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@ARTICLE{Sieckmann:281535,
author = {Sieckmann, Katharina and Winnerling, Nora and Silva
Ribeiro, Dalila Juliana and Yüksel, Seniz and Kardinal,
Ronja and Steinheuer, Lisa Maria and Frechen, Fabian and
Corrêa, Luis Henrique and Schermann, Geza and Klausen,
Christina and Blank-Stein, Nelli and Schulte-Schrepping,
Jonas and Osei-Sarpong, Collins and Becker, Matthias and
Bonaguro, Lorenzo and Beyer, Marc and May-Simera, Helen
Louise and Zurkovic, Jelena and Thiele, Christoph and
Thurley, Kevin and Sorokin, Lydia and Ruiz de Almodovar,
Carmen and Mass, Elvira and Wachten, Dagmar},
title = {{BBS}8-dependent ciliary {H}edgehog signaling governs cell
fate in the white adipose tissue.},
journal = {The EMBO journal},
volume = {44},
number = {19},
issn = {0261-4189},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {DZNE-2025-01153},
pages = {5315 - 5336},
year = {2025},
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.},
keywords = {Animals / Adipose Tissue, White: metabolism / Adipose
Tissue, White: cytology / Adipose Tissue, White: pathology /
Mice / Hedgehog Proteins: metabolism / Hedgehog Proteins:
genetics / Signal Transduction / Cilia: metabolism / Mice,
Knockout / Cell Differentiation / Adipogenesis /
Bardet-Biedl Syndrome: metabolism / Bardet-Biedl Syndrome:
genetics / Bardet-Biedl Syndrome: pathology / Obesity:
metabolism / Obesity: genetics / Obesity: pathology /
Adipocytes: metabolism / Adipocytes: cytology /
Microtubule-Associated Proteins: metabolism /
Microtubule-Associated Proteins: genetics / Adipose Tissue
(Other) / BBS (Other) / Cell Fate (Other) / Cilia (Other) /
Hedgehog Proteins (NLM Chemicals) / Microtubule-Associated
Proteins (NLM Chemicals)},
cin = {AG Schultze / AG Beyer / AG Becker / AG Bonaguro},
ddc = {570},
cid = {I:(DE-2719)1013038 / I:(DE-2719)1013035 /
I:(DE-2719)5000079 / I:(DE-2719)1016005},
pnm = {354 - Disease Prevention and Healthy Aging (POF4-354) / 351
- Brain Function (POF4-351)},
pid = {G:(DE-HGF)POF4-354 / G:(DE-HGF)POF4-351},
experiment = {EXP:(DE-2719)PRECISE-20190321},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40836034},
pmc = {pmc:PMC12489102},
doi = {10.1038/s44318-025-00524-y},
url = {https://pub.dzne.de/record/281535},
}