OPA1 Protein May Influence Fat Intake and Weight Gain in Mice

Poor diet and obesity-related health issues are becoming increasingly common, prompting researchers to search for the precise biological processes that drive a preference for fatty foods - and for possible ways to reduce that preference.

Identifying the brain cells and neural routes that make people more likely to overeat or choose unhealthy food, even when they understand the risks, could ultimately make it possible to steer those systems in a healthier direction.

A research team led by Osaka Metropolitan University in Japan has now shown that one neural protein can substantially influence fat consumption and weight gain in mice.

OPA1 protein, fat intake and weight gain

Published in the FASEB Journal, the study highlights optic atrophy-1 (OPA1) as a protein deserving further investigation. OPA1 helps mitochondria - the structures that provide cells with energy - function properly, and its absence alters eating behaviour.

"Our findings provide key insights into the mechanisms underlying obesity from the perspective of neuronal energy metabolism," says nutritionist Shigenobu Matsumura, from Osaka Metropolitan University.

The scientists set out to build on earlier animal research associating the absence of OPA1 with obesity. Their focus this time was OPA1 within appetite-related neurons that contain the melanocortin 4 receptor (MC4R) protein.

MC4R-containing neurons have an important function in the hypothalamus, a brain region that plays a major part in regulating the body's energy use, or metabolism, as well as appetite and hunger. These cells signal both when we should eat and when energy should be burned.

Compared with control mice, genetically modified mice without OPA1 in their MC4R neurons showed a markedly stronger preference for dietary fat and put on weight more rapidly. The effect was greater in female mice than in male mice.

How OPA1 affects MC4R neurons

The mice eventually became obese, although it took several weeks for this to develop. This suggests OPA1 may become increasingly significant with age, while recognising that mice have lifespans measured in months rather than years.

"This study provides new insight into how mitochondrial function in the hypothalamus is linked to energy metabolism under conditions of dietary fat intake," write the researchers.

Taken together, the results provide strong evidence that absent or dysfunctional OPA1 makes these appetite-regulating neurons work less efficiently. This appears to result from lower mitochondria-derived energy, which OPA1 normally helps to maintain.

There are important qualifications to the findings. By using an anti-obesity medicine to reactivate MC4R signalling, the researchers showed that OPA1 loss did not completely disrupt MC4R communication.

The medicine produced the expected response in male mice irrespective of their OPA1 status. In females, however, the loss of OPA1 weakened the medicine's capacity to curb food intake. This indicates that the sex differences observed across the study may also affect how mice respond to treatment.

"Pharmacological activation of MC4R suppressed food intake under baseline-matched conditions, indicating that MC4R signaling is not abolished," write the researchers.

Implications for obesity treatment

Naturally, this work was carried out solely in mouse models, meaning the same mechanisms and pathways may not necessarily operate in the human brain. However, decades of research using mice as models for humans suggest that this is plausible.

Should the findings be reproduced in people, they could relate directly to choices made while buying food or deciding where to dine out. In some instances, unhealthy decisions and their effects could partly depend on the OPA1 protein and whether it is functioning at full capacity.

Obesity is known to be a major public-health concern, raising the likelihood of further complications involving heart disease, diabetes, osteoarthritis and more.

In the future, methods for addressing these minute energy failures in particular neurons may offer another route for treatments targeting overeating and obesity. Clearly, though, both conditions involve numerous interacting causes and triggers.

"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," says Matsumura.

The research has been published in the FASEB Journal.

This article was fact-checked and edited by Fiona MacDonald. Although we take pride in our process, we are only human. If you notice an error, please let us know.