Biologists find that removing a protein inhibitor restores metabolic balance.
UC Irvine biologists found that suppressing the SAPS3 component in mice allowed them to maintain a normal energy balance despite consuming a high-fat diet. This discovery could lead to treatments for obesity, diabetes and other metabolic disorders by targeting SAPS3 inhibition.
Eating a lot of fat increases the risk of metabolic disorders, but the mechanisms behind the problem have not been well understood. Now, University of California Irvine (UCI) biologists have made a key discovery on how to ward off the harmful effects caused by a high-fat diet. Their study was recently published in the scientific journal Nature Communication.
The UC Irvine research focused on a protein complex called AMPK, which senses the body’s nutrition and takes action to keep it balanced. For example, if AMPK senses that glucose is low, it can stimulate the breakdown of lipids to produce energy in its place. Scientists know that consuming large amounts of fat blocks the activity of AMPK, leading to an imbalance in metabolism. However, until now, how cells block this mechanism has not been widely studied, especially in living models.
UCI biologists decided to investigate, believing that an AMPK component called SAPS3 plays an important role. They eliminated SAPS3 from the genome of a group of mice and gave them meals containing 45% fat. The results were surprising even to the research team.
“Removing the inhibitory component of SAPS3 released AMPK in these mice to activate, allowing them to maintain normal energy balance despite consuming a large amount of fat,” said Mei Kong, Professor of Molecular Biology and Biochemistry and corresponding author of the study. “We were surprised at how well they maintained a normal weight, preventing obesity and the development of diabetes.”
The discovery could eventually lead to a new way of approaching conditions related to metabolism. “If we block this inhibition activity, we could help people reactivate their AMPK,” said first author Ying Yang, project scientist at Kong’s lab. “It could help overcome conditions such as obesity, diabetes, fatty liver disease and others. It is important to recognize how important normal metabolic function is to every aspect of the body.
Researchers are working on the development of molecules that could inhibit SAPS3 and restore metabolic balance. They plan to next investigate the role of SAPS3 in other conditions with disrupted metabolic systems, such as cancer and aging.
The finding comes as metabolism-related diseases such as obesity and diabetes continue to rise. According to the World Obesity Federation, more than half of the world’s population is expected to be overweight or obese by 2035, up from 38% in 2020. The number of people with diabetes worldwide is expected to reach 578 million by 2030, up 25% from 2019, reports the National Center for Biotechnology Information.
Reference: “The SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis during food challenge in male mice” by Ying Yang, Michael A. Reid, Eric A. Hanse , Haiqing Li, Yuanding Li, Bryan I. Ruiz, Qi Fan and Mei Kong, March 13, 2023, Nature Communication.
The project was supported by the National Institutes of Health and the American Cancer Society.