Popular GLP-1 drugs for weight loss, such as Wegovy and Zepbound, offer an incredible new tool to those trying to lose weight. However, they are not without side effects, such as loss of muscle mass, which can be especially worrisome for older adults.
Researchers are still investigating other avenues toward therapeutics that may be effective with less muscle wasting.
New research led by Liangyu Rui, PhD, of the Department of Molecular and Integrative Physiology at the University of Michigan Medical School, outlines a missing step in one of these alternative pathways, an important discovery in the fight against obesity.
The pathway, known as the central melanocortin circuit that regulates energy homeostasis, is controlled by specialized brain cells known as POMC neurons.
“POMC neurons release POMC-derived peptides, and then downstream neurons express receptors for these peptides. This circuit is well established for regulating body weight and metabolism,” said Rui, who is also a member of UM’s Elisabeth Weiser Caswell Diabetes Center.
While much of the focus has been on the POMC protein as a driver of this appetite-regulating circuit, Rui’s team took a step back and wondered what role changes in RNA affect the production of the POMC protein.
“We found that POMC RNA is extensively chemically modified, in a process called m6A modification,” explains Rui. The modification is carried out by enzymes that dictate the fate of the RNA and ultimately determine whether it is stable, shortened or destroyed.
“There are many studies of this type of RNA modification in cancer. These m6A writers, erasers and readers are regulatory systems used by cells, especially cancer cells. But this process has not been studied much in neurons that drive obesity.”
To study the role of these m6A writers and readers more closely, the team created mice that lacked the POMC RNA modifying enzyme, or m6A reader, and found that they developed insatiable appetite, obesity, glucose intolerance, insulin resistance, and fatty liver disease.
Conversely, overexpressing these proteins in POMC neurons protects against diet-induced obesity.
Different proteins regulating RNA modification and fate help balance appetite and body weight, and perhaps obesity is a signal of imbalance in one of these readers.
Their results were recently published Nature communication.
Further research may uncover ways to use this newly discovered modulating action to target POMC neurons for weight control.
Continued funding is critical for discovery science to understand the causes of obesity and other diseases.
“Basic science like this study is critical to providing potential treatment targets. How can we target them if we don’t know about them?”
Additional authors: Yuan Lee, Min-Hyun Kim, Decheng Ren
Funding/Disclosure: This research was supported by grants R01 DK114220, R01 DK130111, and R01 DK141559 (LR) from the National Institutes of Health and 20POST35210557 (YL) from the American Heart Association.
Paper cited: “POMC Neuron METTL14/m6A/YTHDC1/YTHDF2 Pathways Protect Energy Balance, Body Weight, and Metabolism” Communicate with nature. DOI: 10.1038/s41467-026-71672-w
Sign up for the Health Lab newsletter today. Get medical advice from top experts and learn about new scientific discoveries every week.
Sign up for the Health Lab Podcast. Add us wherever you listen to your favorite shows.
–
Previously published Also at michiganmedicine.org Creative Commons License
***
–
The world is changing fast. We help keep you.
We will send you 1 post, 3 times per week
All premium members can watch The Good Men Project without any ads. Need more information? A full list of benefits is here.
–
Photo credit: splash
