Sci. Aging Knowl. Environ., 11 February 2004
Firing up the liver's fat metabolism staves off beginnings of diabetes
Sweating and straining through a half-hour on the stair climber rouses the heart, but getting the liver to work harder might be crucial for preventing diabetes. A new study reveals that goading the liver to burn more fat rescues rats from insulin resistance, a defect in sugar processing that usually heralds the disease. The results could help researchers craft drugs to avert diabetes.
Insulin resistance occurs when cells, mainly in the muscles, disregard the hormone's commands to sop up glucose from the blood. Eating too much lipid-rich food and building up fat in the muscles, liver, and pancreas can provoke the defect. Researchers knew that the liver contributes to insulin resistance, but biochemist Christopher Newgard of Duke University in Durham, North Carolina, and colleagues wanted to determine whether the amount of fat the organ stows influences how cells elsewhere in the body respond to insulin. The researchers also wanted to learn more about the molecular mechanisms that induce the condition; previous work linked fat breakdown products called free fatty acids to insulin resistance.
They fed rats a diet in which fat provided 40% of the calories--one-third higher than the U.S. Department of Agriculture's recommended value for people but about what many Americans eat, Newgard says. After 11 weeks, the fat-gobbling rodents grew tubby and their blood showed early signs of diabetes, including large amounts of insulin, free fatty acids, and triglycerides, a form of fat. The researchers then cranked up the activity of the enzyme malonyl-CoA decarboxylase, which spurs the liver to burn fat instead of packing it away. To perform this trick, they exposed some rats to a virus carrying the gene for the enzyme. Control rodents received viruses toting a nonfunctional version. Five days after the treatment, quantities of insulin and free fatty acids had plunged in animals with increased enzyme activity. Further tests indicated that these rats showed a higher sensitivity to insulin in their muscles and liver than controls did. The findings demonstrate that changing how the liver processes fats can improve insulin sensitivity throughout the body, says Newgard.
Although the researchers aren't sure how boosting the enzyme tunes metabolism, the study provides a hint. When they measured amounts of several dozen molecules produced by the breakdown of lipids, they found that the high-fat diet hiked muscle concentrations of one: a compound called -hydroxybutyrate. Its quantities plunged after the viral treatment. The researchers speculate that the reduction of free fatty acids in the blood trims the amount of -hydroxybutyrate in the muscles, which curbs insulin resistance.
The observation that -hydroxybutyrate rises with fat consumption is intriguing, says Guenther Boden, a diabetes researcher at Temple University School of Medicine in Philadelphia, Pennsylvania. However, scientists need to provide stronger evidence that it promotes insulin resistance, he says. Showing that changes in liver fat metabolism can relieve insulin resistance in muscle cells is very important, says physiologist Richard Bergman of the University of Southern California in Los Angeles. Drugs that prod liver enzymes to burn fat might stymie diabetes, he says. Such compounds would allow patients to give their livers a workout without lifting a finger.
February 11, 2004
Suggested by Amir Sadighi Akha.
Science of Aging Knowledge Environment. ISSN 1539-6150