Altered β-Catenin Expression In β Cells Mediates A Crosstalk With Adipocytes By Lactate To Exacerbate Obesity And Insulin Resistance

Objective: Although the Wnt/β-catenin signaling has been recognized to regulate cell growth and differentiation in many tissues and organs,its exact impact in islet beta cells on the development of obesity and metabolic disorders remains largely unexplored.Methods: In this study,we detected the levels of β-catenin in different states and in different cells by immunofluorescence,RT-PCR,WB and other technologies.Then,CRISPR-Cas9 technology was used to construct transgenic mice with specific overexpression of β-catenin in β cells,which were used as a model to analyze the effect ofβ-catenin on obesity under high lipid metabolic load.The effects of high expressionβ-catenin were observed by comparing the differences in body weight,blood glucose,insulin resistance status,and metabolic level of mice.At the cellular level,metabolomic sequencing and supernatant transfer assays were performed to explore the dialogue mechanism between β cells and adipocytes.Results: Herein in this report,we confirmed that metabolic stress specifically inducesβ-catenin expression in the pancreatic beta cells.Studies in mice with beta cell specificβ-catenin overexpression demonstrated that β-catenin overexpression in beta cells rendered the mice more susceptible to the development of metabolic disorders(e.g.,obesity and insulin resistance)following high-fat diet(HFD)challenge.However,ectopic β-catenin did not cause an observable impact on beta-cell identity and functionality,and no perceptible abnormality was noted once the mice were fed with normal diet.After metabolomic detecting in NIT-1 cell supernatant,we observed that overexpression of β-catenin results in metabolic rewiring featured by an increase of lactate secretion.In human subjects with obesity or T2 DM,the heightened plasma level of lactate positively correlates to the body mass index(BMI)and waist circumference.Mechanistically,HFD activates β-catenin to transcribe the genes in favor of lactate synthesis and secretion.Further,instead of transferred by MCT-4,the circulating lactate serves as a messenger molecule rather than metabolic fuel,which specifically targets GPR81 to repress lipolysis of adipocyte,thereby exacerbating the development of obesity associated metabolic syndrome.Conclusions: Our results underscore a critical role of β-catenin signaling in beta cells in regulating metabolic homeostasis in adipocytes,and extend our understanding of a crosstalk between beta cells and adipocytes in the pathogenesis of obesity and insulin resistance.