Iron accumulation in hypothalamus promotes age-dependent obesity and metabolic dysfunction of male mice

With the progression of aging, age-dependent obesity and metabolic disorders have garnered increasing attention, yet their underlying mechanisms remain poorly understood. Dysregulation of iron homeostasis is strongly linked to aging; however, its role in age-dependent obesity remains unclear. As the hypothalamus, a key regulator of energy homeostasis, plays a pivotal role in metabolic regulation during aging, we investigated whether hypothalamic iron accumulation contributes to age-dependent obesity. We first observed elevated iron levels in the hypothalamus of aged mice, particularly in the arcuate nucleus. To test whether reducing iron could mitigate obesity, we intranasally administered the iron chelator deferiprone to aged mice and found that it effectively lowered hypothalamic iron levels and ameliorated metabolic function. Using a ferric ammonium citrate-induced iron overload cell model, we discovered that excess iron triggers mitochondrial dysfunction and oxidative stress, leading to ROS-dependent nuclear translocation of forkhead box protein O1 (FoxO1) and subsequent upregulation of AgRP expression. To confirm this mechanism in vivo, we generated agouti-related peptide (AgRP) neuron-specific transferrin receptor 1(Tfrc) knockout mice and found that reducing iron uptake in these neurons decreased ROS levels, inhibited FoxO1 nuclear translocation, and suppressed AgRP neuronal activity in aged mice. This intervention ultimately protected against age-related obesity and metabolic dysfunction. Our study identifies a critical iron accumulation-ROS-FoxO1-AgRP signaling axis in hypothalamic neurons as a key driver of age-dependent obesity. This study elucidates the broader implications of iron homeostasis dysregulation in aging-associated pathologies and offers novel perspectives for investigating age-dependent obesity.