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Salk scientists detect molecular obesity link to insulin resistance, type II diabetes

A molecular switch found in the fat tissue of obese mice is a critical factor in the development of insulin resistance, report scientists at the Salk Institute for Biological Studies.

Previously found to increase glucose production by the liver during fasting, the culprit—a protein known as CREB—is also activated in fat tissue of obese mice where it promotes insulin resistance.

Their findings, published in the March issue of Cell Metabolism, suggest that CREB activity could provide an early warning for obese people predisposed to develop insulin resistance and may lead to new diabetes treatments that would not require weight loss.

"Obesity is a major risk factor for the development of type II diabetes," says Marc Montminy, M.D., Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology who led the current study, "but not everyone who is obese becomes insulin resistant, so identifying the initial events that trigger resistance represents an important goal for diabetes research."

High fat diets have led to a surge in the adult-onset form of diabetes, known as type II, which occurs when patients' tissues become resistant to insulin, a hormone produced when we eat that controls how cells use glucose as an energy source. At last count, 23.6 million people in the United States suffer from diabetes, with another 57 million classed as having pre diabetes-like symptoms, numbers that are set to increase along with our ever-expanding waistbands.

"Given that obesity is now at its highest levels and expected to worsen in the near future, therapies that could potentially halt the genesis of type II diabetes in the face of obesity will be of great value," says co-first author Maziyar Saberi, Ph.D., a postdoctoral researcher in the Division of Endocrinology and Metabolism at the University of California, San Diego.

To understand insulin resistance, the Salk scientists turned to their knowledge of what happens when animals fast, since the two states have many features in common. When our bodies go without food we begin to break up fat and use it as an alternative energy source while the body's preferred choice, glucose, is off the menu. This process, known as lipolysis, is tightly regulated; when we eat again the resulting insulin switches lipolysis back off in favor of using sugar as fuel.

"Fasting in many ways therefore resembles what an insulin resistant state is about," explains Montminy, "increased production of glucose in the liver, decreased glucose uptake in muscle, increased lipolysis in the fat cells and no production of insulin." Where normal fasting and diabetes differ however is that lipolysis in patients with insulin resistance goes unchecked.

Previous work by Montminy and colleagues uncovered a protein known as CREB that orchestrates the body's response to fasting. When blood glucose levels run low, CREB revs up glucose production in the liver to maintain the brain's energy supply. But just as the scientists' model had predicted, CREB is also activated in the fat tissue of insulin-resistant, obese mice.

To test whether getting rid of CREB specifically in the fat might prove beneficial, postdoctoral researcher and co-first author Ling Qi, Ph.D., created mice that secrete a synthetic protein known as ACREB in mature fat cells. ACREB sticks to CREB with a high affinity, soaking it up and preventing it from binding to DNA and switching on its target genes.

At first glance the mice containing ACREB in their fat cells appeared normal. But when the scientists fed these mice a high fat, junk food-like diet they observed something remarkable. Although they became obese, gluttonous ACREB mice did not display the symptoms of diabetes such a feeding frenzy would usually cause. "Simply blocking CREB's activity improved insulin sensitivity and reduced inflammation in the obese animals," observed Qi.

And the good news didn't stop there. Even more intriguing was what happened in other tissues when CREB was turned off in adipose fat tissue. Not only did the obese ACREB mice maintain the ability to sense insulin in fat, this beneficial effect spread to the muscle and liver.

Such inter-tissue communication suggested a role for CREB in the secretion of hormones, which can travel freely through the body. One such fat-derived hormone is adiponectin, which is known to increase tissues' responsiveness to the effects of insulin. And indeed, adiponectin levels were elevated in ACREB mice, possibly explaining the mice's improved insulin sensitivity.

The scientists are now testing whether disrupting other proteins that act alongside CREB to switch on genes in the fat will have the same effect. Finding one that is specific to fat cells might allow therapies that could mimic the effect seen in the ACREB mice with out disrupting CREB's key functions in other tissues. In the meantime, high CREB activity in fat tissue may prove a valuable early indicator of a pre-diabetic state.

Gina Kirchweger | EurekAlert!
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