Mitochondrial protein deficiency drives increased fat intake and obesity

Obesity is a global health concern that can contribute to diabetes, cardiovascular disease, and other metabolic disorders. Though there are many health conditions that can lead to it, an increasingly worrying cause is right on the grocery shelf, high-fat foods. These foods are known to be hard to resist and can promote overeating. For many, this can be mistaken as a stomach problem, but research has found appetite to be neurologically based. Despite this, the neural mechanisms linking the regulation of appetite and body weight to dietary fat intake remain unclear.

Building on this food for thought, a research group, led by Professor Shigenobu Matsumura from Osaka Metropolitan University's Graduate School of Human Life and Ecology, investigated the role of optic atrophy-1 (OPA1), a mitochondrial fusion protein found in the hypothalamic MC4R neurons that help maintain mitochondrial function and energy metabolism. Using wild type and MC4R neuron-specific OPA1 knockout mice, the team examined OPA1 regulatory effects on appetite control and body weight through the free feeding of soybean oil as a dietary fat source.

The researchers found that soybean oil increased OPA1 expression in male wild-type mice but not in females. The mice lacking OPA1 showed increased food intake, age-related weight gain, and the development of obesity. When given free access to both standard chow and soybean oil, the mice consumed more fat and gained weight, with the effects being particularly pronounced in females.

The team also examined the effects of setmelanotide, an anti-obesity MC4R agonist. While the drug effectively suppressed appetite in both the control and OPA1-deficient male mice, its appetite-suppressing effect was significantly reduced in OPA1-deficient females.

Our findings provide key insights into the mechanisms underlying obesity from the perspective of neuronal energy metabolism. 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."

Professor Shigenobu Matsumura, Osaka Metropolitan University's Graduate School of Human Life and Ecology

The findings were published in the FASEB Journal.