MECHANISMS used to slow metabolism in obese bodies and during dieting have been uncovered by researchers from the University of California San Diego, California, USA, increasing understanding of why it can be difficult for obese people to lose weight. The study has therefore identified a potential drug development pathway to treat people with conditions linked to obesity, such as Type 2 diabetes.
Two Feedback Loops
The team discovered that two feedback loops involving the TBK1 enzyme help reduce energy expenditure in obesity. In the first, obesity-triggered chronic stress causes inflammation through the activation of the NF-κB pathway, which induces genes including TBK1 that are linked with inflammation and obesity. The activated TBK1 gene reduces the ability of a cell to burn calories by shutting down AMPK, a master regulator of energy expenditure. The AMPK enzyme is therefore prevented from instructing cells to burn fat as an energy resource during fasting.
In the second feedback loop, inflammation was shown to be reduced by TBK1, which in turn inhibits NF-κB. While in obese mice the researchers observed that deleting TBK1 caused both weight loss and increased inflammation, there was no change in normal mice, explaining how inflammation might be reduced by restricting calories. The findings show that treatments inhibiting TBK1 could potentially help patients with conditions like Type 2 diabetes and fatty liver disease.
“Inhibiting TBK1 has the potential to restore energy balance in states of obesity by enhancing the ability to burn some fat,” explained Dr Alan Saltiel, University of California San Diego. “This is probably not the only pathway accounting for energy expenditure in fasting or obesity, but this information provides new insight into how we might develop drugs that inhibit TBK1 or other enzymes involved in metabolism.”
The team believe that a drug called amlexanox could be used for this purpose. Previous studies have shown its effectiveness in reducing blood glucose levels in Type 2 diabetes patients, and in leading to weight loss and increased insulin sensitivity in obese mice. This new study has possibly revealed how these outcomes were met.
James Coker, Reporter
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