OPA1 Protein May Influence Fat Intake and Weight Gain in Mice

As health conditions associated with poor diets and obesity become increasingly common, scientists are seeking to pinpoint the biological processes that drive a taste for fatty foods - and identify possible ways to reduce it.

If researchers can identify the brain cells and neural routes that make people more likely to overeat or choose unhealthy food, even while understanding the harm it may cause, they may also be able 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.

Published in the FASEB Journal, the study highlights optic atrophy-1 (OPA1) as a protein deserving further examination. OPA1 supports the proper functioning of mitochondria, the energy-producing structures within cells, 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.

OPA1 and MC4R neurons in appetite control

Building on earlier animal research connecting OPA1 loss with obesity, the researchers examined OPA1 within appetite-related neurons that carry the melanocortin 4 receptor (MC4R) protein.

Neurons containing MC4R have an essential function in the hypothalamus, a brain region that largely regulates the body's energy management, or metabolism, as well as hunger and appetite. These cells signal both when we should eat and when energy should be burned.

Compared with control mice, mice genetically modified to lack OPA1 in their MC4R neurons showed a markedly stronger preference for fat in their diet and put on weight more rapidly. These effects were greater in female mice than in males.

The mice eventually became obese, although this development took several weeks. This suggests that OPA1 could become more significant with age, while recognising that mice live for 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 findings provide strong evidence that absent or dysfunctional OPA1 makes these appetite-regulating neurons less efficient. This appears to result from reduced mitochondria-derived energy, which OPA1 normally helps maintain.

OPA1 loss affects treatment response in female mice

There are important subtleties in the results. By reactivating MC4R signalling with an anti-obesity medicine, the team showed that losing OPA1 did not completely disrupt MC4R messaging.

The medicine produced the anticipated effect in male mice regardless of their OPA1 status. In females, however, OPA1 loss weakened the medicine's capacity to curb food intake. This indicates that the sex-based differences observed across the study also apply to 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.

Naturally, this research was conducted solely in mouse models, so the same mechanisms and pathways cannot be assumed to operate in the human brain. Nevertheless, decades of research using mice as models for humans suggest that this is plausible.

What the findings could mean for obesity

Should the results be reproduced in humans, they could relate directly to the choices made when buying food or deciding where to eat. In some circumstances, unhealthy decisions and their consequences may partly be influenced by the OPA1 protein and whether it is functioning at full capacity.

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

In the longer term, approaches that address the minute energy shortfalls in these particular neurons may offer another route for treating overeating and obesity. Clearly, however, these conditions involve numerous overlapping 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 by Fiona MacDonald 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.