343-OR: The Mitochondrial Protein OPA1 Governs Preadipocyte Proliferation and Metabolic Homeostasis through Ca2+ Mechanical Force/Glycolysis Pathway

Introduction and Objective: The proliferation of preadipocytes favors global metabolic homeostasis. Our study aims to explore the role of mitochondrial protein Optic atrophy 1 (OPA1) in preadipocytes in regulating metabolic disorders and elucidate underlying mechanisms.Methods: We generate preadipocyte-specific KO mice (OPA1^PKO) with OPA1^flox/flox and Pdgfrα-Cre mice and overexpression mice (OPA1^OE) by AAV-DIO injection in Pdgfrα-Cre mice. Mice are subjected to an HFD to monitor preadipocyte proliferation and metabolic phenotypes. Seahorse assays, Ca²⁺and mechanical force measurements are performed in primary preadipocytes.Results:OPA1^PKO mice are protected from glucose and insulin intolerance after HFD. It is due to the increased proliferation of Pdgfrα⁺ cells that promotes hyperplasia. In contrast, OPA1^OE mice exhibit decreased hyperplasia and severe metabolic disorders. Mechanistically, OPA1 KO increases glycolysis to promote the proliferation of preadipocytes through intracellular Ca²⁺ / mechanical force pathways. Inhibition of Ca²⁺ and glycolysis reverse these effects. Finally, OPA1 in Pdgfrα⁺cells from human visceral fat is positively correlated with HOMA-IR and serum TG.Conclusion: we uncover a novel function of OPA1 as a regulator of preadipocyte proliferation and adipose hyperplasia in metabolic homeostasis.

Y. Shu: None. J. Zheng: None. X. Lyu: None. H. Yu: None. J. Yan: None. C. Hu: None.



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