A recent study published in The FASEB Journal provides evidence that a specific mitochondrial protein in the brain helps regulate appetite and body weight in response to dietary fat intake. The study shows that a deficiency of this protein in a specific group of appetite-controlling neurons leads to increased fat intake and obesity in mice—an effect that is particularly pronounced in females.
“I think an important takeaway is that the brain responds not only to the amount of food consumed but also differently depending on the type of food eaten,” said Shigenobu Matsumura of the Department of Nutrition at Osaka Metropolitan University. “Our research suggests that mitochondria in a specific population of neurons—MC4R neurons—are important for controlling appetite for dietary fat and regulating body weight.”
The melanocortin-4 receptor (often abbreviated as MC4R) is a signaling protein located in the hypothalamus, a region of the brain that regulates hunger and energy balance. A 1997 study published in the journal Cell demonstrated that disrupting the MC4R pathway in mice leads to severe obesity and overeating. Building on this, a 2019 review in Trends in Molecular Medicine discussed the MC4R signaling pathway as a key target for treating obesity in humans.
Brain cells consume vast amounts of energy, making them heavily dependent on mitochondria—the energy-producing structures within cells. These structures constantly fuse and divide, adapting to metabolic demands. Optic atrophy 1 (OPA1) is a protein that regulates inner mitochondrial membrane fusion and maintains the organelle’s internal structure.
While the importance of MC4R and mitochondria in metabolism is well documented, the impact of dietary fats on these cellular processes remains incompletely understood. A 2022 review published in the International Journal of Molecular Sciences detailed how the hormone estrogen regulates mitochondrial fusion and fission, suggesting potential sex-based biological differences in responses to metabolic stress. This gap in knowledge prompted the current research team to investigate how OPA1 within MC4R neurons responds to fat intake and influences body weight in both sexes.
“We were interested in whether the type of food we consume affects neuronal energy metabolism and, if so, how significant this is for the regulation of appetite and body weight,” explained Matsumura.
The researchers first examined the effects of dietary fats on wild-type mice. Eight-week-old mice were given voluntary access to liquid soybean oil alongside their standard chow. After six weeks on this regimen, the scientists analyzed the animals’ brains.
The researchers found a 1.6-fold relative increase in OPA1 gene expression in the hypothalamus of male mice compared to males fed only the standard diet. No such increase in OPA1 expression was observed in female mice. Since brain cells typically use sugars as fuel, this lipid-driven genetic response was an unexpected finding. “The most surprising discovery was that dietary fat intake altered the expression of genes associated with neuronal mitochondria,” said Matsumura. “In general, neurons primarily use carbohydrates as an energy source, and one would expect mitochondrial activity to increase alongside rising fatty acid intake. Given this, we did not anticipate that increased fat consumption would affect mitochondrial gene expression in this manner.”
The team then genetically modified mice to lack the OPA1 protein specifically in neurons expressing MC4R. Over the course of several months, they monitored the body weight and food intake of these knockout mice alongside normal control mice. Using specialized metabolic chambers, they also measured the animals’ oxygen consumption, carbon dioxide output, and daily physical activity.
Even when fed a standard diet, OPA1 knockout mice of both sexes gradually became heavier than the control animals. Noticeable weight differences began to emerge at approximately 18–20 weeks of age. At this point, the knockout mice began consuming more food than the control animals, suggesting that OPA1 helps these neurons properly regulate appetite, even in the absence of high …high-calorie food.
Next, the researchers offered another group of eight-week-old mice the option to voluntarily consume soybean oil. Control mice showed relatively stable body weight trends while consuming the oil. In contrast, OPA1 knockout mice consumed more soybean oil and developed rapid, progressive obesity. This weight gain was particularly pronounced in female knockout mice. By 22 weeks of age, the average body weight of female knockout mice was nearly 50 grams, compared to approximately 35 grams for control females.
These findings alter researchers’ understanding of weight gain at the cellular level. “I think one of the interesting aspects of this study is the link between dietary fats, neuronal energy metabolism, and appetite regulation,” noted Matsumura. “Obesity is often discussed primarily in terms of the amount of food consumed, but our results show that the energy metabolism of specific neurons can also influence how strongly the brain responds to dietary fats.”
To determine whether the MC4R signaling pathway was completely disrupted in these genetically modified mice, the researchers administered setmelanotide, a drug that activates MC4R. After a 24-hour fast, they administered either a placebo or the drug to groups of six to seven mice and measured food intake. In control mice and male knockout mice, the drug successfully suppressed food intake over the subsequent four hours.
In female knockout mice, however, the appetite-suppressing effect of setmelanotide was diminished. This indicates that the loss of OPA1 disrupts MC4R signaling metabolic processes more severely in females, rather than simply completely disabling the receptor. The researchers also measured gene expression and found that male mice consuming soybean oil exhibited coordinated changes in genes related to appetite. Female mice showed far less consistent genetic responses to fat intake.
“Interestingly, we found clear sex-based differences, suggesting that the mechanisms regulating dietary fat intake may differ between males and females,” added Matsumura. “Furthermore, the sex differences we observed could be important for understanding why the mechanisms underlying obesity may vary between men and women.”
Mouse models of metabolism do not perfectly replicate human metabolic disorders, meaning these mechanisms require further validation. The study used hypothalamic tissue analysis to measure gene expression, an approach that might mask subtle changes occurring within specific cell types.
“The most important point is that these results were obtained in mice, so we do not yet know if the same mechanism operates in humans,” said Matsumura. “We also used soybean oil as the source of dietary fat, and it remains to be determined whether different types of dietary fats have the same effect. Additionally, we do not yet fully understand the mechanism responsible for the sex differences.”
Further research is needed to isolate these specific neurons and gain a precise understanding of their internal functioning. “We would like to understand how dietary fats regulate OPA1 and mitochondrial function in MC4R neurons, and why this regulation differs between males and females,” explained Matsumura. “We are also interested in whether different types of dietary fats trigger different responses.” Ultimately, we hope to determine whether this mechanism is relevant to human obesity and whether mitochondrial function can help explain differences in response to MC4R-targeted obesity treatments.
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