47-OR: OPA1 Reprograms Macrophage Metabolism to Enforce Tolerance of Inflammation in Obesity

Introduction & Objective: Adipose tissue macrophages (ATMs) are key players orchestrating metabolic homeostasis through regulating metabolic inflammation. Mitochondrial dynamics and metabolic remodeling are pivotal for the function of macrophages. The aim of our study is to explore the role of the macrophage mitochondrial fusion protein, optic atrophy 1 (OPA1) in metabolic disorders and elucidate the underlying mechanisms.

Methods: We generate myeloid cell-specific OPA1 knockout and transgenic mice, subject them to a NCD or HFD to evaluate metabolic and inflammatory phenotypes. By using immunoblot analysis, flow cytometry, seahorse metabolic assays, metabolism assessment, combined with culturing bone marrow derived macrophages to reveal the molecular mechanisms of OPA1 in regulating metabolic reprogramming in macrophages.

Results: Myeloid-specific KO of OPA1 induces M2-like to M1-like macrophages shift in AT, thus promoting metabolic inflammation and exacerbating HFD-induced systemic insulin resistance, glucose dysregulation and liver steatosis in mice. In vitro studies show OPA1 loss impairs mitochondrial oxidative metabolism and inhibits JAK1/STAT6 pathway, resulting in decreased M2 polarization upon IL-4 stimulation. Mechanistically, OPA1 KO impairs the activity of itaconate transporter-Slc25a11 locating in the inner membrane of mitochondrial, leading to itaconate accumulation within the mitochondrial to suppress JAK1/STAT6. Further, mice with transgenic overexpression of OPA1 exhibit improved inflammation and metabolic homeostasis.

Conclusion: We reveal a novel role of OPA1 as a positive regulator of M2 macrophages polarization by governing metabolic reprogramming. Targeting macrophage OPA1 could represent a therapeutic target for AT inflammation and metabolic diseases.