The Popular Press responds...
With the scientific press publishing articles that were offering a genetic basis for binge-eating behavior, the popular press reacted excitedly. An article published on CNN.com coupled the information from this study to statistics from an NIH study showing that 30% of Americans are obese and that up to 4 million Americans partake in binge-eating behavior. The article presents the facts of the study relatively accurately although not objectively. The title itself – “Study: Genes may be at fault for binge-eating” – shows that it is already biased towards raising curiosity and to showing people that they have an excuse for their binge-eating behavior (CNN, 2003).
The article states that “if the mutated gene makes too little protein, the body feels too much hunger” (CNN, 2003). It, thus, implies that any mutation in the gene is responsible for causing binge-eating which is not the case as can be seen from the Branson et al. study in which several mutations were found in the control non-obese population which also appeared at the exact same frequency in the obese population, thereby showing that they were most likely not responsible for binge-eating behavior. Moreover, it also assumes that a mutation only implied less protein as opposed to a complete lack of functional protein. This is important especially in this study, since the intensity of the binge-eating phenotype is seen to increase from heterozygotes to homozygotes showing the significance of the distinction between low level of the protein and an absence of it.
Furthermore, the article claims that in the Farooqi et al. study, researchers could predict how much children would eat at a meal from simple DNA tests when there is no indication of such a possibility in the paper itself. The article also cites Fritz Horber of the Branson et al. study stating that the mc4r gene is of particular interest since “it is perhaps the most stubbornly resistant to dieting and exercise” (CNN, 2003). The article does not cite a source for this information and, thus, the reliability of this apparent quote from Horber is low. Moreover, there is not evidence nor any discussion of the mc4r gene being resistant to dieting and exercise in the scientific paper published by Branson et al.
The article also shows that laypersons will pick up snippets of the details of this new gene and will view the picture through a skewed perspective. It cites an example of the popularity of the new gene manifested in the subjects of the Farooqi et al. study: one of the families involved in the study made themselves t-shirts saying “We’ve got an MC4 mutation” (CNN, 2003). While the ridiculousness of this reaction is apparent, the mutation, it must be clarified is in the mc4r gene and not the “MC4” gene. Whether this is a typo on part of CNN.com or on the part of the family that made the t-shirts, it is not clear, although another article on the same topic published on Talkaboutsupport.com also quotes the same slogan with the typo.
Much worse is an article on these studies on Psychologytoday.com. In the first paragraph itself, the article attempts to link binge-eating to obesity, although this is not necessarily true, by placing the following sentences adjacent to each other: “… a specific gene that is linked to the uncontrollable desire to eat. There has been much research investigating the hereditary factors involved in obesity” (Allen, 2003). Moreover, the study assumes that all mutations in mc4r lead to binge-eating phenotype without mentioning that there are some mutations even in that very gene do not have the concerned phenotype i.e. characterized by food-seeking behavior or binge-eating. This article does not even mention that while 100% of people with mutation were binge-eaters, 14% of non-carriers were also binge-eaters.
The most reliable popular press article I found for this study was on WebMD, a Medical News Archive. In addition to presenting the data accurately, the article points out limitations of the study, for instance, that the mc4r gene has been linked to binge-eating only in obese people. It also takes care to distinguish between Binge-Eating Disorder (BED) and Bulimia Nervosa stating that people with BED do not indulge in purging behavior, and cites a statistic from an NIH study showing that while only 2% of people in the US suffer from Binge-Eating Disorder, up to 70% are binge-eaters (WebMD, 2003). Moreover, this is the only article that mentions that researchers studied other related genes – like POMC and LEPR – in the same context. And lastly, it is also the only article that cites sources and references at the end.
What the scientific press says...
Two studies, published back-to-back in the same issue of The New England Journal of Medicine, implicated the Melanocortin-4 Receptor gene (mc4r) as responsible for food-seeking or binge-eating behavior. A study by Branson et al., a joint venture between Swiss, German and American scientists, entitled "Binge Eating as a Major Phenotype of Melanocortin-4 Receptor Gene Mutations" involved a population of 469 obese subjects whose mc4r loci were sequenced and examined against a reference sequence for mutations within the gene. Twenty-four, or 5.1%, of these subjects had mutations in mc4r. Branson et al. used questionnaires as well as the professional expertise of a certified dietician and a psychologist to diagnose binge-eaters. Binge-eating was defined as "the rapid consumption of an unusually large amount of food in the absence of hunger, causing the subject to feel embarassed, depressed, or guilty and out of control" (Branson et al. 2003). They also assessed serum leptin levels by radioabsorptivity, total body fat by dual energy x-ray absorptiometry, and resting energy expenditure by continuous indirect calorimetry. They found that all 24, or 100%, of the mutant cariers, while 14.2% of non-carriers were diagnosed as binge-eaters (Branson et al. 2003). None of the non-obese control subjects were carriers. Thus, 26.4% of the total number of subjects examined were binge-eaters.
Branson et al. identified 5 new mutations, in addition to the 30 previously identified ones, at this locus. Normal weight controls, none of whom were binge-eaters, showed a frequency of mc4r mutations similar to obese people. However, in normal people, mutations in mc4r were mostly due to polymorphism in a specific coding region (Val103Ile) which also appeared in obese people at the same frequency. Branson et al. found no correlation between body fat and carriers of mc4r mutation implying that the negative feedback loop between serum leptin and adipose tissue may be disrupted in these subjects (Branson et al., 2003). They also found no difference in resting energy expenditure in mc4r mutants and in non-carriers, thereby implying that MC4R does not control the resting energy expenditure (Branson et al., 2003). Moreover, given that they found no mutations in the region of POMC that codes for alpha-MSH or for Leptin Receptor (LEPR), they concluded that MC4R dysfunction, rather than either of the aforementioned proteins, is the cause for binge-eating disorder.
The second study, conducted by Farooqi et al., involved a population of 500 obese probands showing severe childhood obesity. By genotyping of genomic DNA, subjects were identified as homozygotes or heterozygotes for the mc4r locus. A group of 100 non-obese subjects was used as a control group for this study. Farooqi et al. assessed body composition by whole-body dual-energy absorptiometry, resting metabolic rate by calorimetry, and bone mineral densities using the data set of the third National Health and Nutrition Examination survey (Farooqi et al., 2003). They also assessed eating behavior, as implied by total energy intake and nutrient composition, in a semi-quantitative manner, for subjects under 16 years of age, and blood samples from all subjects were analyzed for leptin, lipids, glucose, insulin and other molecules, using standard assays (Farooqi et al., 2003). Moreover, to examine the function of wild-type and mutant MC4R, they cloned mc4r into bacterial cells and, on harvesting, assessed luciferase activity, having induced protein production in the presence of various concentrations of alpha-MSH. Since MC4R activation leads to production of intracellular cAMP which stimulates luciferase expression, increased luciferase activity could imply presence of functional MC4R protein (Farooqi et al., 2003).
Farooqi et al. found that 29, or 5.8%, of the subjects had mutations that were not found in non-obese control subjects in the mc4r gene. While all subjects homozygous for mutant mc4r were obese, only 68% of heterozygotes were obese. They also found that MC4R deficiency was characterized by an increase in both fat and lean mass and subjects with MC4R deficiency, showed increased energy intake and food-seeking behavior. Furthermore, they also found a strong correlation between in vitro function of MC4R and severity of clinical phenotype, as homozygotes tended to be less obese (i.e. had a lower body-mass index) than heterozygotes.
Both studies show that MC4R is responsible for food-seeking behavior and that certain mutations in this gene cause the binge-eating phenotype. Although these studies point to the connections between mc4r mutations, binge-eating and obesity, they acknowledge several potential loopholes in the information they had collected at this point in time. For instance, Farooqi et al. noted that food-seeking behavior was characteristic of people with MC4R deficiency. However, they point out, it was less intense as compared to subjects with leptin deficiency, implying that it may not be MC4R itself, but leptin that is responsible for hunger, since it is higher up in the pathway. Branson et al. show that they found no correlation between body fat and MC4R mutation carriers implying that the negative feedback loop between serum leptin and adipose tissue may be disrupted in these subjects. Both studies show that the resultant obese phenotype is a result of the interaction of mutant genes, such as mc4r, and the environment. Moreover, Farooqi et al. point out that their study involved comparison of their obese subjects to body-mass index from a reference United Kingdom population and also that their homozygous mutation carriers were all of Indo-European which made it difficult to make cross-cultural generalizations about the correlation between MC4R mutations and binge-eating behavior.
What does the Melanocortin-4 Receptor gene do?
Melanocortin-4 Receptor (MC4R) is known to be a part of the central melanocortinergic system which also includes the Agouti Related Protein (AGRP), the alpha-melanocyte stimulating hormone (alpha MSH), and melanocortin-3 receptor (MC3R) (Lu, 2001). MC4R plays a role in metabolic regulation and energy intake through a pathway involving leptin (Farooqi et al., 2003). The Pro-opiomelanocortin (POMC) gene encodes the prohormone POMC which is regulated by leptin (Farooqi et al., 2003). The POMC is post-translationally modified by convertases to yield the alpha-MSH (Voisey et al., 2003; Farooqi et al., 2003). The alpha-MSH in turn activates the MC4R which acts on effector nuclei in the hypothalamus leading to a metabolic activity (Farooqi et al. 2003). In the absence of a functional MC4R, leptin activates ARGP which is antagonistic with respect to alpha-MSH (Voisey, 2003). Thus, ARGP inhibits the MC4R present (if any) and creates hunger urges that lead to nutrient intake (Farooqi et al., 2003). Subjects bearing null mutations in the mc4r genes are deficient in the protein and show increased food-intake, obesity and hyperinsulinemia (Farooqi et al., 2003).
Figure 1. Schematic of the hypothalamus showing the activation pathway for MC4R protein by leptin, and its resultant signaling. Yellow arrows indicate the agonistic activation of the MC4R protein by alpha-MSH while black arrows indicate the antagonistic pathway involving ARGP.
Source: Barsh, G. S., Farooqi, I. S., O'Rahilly, S. "Genetics of Body-Weight Regulation." Nature. 404(April 2000): 644-651.
nuThis webpage was produced as an assignment for an undergraduate course at Davidson College.
The Hunger Gene:
Melanocortin-4 Receptor responsible for binge-eating?
Allen, Colin. "Hungry Gene: Binge Eating is not all about will power." 2003. March 25. Psychology Today. <http://cms.psychologytoday.com/articles/index.php?term=pto-20030325-000001> Accessed September 5, 2004.
Boyles, Salynn. "Gene Linked to Binge Eating: Flawed Appetite Suppression Gene Found in Obese Binge Eaters." 2003. WebMD. <http://my.webmd.com/content/Article/62/71656.htm> Accessed September 5, 2004.
Branson, R., Potoczna, N., Kral, J. G., Lentes, K., Hoehe, M. R., and F. F. Horber. 2003, March 20. "Binge Eating as a Major Phenotype of Melanocortin-4 Receptor Gene Mutations." The New England Journal of Medicine. 348(12): 1096-1102.
CNN Archives. "Study: Genes may be at fault for binge-eating." 2003. March 19. <http://www.cnn.com/2003/HEALTH/diet.fitness/03/19/binge.eating.gene.ap> Accessed September 5, 2004.
Farooqi, I. S., Keogh, J. M., Giles, S. H. Y., Lank, E. J., Cheetham, T., and S. O'Rahilly. 2003, March 20. "Clinical Spectrum of Obesity and Mutations in the Melanocortin-4 Receptor Gene." The New England Journal of Medicine. 348(12): 1085-1095.
Lu, X. Y. 2001. "Role of central melanocortin signaling in eating disorders." Psychopharmacology Bulletin. Autumn, 35(4):45-65.
Voisey, J., Carroll, L., and A. van Daal. 2003. Melanocortins and their receptors and antagonists. Current Drug Targets. October, 4(7):586-597.