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Enzyme Implicated in Insulin Resistance
Over time, engorged fat cells make themselves and other tissues in the body resistant to insulin and eventually diabetic. Now, researchers have found a key protein in the metabolic pathway leading to disease in mouse models of obesity and diabetes.
Blame it on the JNK gene. Too much junk food turns into too much fat, which can turn into insulin resistance and diabetes, thanks in part to the JNK1 enzyme that also plays a role in inflammation, say Gürol Tuncman (left), Gökhan Hotamisligil, and their colleagues. (Photo by Jeff Cleary)
In fat, muscle, and liver cells, the protein JNK1 seems to be a crucial component of the biochemical pathway responsible for obesity-induced insulin resistance in animals, according to a report in the Nov. 21
Nature by researchers in the lab of senior author Gökhan Hotamisligil, associate professor of nutrition at HSPH. Surprisingly, JNK1 may even play a role in obesity itself.
Obesity affects more than 50 percent of the US population, is closely associated with insulin resistance, and is one of the leading risk factors for type 2 diabetes. People with this type of diabetes do not produce adequate amounts of insulin or cannot use insulin effectively. It has long been suspected that both obesity and diabetes are linked to inflammatory pathways in cells, particularly in fatty tissue. The new findings identify a key molecular mechanism controlling these inflammatory changes and demonstrate that they are at the root of both diseases.
In a dietary obesity model, genetic knockout mice missing one flavor of the enzyme family, JNK1, gained less weight, grew fewer and smaller fat cells, and carried the fat differently than comparative mice on the same high-fat, high-calorie diet. Even better, the plump Jnk1 knockouts on a high-fat diet had the same low blood glucose and insulin levels of their lean wild type counterparts on normal diets. In a genetic obesity model, mice with JNK1 deficiencies had partial resistance against obesity, high blood sugar, and high insulin levels.
A drug for rheumatoid arthritis works by inhibiting JNK1 and may provide an immediate opportunity for testing in people. In collaboration with others, postdoctoral fellow Görol Tuncman, co-first author and the Mary K. Iacocca fellow in nutrition, is testing the link between genetic variations in JNK and at other loci in a human cohort.
--Carol Cruzan Morton
Copyright 2002 by the President and Fellows of Harvard College
