Altered mice stay svelte on high-fat diet. (Let Them Eat Cake).
When food is scarce, stockpiling energy in fat cells is a survival advantage. But when food is plentiful, as in industrialized countries, genes that promote fat storage lead to obesity (SN: 4/14/01, p. 238). The molecular mechanisms that translate extra calories into fat deposition are largely unknown.
Now, researchers at Kyoto University in Japan have identified a key pathway in the process. Scientists have long known that the hormone called gastric inhibitory polypeptide (GIP) is secreted into the bloodstream by the small intestine in response to ingested foods, particularly fatty ones. GIP binds to cell-surface receptors on distant fat cells, signaling food intake.
In an upcoming Nature Medicine, the Kyoto team shows that if this sequence is disrupted, mice burn excess fat rather than store it, and they become obesity resistant.
Previous research focused on GIP's effect on pancreas cells, not on fat cells, notes Yuichiro Yamada, one of the new study's authors. Because the hormone boosts insulin release from pancreatic cells, scientists have long speculated on a role for GIP in type II diabetes, which is marked by an inefficient response to insulin. But the new study is the first to clearly link GIP and obesity, Yamada and his colleagues say.
The scientists genetically engineered mice to lack the GIP receptor. When fed a high-fat diet during their first year, unaltered mice became obese and developed insulin resistance, a precursor to diabetes. GIP-receptor-deficient mice remained lean and responsive to insulin. These mice were fat-burning machines but appeared otherwise normal, the researchers report.
Then the scientists mated mice deficient in the GIP receptor with mice that lack leptin, a hormone that signals satiety. Leptin-free mice chronically overeat and are extraordinarily obese (SN: 7/29/95, p. 68). On an all-you-can-eat diet, mice that were missing both GIP receptors and leptin gained significantly less weight and body fat than mice that lacked only leptin did.
The next research step will be to develop drugs that block GIP receptors in people, Yamada says. Eventually, a GIP blocker could reduce the need for dangerous therapies, such as stomach-stapling surgery, to reduce food intake in morbidly obese people, he predicts.
"That taking away GIP action might have beneficial effects for obesity and, indirectly, diabetes is a pretty startling new concept," says Daniel J. Drucker of the University of Toronto in Canada. The research is sound, but it defies conventional thinking about GIP, he explains. Researchers previously had focused on boosting GIP action in people with type II diabetes. Now, it seems that inhibiting GIP might counter diabetes.
"It's an intriguing result," adds Jeffrey M. Friedman of the Howard Hughes Medical Institute (HHMI) at Rockefeller University in New York. The gene for the GIP receptor joins a growing list of genes whose inactivation in mice leads to reduced weight and increased metabolism, he says (SN: 6/02/01, p. 342).
The challenge for drug makers will be to find the "magic bullet" that selectively blocks the GIP receptor but doesn't react with closely related receptors, says HHMI investigator Donald F. Steiner of the University of Chicago. Even then, what works in mice may not work in people.
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|Title Annotation:||obesity-related protein Leptin|
|Article Type:||Brief Article|
|Date:||Jun 22, 2002|
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