Fighting obesity by controlling inflammation

Last summer, a research team led by the University of California at San Diego published compelling evidence that a 30-year-old asthma drug called amlexanox could be effective at fighting Type 2 diabetes and obesity. Now they believe they’ve figured out why the drug helps burn calories—and it all ties into inflammation.

The team pegged the enzyme TANK-binding kinase 1 (TBK1) as an important player in controlling how calories are burned in obesity and during fasting. Amlexanox inhibits TBK1, which may enhance the ability to burn fat, they believe. They described their findings in the journal Cell.

The researchers discovered two feedback loops involving TBK1. The first causes inflammation by activating certain genes, including the one that produces TBK1. That, in turn, inhibits another enzyme called AMPK, thereby impeding the burning of calories and causing fat to be stored. But then TBK1 switches roles and inhibits the gene pathway that initially ramped up its production—a second feedback loop that causes inflammation to increase.

During fasting, AMPK senses changes in energy levels and instructs fat cells to burn fat so they can make up for the energy loss, the researchers said in a statement. Problem is, fasting activates TBK1, which then makes it more difficult for the body to burn fat.

“We know that diets alone don't work and this is why,” said Alan Saltiel, Ph.D., director of the UC San Diego Institute for Diabetes and Metabolic Health, in the statement. "This is nature's way of ensuring that you survive if a famine comes."

Saltiel and his team believe their latest research helps explain why amlexanox produced such promising results in last year’s study, which involved 21 people with obesity and Type 2 diabetes. About one-third of the participants responded well to the drug. Samples of fat cells that had been taken before the study showed increased inflammation in those responders—a sign, the researchers believed, that inflammation predisposes obese people to lose weight while taking the anti-inflammatory compound.

Inflammation was also the central theme of a separate study published earlier this week by researchers at Johns Hopkins University. They found that bacterial, fungal and viral genes in the intestines of mice affect Toll-like receptor 4 (TLR4), a protein that’s involved in inflammation signaling. They published their findings in the journal Mucosal Immunology.

The Johns Hopkins team compared normal mice to those engineered to lack TLR4 in three different types of cells. Mice without the protein in cells of their intestines had symptoms of metabolic syndrome, including obesity and insulin resistance. When they fed all the mice a high-fat diet, they observed an increase in belly fat among the animals lacking TLR4 in intestinal cells.

They then gave those mice antibiotics, which prevented metabolic syndrome, they said. They believe manipulating gut bacteria may be a promising approach to fighting obesity and other symptoms of metabolic syndrome.

So what does all this new insight into the link between inflammation and obesity portend for drug development in this field? UCSD’s Saltiel believes that further studies elucidating the role of inflammation—and proteins that affect it—in obesity and related disorders. TBK1 "is probably not the only pathway accounting for energy expenditure in fasting or obesity,” he says, “but this information provides new insight into how we might develop drugs that inhibit TBK1 or other enzymes involved in metabolism."