Mitochondrial Protein OPA1 Deficiency Drives Sex-Specific Fat Intake and Obesity, Study Finds
Key Insights
Researchers at Osaka Metropolitan University found that the mitochondrial fusion protein OPA1 (search) in hypothalamic MC4R (search) neurons regulates appetite and body weight in a sex-dependent manner.
Mice lacking OPA1 (search) consumed more food, gained more weight with age, and preferentially consumed more dietary fat, with effects especially pronounced in females.
The anti-obesity (search) MC4R (search) agonist setmelanotide suppressed appetite in males but showed significantly weaker appetite-suppressing effects in OPA1 (search)-deficient females.
A research team led by Professor Shigenobu Matsumura of Osaka Metropolitan University's Graduate School of Human Life and Ecology has identified a sex-specific role for the mitochondrial fusion protein optic atrophy 1 (OPA1 (search)) in regulating appetite, fat intake, and body weight. The findings, published in the FASEB Journal, shed new light on how dietary fat interacts with neural systems controlling hunger and may help guide the development of sex-aware obesity (search) treatments.
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. To investigate this connection, the researchers focused on OPA1 (search), a mitochondrial fusion protein found in hypothalamic MC4R (search) neurons that plays a role in maintaining mitochondrial function and energy metabolism.
The team compared wild-type mice with mice in which OPA1 (search) had been specifically removed from MC4R (search) 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 (search) 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 (search).
When the animals could freely choose between standard chow and soybean oil, the OPA1 (search)-deficient mice consumed more fat and gained additional weight. These effects were especially strong in females.
Obesity (search) Drug Response Also Varied by Sex
The researchers also tested setmelanotide, an anti-obesity (search) MC4R (search) agonist. The drug successfully reduced appetite in both control males and OPA1 (search)-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 (search) from the perspective of neuronal energy metabolism," said Professor Matsumura. "The sex differences observed in OPA1 (search) 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 study underscores the neurological basis of appetite regulation and highlights how mitochondrial function within MC4R (search) neurons may represent a previously underappreciated link between dietary fat and obesity (search). By demonstrating that both OPA1 (search) responses and the efficacy of an MC4R-targeting therapy differ by sex, the work points toward a need for treatment strategies that account for biological sex in addressing obesity and related metabolic disorders.