OPA1 neural protein loss drives high-fat overeating in mice, study finds

A Japanese research group has published findings from a mouse model study describing how the loss of a protein in the brain can impact weight gain by stimulating cravings that lead to overeating. Specifically, scientists looked at the role of a mitochondrial fusion protein called optic atrophy-1 (OPA1) in maintaining metabolic health. 

OPA1 is found in the brain’s Melanocortin 4 Receptor (MC4R) neurons in the hypothalamic region, which help modulate mitochondrial functions and energy metabolism. According to the study, its expression increased in response to mice fed a high-fat diet, pointing to its role in sustaining metabolic balance.

Exploring the neurological basis of appetite, Nutrition Insight speaks to lead study author Shigenobu Matsumura, Ph.D., from Osaka Metropolitan University’s Graduate School of Human Life and Ecology, to find out more about the findings’ relevance.

“That is our ongoing experiment,” he tells us. “I can’t show the results, but I can say that fat type is a critical factor determining OPA1 expression.”

Sex-specific findings

For this study, published in FASEB Journal, researchers compared eight to 12-week-old normal control mice and gene-edited mice lacking the OPA1 gene in specific appetite-regulating brain cells. The mice were allowed to free-feed on soybean oil as a dietary fat source.

These foods are known to be hard to resist for mice and can promote overeating, note the study authors. 

The researchers found that soybean oil increased OPA1 expression in control mice but not in females. Mice lacking OPA1 exhibited increased food intake, age-related weight gain, and signs of obesity.

“From the current data, we don’t know why OPA1 expression increased in response to soybean oil ingestion,” says Matsumura. “It might be possible that sex hormones, such as androgens or estrogens, affect or regulate OPA1 expression, causing this sex difference.”

“It may be more interesting if there is sex hormone-independent regulation of OPA1 expression in neuronal cells. Either way, the regulation of dietary fat intake or craving should be different between men and women. That is our new finding.”

Effects of obesity drug

Additionally, the team investigated the effects of setmelanotide, which is an anti-obesity MC4R agonist drug. After 24 hours of food deprivation, the mice received setmelanotide through an injection, dissolving 0.5 or 1 mg per kg. Control mice received an equivalent volume of saline.

Researchers then measured the food intake of mice in both groups at one, two, and four hours after injection. While the drug effectively suppressed appetite in the control and OPA1-deficient male mice, its appetite-suppressing effect was significantly reduced in OPA1-deficient females.

Because OPA1 deficiency reduced the appetite-suppressing effect of setmelanotide in female mice, Matsumula believes that MC4R-targeted drugs may require normal mitochondrial function in target cells (MC4R neurons). 

“Our findings provide key insights into the mechanisms underlying obesity from the perspective of neuronal energy metabolism,” says Matsumura.

“The sex differences observed in OPA1 responses and obesity susceptibility may help inform the development of obesity treatments that take them into account, as well as future personalized medicine approaches.”

The authors stress that obesity remains a global health threat that can lead to diabetes, cardiovascular disease, and various metabolic disorders. They note that high-fat foods are an increasingly prevalent driver of obesity, in addition to various health conditions.

In previous research on the impact of brain proteins on weight gain, scientists focused on K63 ubiquitin, a brain protein that increases with early obesity and aging, which they say can also impair memory in the hippocampus.