Obesity, like cancer, turns out to be many conditions, not just one disease, meaning researchers might be able to custom-tailor treatments to individuals -- not just for the overweight but also for those with diabetes, osteoporosis and other common maladies, scientists reported Wednesday.
The discovery of obesity's complex subdivisions, each with its own genetic identity, could lead to the development of an array of personalized medicines and diagnostic tools, researchers said.
"Obesity and most other common diseases -- heart disease, arthritis, diabetes, asthma, cancer, schizophrenia, etc. -- ... are all due to multiple genetic and environmental factors, and different combinations of these can result in disease," said A. Jake Lusis, professor of microbiology and human genetics at the University of California, Los Angeles.
"If the forms can be separated, it could have enormous clinical implications," he told United Press International. "For example, childhood leukemia is treated in a very different way than other leukemias."
In a technical tour de force, Lusis and colleagues have added an important instrument to their medical bag, a new tool they hope will enable scientists to make such critical distinctions about obesity.
The investigators from UCLA, the pharmaceutical giant Merck and Co. Inc., and its subsidiary, Rosetta Inpharmatics of Kirkland, Wash., combined a variety of high-tech techniques to compare and contrast the makeup of mice genetically predisposed to severe obesity.
Among their mix of techno-tricks: data from DNA micro-arrays, a technology that permits researchers to picture the interactions among thousands of genes simultaneously; whole-genome sequences, the decoding of an organism's entire blueprint of heredity, and clinical information.
Such a comprehensive approach was tried in yeast experiments two years ago. But the new work marks the first time investigators have conducted such a large-scale analysis of three different and complex species: mouse, maize and man.
They took into account slight but significant variations in genetic material, variations that regulate such inherited traits as predisposition to certain diseases or a particular hair color or height. They also gauged the amount and type of specific genes expressed, or produced, in a particular cell.
"This is an important milestone in establishing this approach, which I believe has the promise of providing significant biological insights," Ariel Darvasi of the Hebrew University of Jerusalem, who analyzed the findings in an accompanying commentary, told UPI.
As reported in the March 20 issue of the British journal Nature, to test their strategy, researchers zeroed in on obesity, a growing health problem across the globe. They got meaty results, revealing an entire new layer of complexity in the potentially life-threatening condition that affects more than 300 million people worldwide.
The number of cases of obesity -- a condition with severe, even fatal, health consequences -- has ballooned since the 1960s, with no signs of abating. In the United States, severe obesity affects one-third of the adult population, or some 60 million people. It also exacts a heavy death toll -- 300,000 annually -- and expenditures -- some $100 billion in health care annually, American Obesity Association officials estimated.
More than 127 million Americans fall into the overweight or obese category. The former is defined as having a Body Mass Index -- a weight-to-height ratio -- of between 25 and 29.9, and the latter as measuring 30 or more on the BMI scale.
The investigators found equally overweight mice can be subdivided into two groups on the basis of their genes. They also discovered a "hotspot" of obesity-related genes on chromosome 2. There are 23 pairs of chromosomes -- structures that house the genes that contain an organism's hereditary instructions -- in the center of every human cell.
A certain number of chromosomes characterizes each species, so in contrast to the human 46, the potato has 48 and the fruit fly, Drosophila, eight.
The new combined approach could help researchers to identify disease-related genes they might miss otherwise, scientists said.
"Obesity is very complex and likely the result of variations in many different genes in many different pathways, in addition to strong environmental interactions," lead study author Eric Schadt, director of research genetics at Rosetta, told UPI.
"What is novel in our study is the use of gene expression arrays to identify different subtypes of the disease, and then using the combined gene expression and genetics to show that the different subtypes are caused by different genes."
In other experiments, the researchers applied their technique successfully to maize and man, showing the same genetic patterns they had observed in the rodents also occurred in those species.
"This indicates that the more general approach we detailed in mouse will likely work in humans and plants as well," Schadt said.
The findings carry important implications, researchers said.
"The combination of genetic information and gene expression is expected to significantly advance the fulfillment of the long-awaited promises of genomics to improve healthcare," Darvasi said in a telephone interview from his home in Israel.
The work should provide a template for other researchers working to fill in the missing pieces of a wide array of genetic puzzles, from aging to depression, said Dr. Stephen Friend, senior vice president of molecular profiling and basic cancer research at Merck and president of Rosetta.
"I'm optimistic we have a way now to go back and re-examine many other diseases, (leading to) the discovery of treatments to match the patient," he said in a telephone interview.
Schadt predicted the new approach would start making inroads into the clinic within two years.
In the study, the results of which also will be announced in a review paper in Biochemical Transactions on April 3, genetically altered inbred mice that shared a common gene pool, living quarters and high-fat diet, nevertheless developed different levels of body fat: high, normal and low.
The researchers classified the mice in the upper 20th percentile of body fat as obese.
"All mice ... in the high-fat group would be similarly characterized clinically, but the expression data tell a different tale," Schadt explained. "It shows that very different processes are at play in the livers of these mice and that some of the mice are under the control of one genetic site, while another group is under the control of another."
Some of the obese mice might develop diabetes, while others might remain healthy, Schadt noted. He added that drugs targeting one of the genetic sites affecting only one of the subtypes would do nothing for the other animals. Despite their similar body-fat-content profiles, underlying genetic differences clearly separate the animals into at least two groups, he said.
If such distinctions exist within a population as homogenous as the highly controlled mice, the human condition must be far more complex, Schadt pointed out. But he that said his team aims to make the human problem more manageable.
"This is a very promising approach to study diseases and not only be able to identify different factors affecting disease," Friend told UPI, "but also to be able to identify different subgroups within obesity or any other disease and to determine which treatment is most appropriate for which individual."
