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Genes, Mother’s Milk and Diabesity
Scientists map genome interactions and detect influence of mother's milk on
obesity-induced diabetes
Edward R. Winstead

Featured Article.

Obese laboratory mice are simple creatures in a complex world. Most obesity studies in mice use animals that have a single genetic flaw, such as the 'ob/ob' mouse. The adult ob/ob mouse is obese because of a defect in the leptin gene. In the mid-nineties, scientists discovered that injecting mice with the leptin protein normalized their weight. This finding led people to predict that new, leptin-based therapies would revolutionize the treatment of human obesity.

Example of what can happen to male offspring of Non-obese, Non-diabetic and New Zealand Obese parents at 52 weeks of age (right). Shown here with 9-month-old relative of the Non-obese, Non-diabetic strain.

The leptin revolution never happened. Inherited leptin defects in humans are rare—two cousins in a Pakistani family may be the only cases of severe obesity blamed on the leptin gene. The experimental use of leptin therapy in humans has been a disappointment, perhaps because the leptin protein does slightly different things in humans and mice. A clinical trial of leptin injections, completed in 1999, found that only a minority of patients achieved modest weight loss while taking high doses of the protein.

"The destruction of the leptin gene is not the reason people become obese," says Edward H. Leiter, a senior staff scientist at the Jackson Laboratory in Bar Harbor, Maine. Clearly, the current epidemic of obesity in some populations is due to many genetic and environmental factors and not to defects in single genes. So, says Leiter, "if you really want to understand human obesity, you need a mouse model that reflects what goes on in humans."

He and two colleagues at the Jackson Laboratory recently developed a mouse model to investigate what is sometimes known as diabesity. Obesity is a major risk factor for type II diabetes in humans, and diabesity refers to type II diabetes that arises concurrently—or in response to—a significant gain in body weight.

The mouse study yielded chromosome regions likely to contain 'diabesity' genes. These are genes that interact with other genes and environmental factors to produce obesity-induced diabetes. A stretch of mouse chromosome 1, for example, appears to harbor more than one gene contributing to diabesity-related traits, such as weight gain or insulin defects.

Detail from graphic summarizing the results of a genome-wide search through all pairs of genetic loci for associations with a trait 'percent fat'. View full

A surprise of the study was the influence of mother's milk: Offspring nursed by obese moms had significantly higher rates of diabesity than other offspring. Something involving gestation or nursing must be to blame, the researchers concluded. To test the milk hypothesis, they created different 'maternal environments' by using foster mothers as nurses for some offspring.

The notion that susceptibility genes and environmental factors interact to cause disease is hardly novel. "What's new here is that we can now map interactions using tools that let us break open the complexity of disease," says Gary Churchill, a statistical geneticist at the Jackson Laboratory. His group develops computer models for capturing the interacting components of complex genetic traits such as coat color in the mouse.

Some of Churchill's analytical tools were more effective because the founding parent mice were unrelated. Certain interactions showed up because of the contrast in genetic backgrounds, he says. Diversity was essential, says Leiter, for another reason: Humans are not inbred, so mouse pups with unrelated parents are more like human babies than are inbred ob/ob mice.

The diabesity study had this goal: 'Breed' as bad a genome as possible and then figure out how it breaks down. The exercise was like "getting a Yugo vehicle and replacing the Michelin tires with Firestone tires," says Leiter.

One parent mouse was the obese, diabetes-prone New Zealand Obese strain; the other was a relatively lean strain called Non-obese, Non-diabetic. Neither parent on its own progresses to diabesity, but the 'mixing' of susceptibility genes in the offspring under certain environmental conditions created a kind of threshold effect. Among first-generation offspring, virtually all males developed diabesity.

"The Non-obese, Non-diabetic mouse does not develop type II diabetes, but it does have late-onset mild obesity and insulin-related defects," says Peter Reifsnyder, who designed the breeding experiments. "So both strains have an underlying susceptibility, and when you combine the genomes, 100 percent of the males develop diabesity." For reasons that are not clear, females had lowers rates of disease, as in human populations.

Female offspring (brown mice) of Non-obese, Non-diabetic and New Zealand Obese strains. Shown here with 9-month-old relative of the Non-obese, Non-diabetic strain.

Males of the first generation were bred to females of the parental strains, yielding another generation of mice with varying risks for diabesity. Churchill's computers analyzed data on the distribution of body weight and incidence of diabesity among the mice; they also tracked the inheritance of DNA markers linked to disease.

The computers generated the locations of diabesity hotspots in the genome. Some regions, it turned out, had negative effects only in the presence of other regions. It was as though the genes were having a conversation, and the conversation only took place when the genes could interact. The region of chromosome 1, for example, interacted negatively with a region on chromosome 2 contributed by the Non-obese, Non-diabetic parent.

Leiter's group has not announced any specific genes, but a description of the study appeared in a recent issue of Genome Research. "We want to get the word out to the community that this project was not a big deal computationally," says Churchill. "I was doing computations at home on my laptop."

To be sure, leptin has led to a new understanding of metabolism and obesity. The human and mouse leptin genes were identified by Jeffrey Friedman and his team at the Rockefeller University in New York in 1995. Since then, genomics has emerged.

‘This is a classic case of the environment affecting the penetrance of genes.’

It is now feasible, Leiter's group says, to build and dissect mouse models that begin to share aspects of complex human disease. The next stages of the diabesity project—narrowing regions and identifying specific genes of interest—may be best suited to technologies such as microarrays that allow genome-wide analyses of gene expression. With the expected completion of mouse and human genome sequences, finding genes and their counterparts in other species will be accomplished largely through computer databases searches.

Nothing about the cross-talking mouse genomes surprised the researchers. They designed the study, after all, to capture the complexity of genes working as coordinated groups. "The bottom line is that if diseases were simple, they wouldn't be common," says Churchill. "Evolution would have weeded out 'disease' genes."

The researchers were surprised, however, to discover that mother's milk could accelerate an animal's progression to diabesity. "That day was over the top," recalls Churchill. "Having an environmental effect that depends on the genotypes was a pretty cool thing."

The milk added a new dimension of complexity: three-way interactions among cross-talking pairs of genes and unknown environmental factors. Without the confounding influence of the milk, certain gene-gene interactions apparently had no negative effects. And the milk revealed interactions that the computers otherwise would have missed.

"Our ability to detect genes that were talking to each other was almost entirely contingent on our ability to identify the nature of the maternal environment," explains Leiter. "This is a classic case of the environment affecting the penetrance of genes." (Penetrance is the incidence of disease among mice with the genes for diabesity.)

Because the mice were raised from birth in virtually identical environments at the Jackson Laboratory, the researchers thought that confounding environmental influences had been eliminated from the study. "The nursing effect was an accident of the cross, and we were not expecting it," says Peter Reifsnyder. "What's striking is the life-long nature of the influence." The mice that were the biggest at three weeks of age were still the biggest at 24 weeks of age.

The researchers are analyzing the milk to determine the factors that may be relevant to diabesity. Leiter's laboratory does not regularly do that kind of protein analysis and the process is taking longer than expected. Just collecting the samples delayed the project. "You don't get much milk from milking a mouse," says Leiter.

As the leptin experience shows, what the researchers find in the mouse milk may or may not be relevant to humans. Regardless, Reifsnyder emphasizes that human breast milk has far more pluses than minuses for babies. "By no means should women think that nursing their babies is a bad idea," he says.

The term diabesity appears in the literature at least since 1980. It was invented by Ethan A. Sims, Professor Emeritus in Medicine at the University of Vermont College of Medicine, according to Leiter, who adds: "It's catching on."

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Reifsnyder, P.C., Churchill, G., and Leiter, E. H. Maternal environment and genotype interact to establish diabesity in mice. Genome Res 10, 1568-1578 (October 2000).

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