BETHESDA, MD (August 30, 2006) – Until about 15 years ago, insulin was believed primarily responsible for turning carbohydrates into fat. But then it became apparent that diet alone could stimulate glucose metabolism and fat synthesis, even when insulin levels were low or absent.
Five years ago, researchers discovered that a substance known as ChREBP (carbohydrate response element binding protein), quite independent of insulin, initiated a sequence responsible for converting excess carbohydrates to fatty acids for long-term storage.
In a study that appears in this month's edition of the American Journal of Physiology-Endocrinology and Metabolism, the same laboratory that identified ChREBP (pronounced "kreb") and its role in fat storage has discovered that the absence of ChREBP in mice keeps normally obese mice from becoming fat, lowers their blood triglycerides (a type of fat) and reduces the insulin resistance related to type 2 diabetes
The research, titled "Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob/ob) mice," was carried out by University of Texas researchers Katsumi Iizuka, Bonnie Miller and Kosaku Uyeda of the UT Southwestern Medical Center, in Dallas. Uyeda is also associated with the Veterans Affairs Medical Center in Dallas. The American Physiological Society published the study.
"Carbohydrates are broken down into glucose and other simple sugars by digestion," explained Uyeda, the principal investigator. "These sugars enter the bloodstream and are mostly taken up by the liver." The liver does different things with the sugars, depending upon the body's energy needs. But if the body has enough energy, with the help of ChREBP, it converts glucose into fatty acids and stores it.
"Many people believe that evolutionary pressure favored those who could convert excess carbohydrate to fat and store it because they were better able to survive food shortages," said Uyeda. "Unfortunately for the waistlines and health of many people today, the conversion of glucose into fatty acids by the liver occurs all too readily."
Mice without ChREBP
The researchers used four groups of mice. One group lacked a functional ChREBP gene. Because these mice were unable to synthesize ChREBP, they converted very little carbohydrate to fat and remained relatively thin, even when they ate a very high carbohydrate diet, Uyeda explained.
The second group was a strain of obese mice that do not produce leptin, a hormone that tells us to stop eating when we are full, Uyeda said. "Since these mice don't make leptin, they eat large amounts of food, become obese and develop symptoms of insulin resistance and type 2 diabetes," he said.
The third group was a combination of the first two: They did not produce leptin and so were prone to obesity but they also lacked the functional ChREBP gene, which tends to keep mice lean. The fourth group of normal mice acted as controls.
"We found that the third group (that did not have ChREBP and did not produce leptin) did not become obese, had lower blood glucose levels than the obese group and were less insulin resistant," Uyeda said. "We also were very surprised to find that these mice ate much less than the obese mice of the second group."
"These results show the important role ChREBP plays in metabolism and appetite control in mice and, presumably, humans," Uyeda said. "Ultimately we hope to develop drugs to inactivate and control ChREBP to overcome these two major health problems of obesity and diabetes."
Research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health and the Veterans Administration.
The American Physiological Society was founded in 1887 to foster basic and applied bioscience. The Bethesda, Maryland-based society has more than 10,500 members and publishes 14 peer-reviewed journals containing almost 4,000 articles annually.
APS provides a wide range of research, educational and career support and programming to further the contributions of physiology to understanding the mechanisms of diseased and healthy states. In 2004, APS received the Presidential Award for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).
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