Genome tweak offsets high-fat diet in mice

A new finding could lead to ways to ward off the harmful effects of a high-fat diet.

Eating lots of fats increases the risk of metabolic disorders, but the mechanisms behind the problem have not been well understood. The new study appears in Nature Communications.

The study centers on a protein complex called AMPK, which senses the body’s nutrition and takes action to keep it balanced. For example, if AMPK detects that glucose is low, it can boost lipid breakdown to produce energy in its place. Scientists have known that consuming high amounts of fat blocks AMPK’s activity, leading the metabolism to go out of balance. However, until now, how cells block this mechanism has not been widely examined, especially in live models.

The biologists decided to investigate, believing an AMPK component called SAPS3 serves a significant role. They eliminated SAPS3 from the genome of a group of mice and fed them meals with a 45% fat content. The results even startled the research team.

“Removing the SAPS3-inhibiting component freed the AMPK in these mice to activate, allowing them to maintain a normal energy balance despite eating a large amount of fat,” says Mei Kong, professor of molecular biology and biochemistry at the University California, Irvine and the study’s corresponding author. “We were surprised by how well they maintained normal weight, avoiding obesity and development of diabetes.”

The discovery could eventually lead to a new way to approach metabolism-related conditions. “If we block this inhibition activity, we could help people reactivate their AMPK,” says first author Ying Yang, a project scientist in the Kong lab. “It could help in overcoming disorders such as obesity, diabetes, fatty liver disease, and others. It’s important to recognize how important normal metabolic function is for every aspect of the body.”

The researchers are working on developing molecules that could inhibit SAPS3 and restore the metabolism’s balance. They plan to next study SAPS3’s role in other conditions with disturbed metabolic systems, such as cancer and aging.

The discovery comes as metabolic-related diseases such as obesity and diabetes continue to rise. More than half of the global population is expected to be overweight or obese by 2035, compared to 38% in 2020, according to the World Obesity Federation. The number of people worldwide with diabetes is expected to rise to 578 million by 2030, up 25% from 2019, reports the National Center for Biotechnology Information.

Support for the project came from the National Institutes of Health and the American Cancer Society.

Source: UC Irvine

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