F riedman led the team that discovered the obesity hormone, Leptin, by studying genetic mechanisms of weight regulation in mice. The fat mouse had been "discovered" at the Jackson Laboratory in Bar Harbor, Maine in the early 1950s. This mutant mouse was so huge that researchers assumed that it was pregnant, until it was discovered that it was a male mouse. Friedman was inspired by the work of Ethan Allen Sims, a physician at the University of Vermont College of Medicine who had been exploring the link between obesity and diabetes using male inmates at the Vermont state prison. Allen found that only very few inmates could easily put on weight, and these found it the most difficult to lose it.
In late 1994, Friedman's research had received national recognition after the isolation of the obesity gene (ob) and its human homologue had been publicized (Zhang et al. 1994). This was a key paper for any further research in the field of obesity and dieting because it specified the exact code of this gene. Its central importance and credibility in this particular field of research is that any researcher wanting to study this gene in ob mice must have information about the gene itself. Knowing the exact code allows hypotheses to be set up about whether the physiological problem is a defect in the protein that the ob gene makes, or whether it is the perhaps defective receptor of ob that is the problem.
In this case, as subsequent studies were able to confirm, there are in fact multiple ways of having an obese phenotype (i.e., a fat mouse). In some cases, the ob gene itself is defective, and in others, the receptor gene is defective (a different gene, called db). Of course, other genes entirely can also cause obesity. This paper was the starting point for any closer examination of what the gene products resulting in obesity are, and how they interact. Their paper is credible as the techniques used to determine this sequence are standard, universally accepted genetic methods for finding genes. It was done as follows: First, recombination studies are done. This means that researchers allow mice to breed in large numbers and then look for inheritance patterns that do not necessarily follow Mendelian patterns. By comparing numbers of fat to lean offspring in relation to some other genetically related trait (molecular markers), it is possible to determine approximately where on a chromosome (and on which chromosome) a mutation is.
The chromosome and the gene's approximate location were already known to Friedman and his colleagues. The next step was to continue to narrow down where on the chromosome ob is by comparing it to other genes close to it (by making a genetic map, which gets increasingly specific). After this, they had a very small (comparatively) region of DNA which they know contains the gene, and by insetting the region via recombinant techniques in bacteria and growing them, they can see which parts are expressed, and are therefore part of the gene. Furthermore, the sequences are compared to standard DNA libraries to see if homology to other genes exists. In the case of Friedman's work, this technique worked because the product of the gene, a protein called Leptin, was already known, and so they only had to compare the region of DNA and its putative gene product to the protein Leptin to see whether they had the right region. These methods are entirely standard, and there is no reason to doubt the report's veracity. Thus, this paper is central because not only is it entirely within the bounds of standard genetic research, but it is also the starting point for any further work. However, its genetic credibility does not absolve its scientific weaknesses, namely that it equates obesity with bad health and considers obesity the cause rather than the symptom of other illnesses.
But Friedman's hypothesis did not rest with the explanation of where the genetic key to obesity in mice lay. He concludes with the evolutionary biological explanation that "heterozygous mutations at ob may provide a selective advantage in human populations subjected to caloric deprivation. Identification of ob offers an entry point into the pathways that regulate adiposity and body weight and should provide a fuller understanding of the pathogenesis of obesity" (Zhang et al. 1994: 431). At that point, the meanings associated with obesity shifted radically from psychological to genetic explanations. However, the genetic explanations were given an evolutionary meaning to explain their "function" (Shell 2001). Fat had to have purpose if it were an inherent part of the genome. It could not be a random or a secondary effect. It had "meaning" in the past when entire populations starved to death. Actually, a counter "just-so-story" could be told about the fat members of prehistoric populations who were the favorite prey of saber-tooth tigers as they ran much slower.
The notion of giving meaning to fat in the evolutionary past made it "natural" rather than pathological. As Friedman later wrote:
In their efforts to lose weight, obese individuals may be fighting a powerful set of evolutionary forces honed in an environment drastically different from that of today Twin studies, adoption studies, and studies of familial aggregation confirm a major contribution of genes to the development of obesity. Indeed, the heritability of obesity is equivalent to that of height and exceeds that of many disorders for which a genetic basis is generally accepted. It is worth noting that height has also increased significantly in Western countries in the 20th century; for example, the average U.S. Civil War soldier was 5'4" tall. Yet, in contrast to the situation with obesity, most people readily accept the fact that genetic factors contribute to differences in stature.
(Friedman 2003: 856)
Strangely, this is precisely the argument that Francis Galton (1822-1911), Charles Darwin's cousin and the creator of "eugenics," made concerning the inheritability of physical characteristics (Galton 1869). He wanted to prove that the British working class was stupid, small, and puny because of their inheritance following his dictum that "nature" outweighed "nurture" (a phrase that he coined). Even his contemporaries dismissed this, noting the radical difference in nutrition between the working class and Galton's ideal upper-middle-class Englishman (Constable 1905).
Subsequent to defining the ob gene, Friedman's laboratory found that injecting leptin into mice decreased their body weight because food intake was reduced and energy expenditure increased. As a result of Friedman's discovery, current research has been aimed at trying to understand the genetic basis of obesity in humans and the role Leptin plays in transmitting its weight-reducing signal.
Currently, Friedman is a professor at the Rockefeller University in New York City and an investigator at the Howard Hughes Medical Institute. Research in progress involves the regulatory mechanisms controlling body weight, Leptin's mechanism of action, and its importance to the pathogenesis of obesity. Other studies try to clarify the mechanism by which Leptin controls feeding. Lastly, efforts to investigate the genetic basis of the high incidence of obesity on the Pacific Island of Kosrae are also in progress (Bonnen et al. 2006). Through Friedman's continued studies of Leptin and his search for other genes that influence weight in humans, he hopes to lay the foundation for developing treatments to fight the global epidemic of obesity.
References and Further Reading Bonnen, P.E., Pe'er, I., Plenge, R.M., Salit, J., Lowe, J.K., Shapero, M.H., Lifton, R.P., Breslow, J.L., Daly, M.J., Reich, D.E., Jones, K.W., Stoffel, M., Altshuler D. and Friedman, J.M. (2006) "Evaluating Potential for Whole-Genome Studies in Kosrae, an Isolated Population in Micronesia," Nature Genetics 38 (2):
Constable, Frank Challice (1905) Poverty and Hereditary Genius: A Criticism of Mr. Francis Galton's Theory of Hereditary Genius, London: A.C. Fifield.
Friedman, J.M. (2002) "The Function of Leptin in Nutrition, Weight, and Physiology," Nutrition Reviews 60 (10, part 2): Si-14, S68-84, and S85-87.
-(2003) "A War on Obesity, Not the Obese," Science
-"Heads of Laboratories," The Rockefeller
University, available online at <http:// www.rockefeller.edu/research/abstract.php?id=4i > (accessed April 18, 2006).
-Howard Hughes Medical Institute, available online at <http://hhmi.org/research/investigators/ friedman_bio.html> (accessed April 12, 2006).
Galton, Francis (1869) Hereditary Genius: An Inquiry into Its Laws and Consequences, London: Macmillan.
Kolata, Gina (2007). Rethinking Thin: The New Science of Weight Loss—and the Myths and Realities of Dieting, New York: Farrar, Straus and Giroux.
Shell, Ellen Ruppel (2001) The Hungry Gene: The Science of Fat and the Future of Thin, New York, Atlantic Monthly Press.
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J.M. (1994) "Positional Cloning of the Mouse Obese Gene and Its Human Homologue," Nature 372 (6505): 425-32.
Was this article helpful?
I can't believe I'm actually writing the book that is going to help you achieve the level of health and fitness that you always dreamed of. Me, little scrawny sickly Darlene that was always last picked in gym class. There's power in a good story here so get this book now.