Effects of β-catenin deficiency on adipose tissue physiology

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-08-05 DOI:10.1016/j.molmet.2025.102226

Romina M. Uranga , Akira Nishii , Jessica N. Maung , Hiroyuki Mori , Brian Desrosiers , Jannis Jacobs , Keegan S. Hoose , Rebecca L. Schill , Devika P. Bagchi , Hannah Guak , Clair Crewe , Ivo D. Dinov , Erin D. Giles , Carey N. Lumeng , Ormond A. MacDougald

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引用次数: 0

Abstract

Objectives

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.

Methods

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.

Results

Our experiments reveal that male, but not female adipocyte-specific β-catenin knockout mice, Ctnnb1^AdKO, 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^AdKO mice is maintained in part by elevated expression of Ctnnb1 mRNA in endothelial cells and in secreted small extracellular vesicles.

Conclusions

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.

Abstract Image

查看原文本刊更多论文

β-连环蛋白缺乏对脂肪组织生理的影响。

目的：来自临床前模型和人类研究的令人信服的证据表明，典型的Wnt/β-catenin信号与白色脂肪组织发育和生理的许多方面的调节有关。这种古老途径的失调会改变肥胖和代谢稳态。在这里，我们探讨了脂肪细胞Wnt/β-连环蛋白信号的破坏如何影响脂肪组织中细胞类型之间的基因表达和串扰。方法：为了研究脂肪组织在脂肪细胞缺乏β-catenin的情况下维持体内平衡的机制，我们采用了标准的代谢表型分析方法，以及大量RNA测序、流式细胞术、单细胞RNA测序和分离分泌的细胞外囊泡。结果：我们的实验显示，雄性脂肪细胞特异性β-catenin敲除小鼠（Ctnnb1AdKO）肥胖和胰岛素抵抗增加，而雌性没有。脂肪细胞的代谢过程（包括脂肪酸代谢）受到抑制，而免疫细胞的线粒体代谢变得更有效，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的转录组，包括脂肪干细胞和祖细胞、巨噬细胞和其他免疫细胞。Ctnnb1AdKO小鼠白色脂肪组织的稳态维持部分是通过内皮细胞和分泌的细胞外小泡中Ctnnb1 mRNA的表达升高来实现的。结论：我们的研究证明了脂肪细胞Wnt信号在调节基质血管细胞和脂肪组织中脂肪细胞的脂质和线粒体代谢过程中的重要性。本研究进一步支持了细胞间Wnt信号网络具有维持体内平衡的补偿能力，并强调了Wnt/β-catenin信号对于理解脂肪组织生理和病理生理的重要性。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.