Mice chow down on a high-fat diet without becoming fat

Not getting fat or developing diabetes while still enjoying a high-fat diet is the dream of many a fast-food fan. Although such dreams remain just that for us humans, they’ve become reality for mice involved in a study at Washington University School of Medicine in St. Louis. The activation of a protein pathway in fat cells in the mice allowed the animals to be fed a high-fat diet without becoming obese.

The research conducted by a team led by senior investigator Fanxin Long, PhD focused on what’s known as the Hedgehog signaling pathway. Not restricted to its spiny namesake, this signaling pathway, which is a key regulator of animal development, is present in all bilaterians (or animals that are bilaterally symmetrical – which is most animals, including humans). It has also been shown to play a role in inhibiting the development of adipose tissue, or fat.

To explore if Hedgehog signaling also has an effect on diet-induced obesity after birth, Long and his team genetically engineered mice so that the Hedgehog pathway in fat cells would activate when they ate a high-fat diet. Over an eight-week period, a control group of mice fed a high-fat diet predictably became obese, but the mice whose Hedgehog pathway had been activated didn’t gain any more weight than another control group fed on a normal diet.

“More importantly, when we did metabolic studies, we found that the animals with the active Hedgehog pathway not only were leaner, they also had lower blood-glucose levels and were more sensitive to insulin,” says Long.

Rather than preventing the mice developing more fat cells, keeping the weight off was due to the activation of the signaling pathway stopping the existing fat cells get bigger.

“Fat gain is due mainly to increased fat cell size,” explains Long. “Each fat cell grows bigger so that it can hold larger fat droplets. We gain weight mainly because fat cells get bigger, as opposed to having more fat cells.”

Long says it may be difficult to translate the findings to humans despite the belief that the pathway works in a similar way in mice and humans. This is due to malfunctioning of the Hedgehog pathway being linked to various diseases, such as basal cell carcinoma. So, the difficulty lies in targeting the pathway without causing unwanted side effects. However, Long is still hopeful the research could lead to a new therapeutic target to treat obesity.

“If we can come up with strategies to carefully target fat cells, then I think activating this pathway could be effective in the fight against obesity,” he says.

The team’s research is published in the journal eLife.

Source: Washington University School of Medicine in St. Louis

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