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Discovery and functional assessment of a novel adipocyte population driven by intracellular Wnt/β-catenin signaling in mammals.

ABSTRACT: Wnt/β-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/β-catenin signaling, as revealed by the Tcf/Lef-GFP reporter allele, in embryonic and adult mouse fat depots, named as Wnt⁺ adipocytes. We showed that this β-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survival. Such adipocytes are distinct from classical ones in transcriptomic and genomic signatures and can be induced from various sources of mesenchymal stromal cells including human cells. Genetic lineage-tracing and targeted cell ablation studies revealed that these adipocytes convert into beige adipocytes directly and are also required for beige fat recruitment under thermal challenge, demonstrating both cell autonomous and non-cell autonomous roles in adaptive thermogenesis. Furthermore, mice bearing targeted ablation of these adipocytes exhibited glucose intolerance, while mice receiving exogenously supplied such cells manifested enhanced glucose utilization. Our studies uncover a unique adipocyte population in regulating beiging in adipose tissues and systemic glucose homeostasis.

SUBMITTER: Liu Z

PROVIDER: S-EPMC9064292 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Discovery and functional assessment of a novel adipocyte population driven by intracellular Wnt/β-catenin signaling in mammals.

Liu Zhi Z Chen Tian T Zhang Sicheng S Yang Tianfang T Gong Yun Y Deng Hong-Wen HW Bai Ding D Tian Weidong W Chen YiPing Y

eLife 20220503

Wnt/β-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/β-catenin signaling, as revealed by the Tcf/Lef-GFP reporter allele, in embryonic and adult mouse fat depots, named as Wnt<sup>+</sup> adipocytes. We showed that this β-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survi ...[more]

PMID: 35503096

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Project description:ObjectivesActivation of the Wnt/β-catenin signaling pathway inhibits adipogenesis by maintaining preadipocytes in an undifferentiated state. We investigated the effect of indirubin-3'-oxime (I3O), which was screened as an activator of the Wnt/β-catenin signaling, on inhibiting the preadipocyte differentiation in vitro and in vivo.Methods3T3L1 preadipocytes were differentiated with 0, 4 or 20 μM of I3O. The I3O effect on adipocyte differentiation was observed by Oil-red-O staining. Activation of Wnt/β-catenin signaling in I3O-treated 3T3L1 cells was shown using immunocytochemical and immunoblotting analyses for β-catenin. The regulation of adipogenic markers was analyzed via real-time reverse transcription-PCR (RT-PCR) and immunoblotting analyses. For the in vivo study, mice were divided into five different dietary groups: chow diet, high-fat diet (HFD), HFD supplemented with I3O at 5, 25 and 100 mg kg(-1). After 8 weeks, adipose and liver tissues were excised from the mice and subject to morphometry, real-time RT-PCR, immunoblotting and histological or immunohistochemical analyses. In addition, adipokine and insulin concentrations in serum of the mice were accessed by enzyme-linked immunosorbent assay.ResultsUsing a cell-based approach to screen a library of pharmacologically active small molecules, we identified I3O as a Wnt/β-catenin pathway activator. I3O inhibited the differentiation of 3T3-L1 cells into mature adipocytes and decreased the expression of adipocyte markers, CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ, at both mRNA and protein levels. In vivo, I3O inhibited the development of obesity in HFD-fed mice by attenuating HFD-induced body weight gain and visceral fat accumulation without showing any significant toxicity. Factors associated with metabolic disorders such as hyperlipidemia and hyperglycemia were also improved by treatment of I3O.ConclusionActivation of the Wnt/β-catenin signaling pathway can be used as a therapeutic strategy for the treatment of obesity and metabolic syndrome and implicates I3O as a candidate anti-obesity agent.

Dataset Information

Discovery and functional assessment of a novel adipocyte population driven by intracellular Wnt/β-catenin signaling in mammals.

Publications

Discovery and functional assessment of a novel adipocyte population driven by intracellular Wnt/β-catenin signaling in mammals.

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