Two independent studies in the Nov. 11 issue of the journal Cell, a Cell Press publication, suggest a common way to pump up muscles and prevent diabetes. The key is a molecule required for fine-tuning metabolism by selectively and subtly modifying core metabolic programs.
Researchers show that loss of this molecule specifically in muscle produces mice with more fat-burning muscle and greater exercise capacity. "We turned mice into super-marathon mice," said Johan Auwerx of École Polytechnique Fédérale de Lausanne. "They had more stamina and more endurance."
Another group of researchers show that loss of the same molecule specifically in fat cells produces mice that become more insulin sensitive even as they grow fatter. Despite being fat, the mice are a lot like animals on diabetes drugs known collectively as TZDs (thiazolidinediones) minus the side effects of water rention and heart diesease. "They were more glucose tolerant, even though they were more obese," said Jerrold Olefsky of the University of California, San Diego. "They were less insulin resistant and had less systemic inflammation -- all features common to TZD treatment."
This molecule is is called NCoR. It integrates complex signaling pathways, adjusting specific metabolic programs in a manner similar to a dimmer switch, Auwerx explains. The particular genes it acts on apparently vary with cell type.
These studies are surprising because earlier work had shown that complete loss of NCoR early in development is fatal. Scientists, including Auwerx and Olefsky, had anticipated that NCoR in specific adult cells would have broader effects than it does.
What these findings suggest is that limiting the levels or activity of NCoR could improve human metabolism for the better. It might be possible to produce drugs that specifically target NCoR activity only in one tissue or another. Olefsky's work suggests that fat is the prime target for improving insulin sensitivity since the mice with changes only in adipose experience systemic improvements.
"There is no doubt where this begins," Olefsky says, "and with this adipocyte [NCoR] knockout you get systemic insulin sensitivity; the liver and muscle gets better too."
The fact that NCoR deficiency comes with benefits in two totally different contexts makes such a treatment strategy that much more compelling, Auwerx said. "At the end of the day, it's doing something good for metabolism," Olefsky said.
- Pingping Li, WuQiang Fan, Jianfeng Xu, Min Lu, Hiroyasu Yamamoto, Johan Auwerx, Dorothy D. Sears, Saswata Talukdar, DaYoung Oh, Ai Chen, Gautam Bandyopadhyay, Miriam Scadeng, Jachelle M. Ofrecio, Sarah Nalbandian, Jerrold M. Olefsky. Adipocyte NCoR Knockout Decreases PPARγ Phosphorylation and Enhances PPARγ Activity and Insulin Sensitivity. Cell, 2011; 147 (4): 815 DOI: 10.1016/j.cell.2011.09.050
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