New study reveals a missing step in a weight control pathway that could be targeted for obesity treatment

Popular GLP-1 drugs for weight loss, like Wegovy and Zepbound, offer those who are trying to lose weight an incredible new tool. However, they aren’t without side effects, like a loss of muscle mass, which can be especially concerning for older adults.

Researchers are still investigating other pathways toward therapeutics that could be just as effective with less muscle wasting.

New research led by Liangyou Rui, Ph.D., of the Department of Molecular & 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 driven by special brain cells called POMC neurons.

“POMC neurons release POMC-derived peptide, and then the downstream neurons express the receptor for this peptide. This circuit has been well established to control the body weight and metabolism,” said Rui, who is also a member of U-M’s Elisabeth Weiser Caswell Diabetes Center.

While there’s been much focus on the POMC protein as a driver of this appetite regulating circuit, Rui’s team took a step back and wondered what, if any, role changes to RNA affect the production of POMC protein.

“We found that the POMC RNA is heavily modified chemically, in a process called m6A modification,” explained Rui. The modification is done by enzymes that write and ultimately determine the fate of the RNA, whether it’s stabilized, shortened or destroyed.

“There's a lot of study of this type of RNA modification in the cancer field. These m6A writers, erasers and readers are regulatory systems used by the cells, especially in cancer cells. But there hasn’t been much study of this process in neurons driving obesity.”

To more closely study the roles of these m6A writers and readers, the team developed mice that lack the POMC RNA modifying enzymes or m6A readers and found that they developed insatiable hunger, obesity, glucose intolerance, insulin resistance, and fatty liver disease.

Conversely, overexpressing these proteins in POMC neurons protects against diet-induced obesity.

The different proteins controlling RNA modification and fate help maintain a balance in appetite and body weight and perhaps obesity is a signal of an imbalance of one of these readers.

Their findings were recently published in Nature Communications.

Further research could uncover ways to use this newly discovered modifying step to target POMC neurons for weight control.

Continued financial support for discovery science is critical for understanding the causes of obesity and other diseases.

"Basic science like this study is important to provide targets for potential treatments. If we don’t know about them, how can we target them?”

Additional authors: Yuan Li, Min-Hyun Kim, Decheng Ren

Funding/disclosures: This study 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 safeguard energy balance, body weight, and metabolism,” Nature Communications. DOI: 10.1038/s41467-026-71672-w

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