Uranga Romina M, Nishii Akira, Maung Jessica N, Mori Hiroyuki, Desrosiers Brian, Jacobs Jannis, Hoose Keegan S, Schill Rebecca L, Bagchi Devika P, Guak Hannah, Crewe Clair, Dinov Ivo D, Giles Erin D, Lumeng Carey N, MacDougald Ormond A
University of Michigan Medical School, Department of Molecular & Integrative Physiology, Ann Arbor, MI, USA; Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina; New College of Florida, Natural Sciences Division, Sarasota, FL, USA.
University of Michigan Medical School, Department of Molecular & Integrative Physiology, Ann Arbor, MI, USA.
Mol Metab. 2025 Aug 7;100:102226. doi: 10.1016/j.molmet.2025.102226.
Compelling evidence from investigation of preclinical models and humans links canonical Wnt/β-catenin signaling to regulation of many aspects of white adipose tissue development and physiology. Dysregulation of this ancient pathway alters adiposity and metabolic homeostasis. Herein we explore how disruption of adipocyte Wnt/β-catenin signaling affects gene expression and crosstalk between cell types within adipose tissue.
To investigate mechanisms through which adipose tissue attempts to maintain homeostasis in the absence of β-catenin in adipocytes, we employed standard methods of metabolic phenotyping as well as bulk RNA sequencing, flow cytometry, single-cell RNA sequencing, and isolation of secreted extracellular vesicles.
Our experiments reveal that male, but not female adipocyte-specific β-catenin knockout mice, Ctnnb1, have an increase in adiposity and insulin resistance. Whereas metabolic processes including fatty acid metabolism were suppressed in adipocytes, mitochondrial metabolism of immune cells was made more efficient, resulting in reduced reactive oxygen species in macrophages and dendritic cells. Deficiency of β-catenin in adipocytes altered the transcriptome of numerous stromal-vascular cell populations including adipose stem and progenitor cells, macrophages, and other immune cells. Homeostasis in white adipose tissue of Ctnnb1 mice is maintained in part by elevated expression of Ctnnb1 mRNA in endothelial cells and in secreted small extracellular vesicles.
Our studies demonstrate the importance of adipocyte Wnt signaling for regulation of lipid and mitochondrial metabolic processes in stromal-vascular cells and adipocytes in adipose tissues. This research provides further support for an intercellular Wnt signaling network with compensatory capability to maintain homeostasis, and underscores importance of Wnt/β-catenin signaling for understanding adipose tissue physiology and pathophysiology.
临床前模型和人体研究的有力证据表明，经典Wnt/β-连环蛋白信号传导与白色脂肪组织发育和生理的多个方面的调节相关。这一古老信号通路的失调会改变肥胖和代谢稳态。在此，我们探讨脂肪细胞Wnt/β-连环蛋白信号传导的破坏如何影响脂肪组织内细胞类型之间的基因表达和相互作用。
为了研究在脂肪细胞中缺乏β-连环蛋白时脂肪组织维持稳态的机制，我们采用了代谢表型分析的标准方法以及批量RNA测序、流式细胞术、单细胞RNA测序和分泌细胞外囊泡的分离。
我们的实验表明，雄性而非雌性脂肪细胞特异性β-连环蛋白敲除小鼠（Ctnnb1）的肥胖和胰岛素抵抗增加。虽然脂肪细胞中的脂肪酸代谢等代谢过程受到抑制，但免疫细胞的线粒体代谢效率提高，导致巨噬细胞和树突状细胞中的活性氧减少。脂肪细胞中β-连环蛋白的缺乏改变了许多基质血管细胞群体的转录组，包括脂肪干细胞和祖细胞、巨噬细胞及其他免疫细胞。Ctnnb1小鼠白色脂肪组织的稳态部分通过内皮细胞和分泌的小细胞外囊泡中Ctnnb1 mRNA表达的升高得以维持。
我们的研究证明了脂肪细胞Wnt信号传导对调节脂肪组织中基质血管细胞和脂肪细胞的脂质及线粒体代谢过程的重要性。本研究为具有维持稳态补偿能力的细胞间Wnt信号网络提供了进一步支持，并强调了Wnt/β-连环蛋白信号传导对理解脂肪组织生理和病理生理的重要性。
