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. Overall design: 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.