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Front Page

NUTRITION

Enzyme Implicated in Insulin Resistance

Pity the poor fat cell. An extra soda in the afternoon, a shorter walk after dinner, and all of a sudden you've gained a few pounds. Clothes strain at the seams, zippers resist closure, and buttons pop off.

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)


The story is much the same underneath. Fat cells balloon as yellowish fatty lipids crowd in, squishing their cytoplasms against the stretched membranes. Bloated fat conveys its distress by releasing proteins called cytokines (some of which mediate inflammation) and fatty acids.

Now, researchers have found an enzyme in cells that listens to fat's biochemical angst and responds by turning down insulin signaling. The study identifies an inflammatory mechanism in mouse models of human obesity, insulin resistance, and type 2 diabetes.

In fat, muscle, and liver cells, the enzyme 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.

"This provides hard evidence that diabetes is an inflammatory disease," Hotamisligil said.

For several years, scientists have been investigating a suspected link between overproduction of a cytokine in fat cells and insulin resistance. Hotamisligil's lab and other groups have been shoring up the downstream evidence. Overproduced in bloated fat cells, the cytokine tumor necrosis factor-alpha jams up insulin signaling by phosphorylating serine residues on the insulin receptor substrate-1 instead of tyrosine residues. (Tyrosine phosphorylation sets up the scaffolding for further insulin signaling in the cell.) Insulin binds to receptors on fat, liver, and muscle cells, but most of the signal doesn't get through.

Working upstream, Hotamisligil and others narrowed their search to a well-studied protein kinase called JNK, better known in apoptosis, regeneration, and inflammation. Three years ago, postdoctoral researcher and co-first author Jiro Hirosumi began testing the functional significance of two JNK enzymes expressed in fat, muscle, and liver, JNK1 and JNK2, in knockout mice developed by co-author Michael Karin at University of California, San Diego.

Jnk1 knockouts turned out to be one of a kind, metabolically speaking. Compared to controls and Jnk2 knockout mice, which grew obese on high-fat diets, Jnk1 knockouts gained about 20 percent less weight, grew fewer and smaller fat cells, and carried the fat differently. Tests ruled out other explanations including food intake, core body temperature, and lipid absorption in the bowel. 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. Other tests revealed little or no insulin resistance and no diabetes. Jnk2 knockouts were not so lucky. Not only did they become fat on a diet high in fat and calories, their insulin and glucose levels soared to diabetic levels.

Postdoctoral fellow Gürol Tuncman, the other first author, picked up the project when it moved from dietary to genetic models and Hirosumi moved back to Japan. Tuncman bred genetically obese mice with targeted mutations in Jnk1. The mice became so fat at six months that they had difficulty walking. Yet those with JNK1 deficiencies had partial resistance against obesity, high blood sugar, and high insulin levels.

In short, both fatty acids and cytokines, the two known main culprits in insulin resistance, activate JNK1, which in turn phosphorylates serine residues on IRS-1, interfering with insulin signaling. Meanwhile, a genetic study of a French family published last year linked JNK abnormalities with diabetes. Tuncman, a Mary K. Iacocca fellow in nutrition, is testing the link between genetic variations at JNK and other loci in a human cohort in collaboration with Eric Rimm, HSPH associate professor of epidemiology and nutrition.

Last year, another inflammatory pathway (IKK-beta) between obesity and insulin resistance was identified with studies of high-dose aspirin by Steven Shoelson, HMS associate professor of medicine and head of cellular and molecular physiology at Joslin Diabetes Center (See Focus, Aug. 31, 2001). Small-scale tests of high-dose aspirin (nine overweight, insulin-resistant people) and a safer variation known as disalcide, approved for use in rheumatoid arthritis, (seven people so far), show preliminary effectiveness in reversing insulin resistance. Similarly, a drug for rheumatoid arthritis works by inhibiting JNK1 and may provide an immediate opportunity for testing in people. However, Shoelson and Hotamisligil strongly discourage off-label, out-of-study use of these drugs.

"In the obesity and diabetes fields, we're finding surprising influences of inflammatory cascades over metabolism and energy balances," said Jeffrey Flier, the George C. Reisman professor of medicine at HMS and Beth Israel Deaconess Medical Center. "Inflammation represents a broad pathway in biology that was originally viewed primarily as a mechanism for limiting infection, which could sometimes damage tissue in a group of disorders such as rheumatoid arthritis and other autoimmune disorders. Obesity and diabetes increasingly appear to be metabolic disorders in which inflammatory pathways play an important, if unanticipated, role."

--Carol Cruzan Morton