Sci. Aging Knowl. Environ., 15 October 2003
Denying a chemical change to a fat-cell protein keeps metabolism healthy
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/41/nw141
Key Words: thiazolidinedione peroxisome proliferator-activated receptor
Short-circuiting a protein's shutoff switch helps mice fight diabetes, according to a new study. The results reveal the importance of the toggle in living animals and could lead to improved treatments that dampen the side effects of existing antidiabetes drugs.
As bodies swell with fat, their cells often lose the capacity to respond to the glucose-controlling hormone insulin. This condition--insulin resistance--presages diabetes, a medical condition in which blood sugar concentrations spin out of control. Activating the fat-cell protein PPAR with drugs called TZDs alleviates symptoms. Researchers want to understand how PPAR influences metabolism, partly because they hope to separate the benefits of TZDs from side effects such as weight gain. PPAR controls the activity of numerous genes, some of which might tweak the ability of cells throughout the body to respond to insulin. Previous cell culture experiments suggested that PPAR switches off when it receives a phosphate molecule. But whether that chemical change influences the protein's function in animals was uncertain.
To investigate, biochemist Mitch Lazar of the University of Pennsylvania School of Medicine in Philadelphia and colleagues engineered mice to produce PPAR that is hardwired in the "on" position: The amino acid that normally accepts the phosphate is swapped for one that can't. After feasting on a high-fat diet, the altered animals resisted diabetes better than did normal animals on the same regimen. They absorbed an injection of glucose quickly and kept insulin amounts low after a postbinge fast. Active PPAR increases fat-cell numbers, so Lazar's team was surprised to discover that the mutant mice weren't obese.
Additional studies revealed changes that might contribute to the rodents' fitter metabolism. Although the animals toted normal amounts of fat, they boasted diminutive fat cells; small fat cells are connected with healthy insulin responses. In addition, the animals carried fewer fatty acids and triglycerides, compounds linked to insulin resistance (see "Greasing Aging's Downward Slide"). Amounts of adiponectin--a PPAR-controlled molecule that appears to help insulin perform its tasks--rose. But other genes prodded by PPAR, including those known to adjust blood lipid concentrations, displayed normal activity. The results suggest that adiponectin rather than one of these genes' products is a "major mechanism for insulin sensitivity," says Lazar.
The study "verifies [the notion] that the phosphorylation site has biological relevance," says molecular biologist Peter Tontonoz of the University of California, Los Angeles. It's surprising, he adds, that the alteration doesn't target the same genes that TZDs do, which suggests that it might work by a different mechanism. That idea is not proven, he cautions: Animals that are administered lower-than-normal quantities of the drugs might respond more as the mutant animals do, for instance. If the mutation does behave differently from TZDs, compounds that prevent PPAR phosphorylation might alleviate side effects, says Lazar. But separating insulin sensitivity from obesity might be more difficult in humans than in mice, notes diabetes researcher C. Ronald Kahn of the Joslin Diabetes Center in Boston. He previously found a PPAR mutation in humans that blocks phosphorylation; individuals with the mutation were morbidly obese but weren't insulin resistant. Further work might reveal whether PPAR will provide new ways to switch off the lights on diabetes.
--R. John Davenport; suggested by Arjumand Ghazi, Greg Liszt, and Arlan Richardson
October 15, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150