G-Protein Signaling Through Tubby Proteins. Science, 292(5524).
[13] Stubdal, H., Lynch, C.A., Moriarty, A., et al. (2000). Targeted Deletion of the tub Mouse Obesity Gene Reveals that tubby is a Loss-of-Function Mutation. Molecular and Cellular Biology, 20(3).
[14] Carroll, K., Gomez, C., & Shapiro, L. (2004). Tubby Proteins: The Plot Thickens. Molecular Cell Biology,
5(1), doi:10.1038/nrm1278.
[15] OMIM. Tubby, Mouse, Homolog of; TUB.
[16] Boggon, T.J., Shan. W.S., Santagata, S., Myers, S.C., & Shapiro, L. (1999). Implication of tubby proteins as transcription factors by structure-based functional analysis. Science, 286(5447) doi: 10.1126/science.286.5447.2119
[17] Kapeller, R., Moriarty, A., Strauss, A., Stubdal, H., Theriault, K., Siebert, E., Chickering, T., Morgenstern, J.P., Tartaglia, L.A., & Lillie, J. (1999). Tyrosine Phosphorylation of Tub and Its Association with Src Homology 2 Domain-containing Proteins Implicate Tub in Intracellular Signaling by Insulin. The Journal of Biological Chemistry, 274(35), 24980, doi:10.1074/jbc.274.35.24980.
[18] Stretton, C., Litherland, G.J., Moynihan, A., Hajduch, E., & Hundal, H.S. (2009). Expression and modulation of TUB by insulin and thyroid hormone in primary rat and murine 3T3-L1 adipocytes, Biochemical and Biophysical Research Communications, 390(4), 1328, doi: 10.1016/j.bbrc.2009.10.147.
[19] Prada, P.O., Quaresma, P.G.F., Caricilli, A.M., et al. (2013). Tub Has a Key Role in Insulin and Leptin Signaling and Action in Vivo in Hypothalamic Nuclei. Diabetes, 62(1),137, doi: 10.2337/db11-1388.
[20] National Institutes of Health. How are Overweight and Obesity Treated?
Site created by Rachael Baird.
Genetics 564 Assignment, Spring 2014
University of Wisconsin-Madison
Last Updated: 5-10-14
Genetics 564 Assignment, Spring 2014
University of Wisconsin-Madison
Last Updated: 5-10-14