From Deep Inside the Brain, Opsin 3 Helps Regulate Food Intake In Mice

Research By: Richard Lang, PhD

Post Date: February 18, 2025 | Publish Date: Feb. 14, 2025

Researchers at Brown University and Cincinnati Children’s found that suppressing OPN3 in mice makes them eat less, raising new questions about the mechanisms involved in regulating human metabolism

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 Feb. 14, 2025, 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,” says Elena Oancea, PhD, a neuroscientist at Brown University and a senior author on the study. “This finding is interesting because loss-of-function mutations in MC4R are a known genetic cause of obesity in humans.”

Richard Lang, PhD, director of the Visual Systems Group at Cincinnati Children’s, also was a senior author on the new study.

The latest results expand upon years of research led by Lang to understand the surprising roles that light-sensing cells can play – not just within the eye, but also within tissues throughout the body that have no connection to vision. In 2020, Lang and colleagues published a breakthrough discovery in the journal Nature that another opsin found in the brain – OPN5 – responds to violet light wavelengths in ways that affect metabolism.

Oancea’s lab has focused on OPN3 for almost a decade, discovering that the protein is present in melanocytes, where it functions in pigmentation. The two labs have been collaborating since 2020.

“These two opsins can have differing functions depending on their locations. OPN5 has long been known to be involved in retinal development, and more recently has been shown to be active in the brain and in the regulation of fat cells,” Lang says. “Both appear active in regulating how the hypothalamus drives metabolic functions, yet they respond to different wavelengths of light. The interplay between these opsins is an exciting line of future study.”

The study in PNAS reports 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.

More research will be needed to determine whether the findings about how OPN3 functions in the mouse brain can be applied to influencing human eating behavior and body weight. Questions also remain about the extent of OPN3’s light sensing functions within the brain.

About the study

In addition to Lang, Cincinnati Children’s co-authors included Jonathan Mercado-Reyes, PhD, Shane D’Souza, PhD, and Shruti Vemaraju, PhD. Experts from Stanford University, and the Instituto Multidisciplinario de Biología Celular in Argentina also contributed.

This study was supported by the Transgenic Animal and Genome Editing Core at Cincinnati Children’s and the Brown University Imaging Facility and Microscopy Core. Funding sources included the National Institutes of Health (R01AR076241, R01EY027077, R01EY032029, R01EY032752, R01EY032566 and R01EY034456), the National Science Foundation, and the Goldman Chair of the Abrahamson Pediatric Eye Institute.

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Publication Information

Original title:	Hypothalamic opsin 3 suppresses MC4R signaling and potentiates Kir7.1 to promote food consumption
Published in:	PNAS
Publish date:	Feb. 14, 2025

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