In flies, a search for the essence of obesity

November 02, 2010

Fruit flies that grow obese after eating a diet loaded with fat could lead the way to the core elements of obesity, according to researchers who report their findings in the November issue of Cell Metabolism, a Cell Press publication.

The findings also get at obesity's origins. The demonstration that flies do become obese on a high-fat diet (HFD), much as humans do, indicates that the ability to become obese goes way, way back, the researchers say.

"The capacity for obesity is evolutionarily ancient," said Sean Oldham of the Sanford-Burnham Medical Research Institute. "The capacity for this disease has been around for 500 million years."

"This gets at a fundamental question in metabolic research," added Rolf Bodmer, also of the Sanford-Burnham Institute. "Organisms must maximize survival under many conditions. It is harder to survive in times of scarcity. As a result, organisms may be poised to maximize their food intake. At the other extreme, this can lead to obesity. It may be that the propensity has always been there."

Fruit flies normally eat fruit, but they will consume fats readily if that is what is given to them. In the new study, Bodmer and Oldham's team fed flies a HFD consisting of 30 percent fat in the form of coconut oil. And the flies got fat.

Flies can only grow so big because they have a rigid exoskeleton, the researchers said. Nevertheless, they showed increases in the amount of body fat they carried. The obese flies also showed many of the familiar signs of obesity; they developed high triglycerides and disruptions in the balance between insulin and blood sugar, along with heart dysfunctions reminiscent of diabetic cardiomyopathies. Detailed studies of heart function in the flies revealed an increase in cardiac lipids, reduced cardiac contractility, blockages, and structural pathologies.

"Whether this directly relates to what we see in humans, we don't know," Bodmer said. "As in diabetic cardiomyopathy, the fly hearts become less efficient." It's not yet clear whether the same molecular pathways underlie the condition in both flies and humans, but that is a question they intend to address through further study.

The researchers did show that one well-studied pathway, known as insulin-TOR, plays an important role in the fly symptoms. Treatments that reduced the insulin-TOR activity prevented the accumulation of excess fat in the insects and protected their heart. Manipulation of the insulin signal in fat tissue or in the heart itself also had a protective effect.

"When we manipulate this pathway in the hearts of flies, they are still obese, but their heart is 'blind' to the systemic effects," Bodmer said. The finding suggests that treatments designed to alter insulin-TOR signaling in specific tissues might hold promise.

More broadly, the fly model may help to unravel the pathways that are central to obesity and the relationships among them. "Obesity is a complicated disease," Oldham said. Many tissues and genes are involved, and in mammals, it can be difficult to sort all that out. Given enough resources, researchers could knock out genes in the fly genome one by one in search of those that influence heart dysfunction or obesity itself, Bodmer added.

"The discovery of these HFD-induced obesity phenotypes in the Drosophila genetic model will permit a detailed dissection of obesity phenotypes, especially with regard to the cardiac lipotoxicity effects (and possibly mimicking aspects of diabetic cardiomyopathy)," the researchers wrote. "In particular, we can now attempt to understand the various contributions of insulin resistance, fat accumulation, and fatty acid oxidation to the HFD-induced obesity phenotypes, including timing requirements. In summary, the advent of the Drosophila HFD-induced obesity model opens up many new horizons to study deregulated processes and diseases of chronic lipid excess."
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Cell Press

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