Study reveals key role of opsin 3 in regulating food intake and energy balance

Scientists discovered years ago that the hypothalamus - which helps to manage body temperature, hunger, sex drive, sleep and more - includes neurons that express the protein opsin 3 (OPN3). Far less clear, however, was what this light-sensing protein does so deep inside the brain.

A study published in PNAS suggests that OPN3 plays an important role in regulating food consumption. 

Our results uncover a mechanism by which the nonvisual opsin receptor OPN3 modulates food intake via the melanocortin 4 receptor MC4R, which is crucial for regulating energy balance and feeding behavior. This finding is interesting because loss-of-function mutations in MC4R are a known genetic cause of obesity in humans."

Elena Oancea, professor of medical science, Carney Institute for Brain Science, Brown University

The study was led by Hala Haddad, who conducted the research while a Ph.D. student and then postdoctoral research associate at Brown, with senior authors Oancea and Richard Lang, director of the Visual Systems Group at Cincinnati Children's.

The research team reported that OPN3 functions together with MC4R and the Kir7.1 potassium channel to regulate certain cell signals as well as neuronal firing in a key area that controls energy balance. Notably, when mice were engineered to lack OPN3 in this part of the hypothalamus, they ate significantly less and were less active than control mice. 

"We're very excited to have, for the first time, a cellular mechanism of what OPN3 is doing in the brain," Oancea said.

Opsin 3 has been the focus of research in Oancea's lab for almost a decade, and the team has discovered that it is present in melanocytes, where it functions in pigmentation, and has developed a mouse model to identify the specific brain regions where this protein is expressed. Researchers in Lang's lab have also been studying OPN3 in fat tissue and in the brain, primarily using mouse genetics tools. The two research teams started collaborating around 2020. 

While their findings add an important insight into the function of OPN3, the researchers said more study is necessary to address whether the mechanism also performs in similar ways in the human brain. 

"While we identified the mechanism and function of OPN3 in this region of the hypothalamus, how this receptor works in other areas of the brain remains elusive," Oancea said. "There must be a common paradigm for OPN3 function in different areas, and we're still looking for that." 

Moreover, "the current analysis does not resolve the question of whether OPN3 can function as a light sensor in the mouse brain," Lang said. "That remains to be addressed in future studies." 

The regulation of eating behavior and body weight is extremely complex, Oancea said. 

"Figuring out how to address these complex issues requires a broader understanding of the cellular processes involved," she said.

This study was supported by the Brown University Imaging Facility and Microscopy Core, and the Transgenic Animal and Genome Editing Core at Cincinnati Children's. Funding for the research came from the National Institutes of Health (R01AR076241, R01EY027077, R01EY032029, R01EY032752, R01EY032566 and R01EY034456) and the National Science Foundation, among other sources.