Scientists who are studying mice with a mutation that makes them resistant to obesity even in the face of a high-fat diet may have identified a new way to treat both obesity and diabetes.

Carrying extra weight is known to trigger a state of chronic, low-grade inflammation in the body, which can lead to insulin resistance and, in turn, diabetes.  When scientists at the University of Michigan discovered that an inflammatory protein called IKKε seemed to be a key step in this pathway, they theorized that they could protect mice fed a high-fat diet from developing signs of diabetes by genetically engineering them to lack the protein.

Much to the researchers’ surprise, IKKε knockout mice were spared from not only from chronic inflammation and insulin resistance⎯they also stayed relatively slim even when fed a lard-like chow with 45% of its calories from fat. After three months on this diet, normal mice gained 20 grams, while the IKKε-deficient mice gained only 12 grams.

“We’ve studied other genes associated with obesity … but this is the first one we’ve found that, when deleted, stops the animal from gaining weight.  The fact that you can disrupt all the effects of a high-fat diet by deleting this one gene in mice is pretty interesting and surprising,” said the study’s senior author, Alan Saltiel, in a statement.

The results were published this week in the journal Cell.

Saltiel’s lab is already working to find drugs that inhibit IKKε and could someday be used to prevent obesity and diabetes in humans.  He estimates that new treatments could be available in about a decade, once successful candidate compounds are identified.

But finding a compound that inhibits IKKε isn’t the only obstacle on the road from the lab to the pharmacy.  Researchers will also need to confirm that IKKe works in humans the same way it does in mice.

Then there’s the issue of safety.  Mice lacking the IKKe gene were protected from obesity and related complications, but they were more susceptible to lethal viral infections than their normal littermates⎯a complication that would need to be carefully evaluated before any attempt to reduce IKKε activity is undertaken in humans.

Image: George Shuklin

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Even the safest drugs can be dangerous for some people.

Acetaminophen (Tylenol®), for example, is responsible for more than a third of the approximately 2000 cases of acute liver failure that occur each year in the United States.  An estimated 10% of the patients experiencing liver failure due to acetaminophen were taking the recommended dose.  Even among people who do not have liver failure in response to acetaminophen, about a third show temporarily increased liver enzyme levels, a sign of toxicity.

A team of researchers led by David Threadgill at North Carolina State University has used a two-stage approach, which starts in mice and then moves to humans, to investigate whether genetics play a part in determining who will suffer from acetaminophen liver toxicity.  Their results, published online this week in the journal Genome Research, suggest that variations in the immune system may be important.

The researchers fed acetaminophen to several genetically distinct strains of mice and found that some had elevated levels of a liver enzyme called ALT, while others were unaffected.  Genetic mapping in these mice revealed several variations that could be responsible for these differences.

The researchers then looked at equivalent variations in human volunteers taking acetaminophen for seven days.  They found an association between SNP rs1467558 in the CD44 gene and ALT levels: having one copy of a T and one copy of a C led to higher ALT levels than having two Cs.

(23andMe customers can check their data for rs1467558 using the Browse Raw Data feature.)

“One of the fascinating things that came out of this study was that the genetic variation in acetaminophen toxicity is not what all the toxicologists would have predicted in the first place.  CD44 doesn’t have anything to do with the rate of metabolism of the drug, but it does have something to do with the immune system,” said Ken Paigen, an executive research fellow at the Jackson Laboratory and a study co-author, in a statement.

There are limits on the interpretation of this study, however. The one person out of the 121 studied who had two Ts at rs1467558 actually had lower ALT levels after taking acetaminophen than people with either CT or CC at this SNP.  This person could be just an anomaly, but more research on this rare genotype will be needed.  Also, the researchers measured only modest elevations in ALT levels in response to normal doses of acetaminophen. Additional studies will be needed to understand if genetic predisposition to these small increases can predict which individuals are more susceptible to the more severe toxicity seen in overdose situations.

According to Threadgill, the success of his two-stage approach has broad implications for drug testing in general.  Genetic variations in humans have not traditionally been taken into account during pre-clinical drug testing in animals.

“If genetic differences are included in early safety testing, more accurate predictions of clinical response will be obtained.  The end result will be safer drugs,” Threadgill said in a statement.

• 23andMe customers can help us learn more about how genes affect drug response by taking the survey Commonly Used Medications Survey.

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