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年龄依赖性 PDGFRβ 信号驱动脂肪细胞祖细胞功能障碍,改变雄性小鼠的米色脂肪生成龛。

Age-dependent Pdgfrβ signaling drives adipocyte progenitor dysfunction to alter the beige adipogenic niche in male mice.

机构信息

Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA.

Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA.

出版信息

Nat Commun. 2023 Mar 31;14(1):1806. doi: 10.1038/s41467-023-37386-z.


DOI:10.1038/s41467-023-37386-z
PMID:37002214
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10066302/
Abstract

Perivascular adipocyte progenitor cells (APCs) can generate cold temperature-induced thermogenic beige adipocytes within white adipose tissue (WAT), an effect that could counteract excess fat mass and metabolic pathologies. Yet, the ability to generate beige adipocytes declines with age, creating a key challenge for their therapeutic potential. Here we show that ageing beige APCs overexpress platelet derived growth factor receptor beta (Pdgfrβ) to prevent beige adipogenesis. We show that genetically deleting Pdgfrβ, in adult male mice, restores beige adipocyte generation whereas activating Pdgfrβ in juvenile mice blocks beige fat formation. Mechanistically, we find that Stat1 phosphorylation mediates Pdgfrβ beige APC signaling to suppress IL-33 induction, which dampens immunological genes such as IL-13 and IL-5. Moreover, pharmacologically targeting Pdgfrβ signaling restores beige adipocyte development by rejuvenating the immunological niche. Thus, targeting Pdgfrβ signaling could be a strategy to restore WAT immune cell function to stimulate beige fat in adult mammals.

摘要

血管周脂肪祖细胞 (APCs) 可以在白色脂肪组织 (WAT) 中产生冷诱导的产热米色脂肪细胞,这一效应可以对抗脂肪过多和代谢病理。然而,米色脂肪细胞的生成能力会随着年龄的增长而下降,这给它们的治疗潜力带来了一个关键挑战。在这里,我们发现衰老的米色 APC 过度表达血小板衍生生长因子受体 β (Pdgfrβ) 以阻止米色脂肪生成。我们发现,在成年雄性小鼠中基因敲除 Pdgfrβ 会恢复米色脂肪细胞的生成,而在幼年小鼠中激活 Pdgfrβ 会阻止米色脂肪的形成。从机制上讲,我们发现 Stat1 磷酸化介导 Pdgfrβ 米色 APC 信号通路来抑制 IL-33 的诱导,从而抑制 IL-13 和 IL-5 等免疫基因。此外,通过靶向 Pdgfrβ 信号通路来恢复 beige 脂肪细胞的发育,可以通过恢复免疫细胞的生态位来实现。因此,靶向 Pdgfrβ 信号通路可能是一种恢复 WAT 免疫细胞功能以刺激成年哺乳动物 beige 脂肪的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/d420b6707102/41467_2023_37386_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/574934d938e1/41467_2023_37386_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/d82c5e6f8a26/41467_2023_37386_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/91f2de87d37c/41467_2023_37386_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/c3d41f2c0a7d/41467_2023_37386_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/61ec05286ebd/41467_2023_37386_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/ab5e24e6a93b/41467_2023_37386_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/d420b6707102/41467_2023_37386_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/574934d938e1/41467_2023_37386_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/d82c5e6f8a26/41467_2023_37386_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/91f2de87d37c/41467_2023_37386_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/c3d41f2c0a7d/41467_2023_37386_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/61ec05286ebd/41467_2023_37386_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/ab5e24e6a93b/41467_2023_37386_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df6b/10066302/d420b6707102/41467_2023_37386_Fig7_HTML.jpg

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[1]
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[2]
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[3]
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引用本文的文献

[1]
Adipose Progenitor Cells in Thermogenesis and Metabolic Regulation.

Physiology (Bethesda). 2025-8-1

[2]
White Adipocyte Stem Cell Expansion Through Infant Formula Feeding: New Insights into Epigenetic Programming Explaining the Early Protein Hypothesis of Obesity.

Int J Mol Sci. 2025-5-8

[3]
Aregs-IGFBP3-mediated SMC-like cells apoptosis impairs beige adipocytes formation in aged mice.

Mol Metab. 2025-5

[4]
Dermal white adipose tissue: A new modulator in wound healing and regeneration.

Regen Ther. 2024-12-5

[5]
Single-cell transcriptomic analysis reveals dynamic activation of cellular signaling pathways regulating beige adipogenesis.

Exp Mol Med. 2024-10

[6]
Suppressing PDGFRβ Signaling Enhances Myocyte Fusion to Promote Skeletal Muscle Regeneration.

bioRxiv. 2024-10-18

[7]
Reversing Pdgfrβ signaling restores metabolically active beige adipocytes by alleviating ILC2 suppression in aged and obese mice.

Mol Metab. 2024-11

[8]
Mechanisms and metabolic consequences of adipocyte progenitor replicative senescence.

Immunometabolism (Cobham). 2024-8-28

[9]
Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.

Nat Commun. 2024-8-22

[10]
Key questions and gaps in understanding adipose tissue macrophages and early-life metabolic programming.

Am J Physiol Endocrinol Metab. 2024-10-1

本文引用的文献

[1]
Remodeling of gene regulatory networks underlying thermogenic stimuli-induced adipose beiging.

Commun Biol. 2022-6-14

[2]
Cold-responsive adipocyte progenitors couple adrenergic signaling to immune cell activation to promote beige adipocyte accrual.

Genes Dev. 2021-10-1

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IL-33 causes thermogenic failure in aging by expanding dysfunctional adipose ILC2.

Cell Metab. 2021-11-2

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Progenitor-like characteristics in a subgroup of UCP1+ cells within white adipose tissue.

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Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity.

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Int J Obes (Lond). 2021-5

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Nat Metab. 2019-9

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Mosaic Mutant Analysis Identifies PDGFRα/PDGFRβ as Negative Regulators of Adipogenesis.

Cell Stem Cell. 2020-5-7

[9]
Parallel Lineage-Tracing Studies Establish Fibroblasts as the Prevailing In Vivo Adipocyte Progenitor.

Cell Rep. 2020-1-14

[10]
Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis.

Cell Metab. 2019-11-14

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