OPA1 in MC4R Neurons Regulates Dietary Fat Intake and Body Weight in Mice

Melanocortin 4 receptor (MC4R) neurons in the hypothalamus regulate appetite and energy balance, and mitochondrial dynamics are important for neuronal function. However, how dietary fat intake affects mitochondrial regulation in the hypothalamus has not been fully clarified. Here we examined the effects of soybean oil intake on hypothalamic mitochondrial gene expression and generated MC4R neuron-specific mitochondrial fusion factor OPA1 (Optic atrophy-1) knockout mice. Voluntary ingestion of soybean oil increased hypothalamic OPA1 expression in wild-type male mice but not in female mice. In contrast, loss of OPA1 in MC4R neurons led to elevated soybean oil consumption and progressive obesity, with a more pronounced obesity phenotype in females. MC4R agonist administration suppressed food intake, but this effect was attenuated specifically in female knockout mice. Together, these results suggest that OPA1 in MC4R neurons is involved in the response to dietary fat intake and contributes to the control of feeding and body weight, with clear differences between males and females. This study provides new insight into how mitochondrial function in the hypothalamus is linked to energy metabolism under conditions of dietary fat intake.