Mechanosensitive Ion Channel Piezo1 Regulates Adipose Inflammation And Systemic Insulin Resistance In Mice

【Aims】Adipocytes function as an energy buffer and change the size and volume significantlyin response to caloric availability.This adipocyte plasticity is important for systemic lipid metabolism and insulin sensitivity.Accompanying the adipocyte size and volume changes,the mechanical pressure against cell wall also alters.Here,we have explored the role of adipose mechanical ion channel Piezo1 in regulating systemic lipid metabolism and insulin sensitivity.【Methods】The organs of wild-type mice were collected and the expression of Piezo1/Piezo2 in various tissues was measured.Wild-type mice were fed on chow or high-fat diet for at least 16 weeks,mature adipocytes and stromal vascular fractions(SVF)of different adipose tissue was isolated respectively.Piezo1 expression was measured between the cells.Adipose-specific Piezo1 knockout mice(adipose-Piezo1-/-)were generated by crossing Piezo1-flox/flox mice to adiponectin-Cre mice.Mice were divided into normal diet group and high fat diet group.Obesity was modelled by feeding with high-fat diet.Body weight,glucose tolerance test,insulin tolerance test,serum insulin,serum free fatty acid,serum triglyceride and other in vivo metabolic indicators were measured.The all the mice were sacrificed,in vitro metabolic indexes such as weight of each organ,measurement of liver lipid content,and measurement of expression of genes related to adipose tissue and liver tissue were performed.H&Estaining of adipose and liver tissues were also performed.SVF were isolated from wildtype mice and exposed to Piezo1 agonist or inhibitor.Metabolism indicators and biochemical markers were assessed.【Results】Piezo1was highly expressed in adipocytes.Adipose Piezo1 expression was increased in obese mice.Adipose-Piezo1-/-mice developed insulin resistance,especially when challenged with HFD.Adipocyte size was reduced while pro-inflammatory and lipolysis genes were increased in HFD-fed adipose-Piezo1-/-mice.Adipose Piezo1 knockdown stimulated fatty acid synthesis in liver and caused hepatic steatosis.In cultured adipocytes,Piezo1 activation decreased,while Piezo1 inhibition elevated pro-inflammatory genes including MCP1,TNFα,and IL-6.TLR4 antagonist TAK-242 abolished adipocyte inflammation induced by Piezo1 inhibition.【Conclusions】Piezo1 may serve as an adaptive mechanism for adipocyte plasticity restraining proinflammatory response in obesity.