WASHINGTON (Reuters) - Altering a single gene turns ordinary mice into marathon racers that can run for hours and eat huge amounts of food without getting fat, a team of researchers reported on Monday.
“PPAR-delta [peroxisome proliferator-activated receptor-delta] and its ligands comprise a key molecular switch to regulate muscle fiber specification, obesity resistance, insulin sensitivity, and most surprisingly, physical endurance,” Dr. Ronald M. Evans and his team report in the October issue of the journal Public Library of Science Biology.
They said their study could lead to an “exercise pill” -- a PPAR-delta agonist -- that gives many of the benefits of training without the need to sweat.
“It is a pill that, in part, mimics the metabolic activity associated with exercise,” Dr. Evans of The Salk Institute in La Jolla, California, said in a telephone interview.
Revving up PPAR-delta has been shown to help increase metabolism, Dr. Evans said. “Part of our goal is the development of treatments for metabolic disease, diabetes and obesity,” he added.
The researchers developed transgenic mice in which the PPAR-delta gene in skeletal muscle is permanently activated. The mice grew more type I slow-twitch muscle fibers, which are rich in mitochondria and are used for endurance-type exercise, as opposed to the fast-twitch muscles used for sprinting.
The researchers expected to see changes in metabolism but were surprised at how extensive they were. The genetically engineered mice could run for an hour longer than normal mice, “which translates to nearly a kilometer further,” they write.
And when fed a high-fat diet, the transgenic animals gained only one-third the amount of weight that wild-type mice gained on the same diet after 97 days. Tests showed they were burning off the fat even when they did not exercise, Dr. Evans said.
Dr. Evans said he is still studying the mice, which are now about 9 months old.
“One of the questions for the future is studying the impact this has on longevity,” he said. “So far, there are no side effects other than that they are resistant to weight gain. They are fertile and they are able to give rise to the next generation of long-distance runners.”
Other studies have led researchers to believe an “exercise pill” is possible. In 2002, investigators reported that increasing production of calmodulin-dependent protein kinase (CaMK) could have similar effects (see Reuters Health report, April11, 2002).
While Dr. Evans and colleagues used genetic manipulation, they said using a pill to create a similar effect is already possible.
They gave normal mice an experimental drug called GW501516 that also activates PPAR-delta. The drug is being developed by GlaxoSmithKline to treat people with fat metabolism disorders. Normal mice given the drug could eat a high-fat diet without gaining weight, Evans said.
Dr. Evans said he is a consultant to Ligand Pharmaceuticals, which developed the drug and licensed it to Glaxo.
Source: PloS Biology 2004;2:e294. [ Google search on this article ]
MeSH Headings:Basal Metabolism: Diagnosis: Diagnostic Techniques, Endocrine: Energy Metabolism: Genetic Engineering: Genetic Techniques: Investigative Techniques: Physical Endurance: Thyroid Function Tests: Diagnostic Techniques and Procedures: Peroxisomes: Analytical, Diagnostic and Therapeutic Techniques and EquipmentCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
