Macrophage OPA1 maintains anti-inflammatory state and metabolic homeostasis by regulating metabolic reprogramming and mtDNA-cGAS-STING pathway

Adipose tissue macrophages (ATMs) play an important role in regulating adipose tissue inflammation and metabolic homeostasis. Mitochondria are pivotal hubs for macrophage-mediated inflammation. Here, we observed a negative correlation between macrophage optic atrophy type 1 (OPA1) and obesity in both humans and mice. Myeloid OPA1-deficient mice were susceptible to obesity and related systemic insulin resistance, glucose dysregulation, and hepatic steatosis upon high-fat diet (HFD). This is due to the impairment of M2-like macrophage features and the promotion of pro-inflammatory phenotypes. Mechanically, OPA1 loss resulted in metabolic reprogramming, as evidenced by reduced mitochondrial respiration, increased glycolysis, and elevated mtDNA release. This activated the cGAS-STING-IRF7 pathway in M2 macrophages, inducing anti-inflammatory conversion to a pro-inflammatory state. In contrast, myeloid OPA1 transgenic mice exhibited reduced inflammation and obesity. Collectively, we identified macrophage OPA1 as a novel regulator of immune metabolism. Targeting OPA1 may represent an effective therapeutic strategy against obesity and metabolic disorders. To investigate the influence of changes in transcriptional patterns that modulate macrophage function via OPA1 signaling, we performed RNA-sequencing (RNA-seq) on BMDMs isolated from OPA1f/f versus OPA1f/f; Lyz2-Cre mice after IL-4 stimulation for 24 h.