Amid the rising prevalence of health issues linked to poor diet and obesity, researchers are investigating the specific biological mechanisms underlying the preference for fatty foods, as well as potential ways to reduce their consumption.
If we can identify the brain cells and neural connections responsible for increasing the likelihood of overeating or preferring unhealthy foods—even when we know they are bad for us—we might then be able to modulate their activity.
Now, researchers at Osaka Metropolitan University in Japan have discovered that a specific neuronal protein can significantly influence fat intake and weight gain in mice.
A study published in the FASEB Journal identified Optic Atrophy 1 (OPA1) as a protein worthy of further investigation. This protein is responsible for the proper functioning of mitochondria, and its absence alters eating habits.
“Our findings provide important insights into the mechanisms underlying obesity from the perspective of neuronal energy metabolism,” says Shigenobu Matsumura of Osaka Metropolitan University.
The researchers sought to build on previous studies linking OPA1 deficiency to obesity in animals; this time, they focused on OPA1 within appetite-regulating neurons that express the melanocortin-4 receptor (MC4R).
MC4R-expressing neurons play a crucial role in the hypothalamus, a region largely responsible for regulating the body’s energy metabolism, as well as appetite and hunger. These neurons signal when it is time to eat and when it is time to burn energy. It was found that mice lacking the OPA1 protein in MC4R neurons showed a significantly greater tendency to consume high-fat food compared to control mice and gained weight more rapidly; this effect was more pronounced in females than in males.
Over time, these mice developed obesity, although it took several weeks for the condition to manifest. It is hypothesized that the role of OPA1 may increase with age, given 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 in the context of dietary fat intake,” the researchers write.
Overall, the study strongly suggests that the absence or dysfunction of OPA1 proteins reduces the efficiency of these appetite-controlling neurons due to a decrease in the mitochondrial energy supply facilitated by OPA1.
However, the study results are nuanced: scientists demonstrated that the absence of OPA1 did not completely disrupt MC4R signaling, as they were able to reactivate the pathway using an anti-obesity drug.
Interestingly, the drug worked as expected in males regardless of OPA1 status. In females, however, the loss of OPA1 diminished the drug’s ability to suppress food intake, indicating that the sex differences observed in the study extend even to the mice’s response to treatment.
“Pharmacological activation of MC4R suppressed food intake at baseline levels, indicating that MC4R signaling remained intact,” the researchers write.
Of course, this study was conducted exclusively on mice, so there is no guarantee that the same processes and pathways are at work in the human brain—even though decades of research using mice as human proxies suggest this is likely. If these results are confirmed in humans, it would directly link our decisions—such as what groceries to buy or where to dine out—to these biological mechanisms. In some instances, unhealthy choices and their consequences may be partly attributed to the OPA1 protein and the efficiency of its function.
Obesity is a major public health concern, as it increases the risk of complications associated with cardiovascular disease, diabetes, osteoarthritis, and other conditions.
Looking ahead, addressing minor disruptions in energy supply within these specific neurons could offer a new avenue for treating overeating and obesity, although these issues clearly stem from a complex interplay of factors and triggers.
“The observed sex-based differences in OPA1 responses and obesity susceptibility could inform the development of obesity treatments that account for these variations, as well as future approaches to personalized medicine,” says Matsumura.
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