Although overeating might seem like a problem that begins in the stomach, appetite is largely regulated by the brain. Scientists still do not fully understand how dietary fat interacts with the neural systems that control hunger, food intake, and body weight.

A Brain Protein Linked to Appetite Control

To investigate this connection, a research team led by Professor Shigenobu Matsumura of Osaka Metropolitan University's Graduate School of Human Life and Ecology focused on optic atrophy 1 (OPA1). This mitochondrial fusion protein is found in hypothalamic MC4R neurons and plays a role in maintaining mitochondrial function and energy metabolism.

The researchers compared wild-type mice with mice in which OPA1 had been specifically removed from MC4R neurons. To explore how the protein influences appetite and body weight, the animals were given free access to soybean oil as a source of dietary fat.

Dietary Fat Produced Different Effects in Males and Females

The results showed that soybean oil increased OPA1 expression in male wild-type mice, but the same increase was not seen in females. Mice that lacked OPA1 ate more food, gained more weight as they aged, and eventually developed obesity.

When the animals could freely choose between standard chow and soybean oil, the OPA1-deficient mice consumed more fat and gained additional weight. These effects were especially strong in females.

Obesity Drug Response Also Varied by Sex

The researchers also tested setmelanotide, an anti-obesity MC4R agonist. The drug successfully reduced appetite in both control males and OPA1-deficient males. In OPA1-deficient females, however, its ability to suppress appetite was significantly weaker.

"Our findings provide key insights into the mechanisms underlying obesity from the perspective of neuronal energy metabolism," said Professor 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 findings were published in the FASEB Journal.