Journal Article

DZNE-2025-01153

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png BBS8-dependent ciliary Hedgehog signaling governs cell fate in the white adipose tissue.

Sieckmann, K. ; Winnerling, N. ; Silva Ribeiro, D. J. ; Yüksel, S. ; Kardinal, R. ; Steinheuer, L. M. ; Frechen, F. ; Corrêa, L. H. ; Schermann, G. ; Klausen, C. ; Blank-Stein, N. ; Schulte-Schrepping, J.DZNE* ; Osei-Sarpong, C.DZNE* ; Becker, M.DZNE* ; Bonaguro, L.DZNE* ; Beyer, M.DZNE* ; May-Simera, H. L. ; Zurkovic, J. ; Thiele, C. ; Thurley, K. ; Sorokin, L. ; Ruiz de Almodovar, C. ; Mass, E. ; Wachten, D.

2025
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s44318-025-00524-y

Abstract: The primary cilium plays a crucial role in regulating whole-body energy metabolism, as reflected in Bardet-Biedl syndrome (BBS), where ciliary dysfunction leads to obesity due to hyperphagia and white adipose tissue (WAT) remodeling. Regulation of the fate and differentiation of adipocyte precursor cells (APCs) is essential for maintaining WAT homeostasis during obesity. Using Bbs8-/- mice that recapitulate the BBS patient phenotype, we demonstrate that primary cilia dysfunction reduces the stem-cell-like P1 APC subpopulation by inducing a phenotypic switch to a fibrogenic progenitor state. This switch is characterized by extracellular matrix (ECM) remodeling and upregulation of the fibrosis marker CD9, even before the onset of obesity. Single-cell RNA sequencing reveals a direct transition of P1 APCs into fibrogenic progenitors, bypassing the committed P2 progenitor state. Ectopic ciliary Hedgehog signaling upon loss of BBS8 appears as a central driver of the molecular changes in Bbs8-/- APCs, altering their differentiation into adipocytes and promoting their lipid uptake. These findings unravel a novel role for primary cilia in governing APC fate by determining the balance between adipogenesis and fibrogenesis, and suggest potential therapeutic targets for obesity.

Keyword(s): Animals (MeSH) ; Adipose Tissue, White: metabolism (MeSH) ; Adipose Tissue, White: cytology (MeSH) ; Adipose Tissue, White: pathology (MeSH) ; Mice (MeSH) ; Hedgehog Proteins: metabolism (MeSH) ; Hedgehog Proteins: genetics (MeSH) ; Signal Transduction (MeSH) ; Cilia: metabolism (MeSH) ; Mice, Knockout (MeSH) ; Cell Differentiation (MeSH) ; Adipogenesis (MeSH) ; Bardet-Biedl Syndrome: metabolism (MeSH) ; Bardet-Biedl Syndrome: genetics (MeSH) ; Bardet-Biedl Syndrome: pathology (MeSH) ; Obesity: metabolism (MeSH) ; Obesity: genetics (MeSH) ; Obesity: pathology (MeSH) ; Adipocytes: metabolism (MeSH) ; Adipocytes: cytology (MeSH) ; Microtubule-Associated Proteins: metabolism (MeSH) ; Microtubule-Associated Proteins: genetics (MeSH) ; Adipose Tissue ; BBS ; Cell Fate ; Cilia ; Hedgehog Proteins ; Microtubule-Associated Proteins

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Contributing Institute(s):

1. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
2. Immunogenomics and Neurodegeneration (AG Beyer)
3. Modular High Performance Computing and Artificial Intelligence (AG Becker)
4. Molecular and Translational Immunaging (AG Bonaguro)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2025

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