Obesity is a disease in itself and a major public health problem in the U.S. The surgeon general recently reported that 61 percent of Americans are overweight - and still counting.
The opposite side of the obesity coin is diabetes mellitus Type II, also known as noninsulin-dependent diabetes (NIDD). Is obesity a side effect of NIDD or, vice versa, is diabetes an adverse consequence of obesity?
Nature dated Nov. 21, 2002, probes this tricky question in an article titled: "A central role for JNK in obesity and insulin resistance." Its senior author is cell biologist and molecular geneticist Gökhan Hotamisligil, an associate professor of nutritional biochemistry at the Harvard School of Public Health in Boston.
"The overall findings in our Nature paper are several," Hotamisligil told BioWorld Today. "One is a molecular link between obesity and diabetes. It's also evidence that the underlying mechanism for these disorders involves inflammation. As long suspected," he continued, "inflammation has something to do with diabetes. This discovery puts that fact into the hard evidence that there is really a primary rather than a secondary inflammatory causal relationship to those two diseases.
"It inflames very interesting tissues," he went on. "For example, fatty tissue itself is inflamed, and produces numerous harmful proteins. Muscle tissue is another inflamed place, important for glucose metabolism. And the liver is significantly inflamed, too. Mechanistically," Hotamisligil observed, "this is a novel finding, because the key to this inflammatory response is the gene we discovered.
"That gene encodes an enzyme called jnk, pronounced junk.' It's an enzyme that surveys the cells, and their response to stress or invading organisms. Its sensor is also activated in the presence of obesity. That's the interesting finding here. Once jnk is triggered by obesity, it jams the pathway governing insulin action. So the response of the cells to the stress is to shut down insulin activity. And that's how one develops diabetes."
Two Of Three Jun Variants Under Study
Hotamisligil explained: " Jun' is short for c-jun-terminal kinase.' This is the name of the gene and the protein it encodes. They are normal genes found in normal bodies. Jun comes in three isoforms. Two of these variant genes, jnk1 and jnk2, are in the tissues of interest to us. The third is found primarily in the brain. So we haven't worked on that isoform. The two genes and their proteins are very similar in sequence and in function. In most cases, they can carry on similar operations, but in this case, each isoform carries out specific assignments. And this is good news for drug-development prospects, because we can leave one isoform behind, and deal only with the other one to reduce undesired side effects, such as interference.
"So if you design a drug that is inhibiting actions of one isoform, that is relevant to obesity and diabetes. You can use it as a therapeutic without compromising some of the endogenous normal functions of this gene.
"Its protein is an enzyme with kinase activity, which puts phosphates on other proteins. The insulin hormone," he added, "also uses a certain pathway in order to generate its own actions. What happens then is that jnk is activated, and starts putting phosphates on the molecules that are necessary for insulin action. Once it does that, the hormone cannot recognize its substrate or molecules, or deliver its signal to them."
Hotamisligil and his co-authors enlisted two strains of mice to test their hypotheses. One line were the ob/ob rodent model of built-in obesity; the other, animals made obese by a high-caloric diet. "Our hypothesis," he recounted, "was that since the jnk enzyme is converting the inflammatory response into abnormal insulin action, and its activity is increased in obesity, we should get rid of that activity or turn it back to normal.
"To test our hypothesis, first we made the animals obese - a common dietary or genetic technique for investigating diabetes. Our initial supposition was that these animals would become less diabetic or not diabetic at all. To detect that, we measured glucose insulin and glucose tolerance. These confirmed that absent this activity the animals were much better, essentially normal. What came as a surprise was that they also became less obese. They did not become as fat as their control littermates.
"In each animal category, we had three groups of mice: normal wild-types, jnk1-deficient and jnk2-deficient. The jnk1-deficient mice were doing wonderfully; the jnk2 not so lucky.
"How to extrapolate from mice to humans," Hotamisligil suggested, "is always a million-dollar question. In the case of obesity and diabetes a billion-dollar question. But in this case," he went on, "I think we have a lot of reasons to be very optimistic. These reasons are fourfold. One is that there is direct evidence to implicate this jnk causal pathway in human diabetes. And we know there is abnormal junk activation in it.
"The evidence," he noted, "is that there are genetic mutations in a regulatory protein of a jnk gene. If you lose that expressed protein you get abnormal jnk activity. And the mutations have been identified in this protein recently in a diabetic family. So it's a proof of principle."
Drug Development Talks With Unnamed Firms
"The second [reason] is, of course, a kinase. Kinases are well known molecules and successful drug targets. Enzymatic activity is the best hope for drug development strategies. And the third piece of evidence, we know, is a good drug target because its compounds have already been developed to inhibit jnk, owing to its anti-inflammatory role in rheumatoid arthritis. Those compounds already out there could very quickly be put to the test in humans.
"The fourth point is that we cannot inhibit just one isoform as we know the activity increases obesity. Therefore, we just have to decrease it back to normal. So these are all very positive things that we look at if we are considering something for drug development.
"We will be working with the industry to pursue drug development and see what happens," Hotamisligil said. "We have negotiations with companies in progress, though we haven't signed anything yet. But we will," he concluded.