TY  - JOUR
AU  - Sieckmann, Katharina
AU  - Winnerling, Nora
AU  - Silva Ribeiro, Dalila Juliana
AU  - Yüksel, Seniz
AU  - Kardinal, Ronja
AU  - Steinheuer, Lisa Maria
AU  - Frechen, Fabian
AU  - Corrêa, Luis Henrique
AU  - Schermann, Geza
AU  - Klausen, Christina
AU  - Blank-Stein, Nelli
AU  - Schulte-Schrepping, Jonas
AU  - Osei-Sarpong, Collins
AU  - Becker, Matthias
AU  - Bonaguro, Lorenzo
AU  - Beyer, Marc
AU  - May-Simera, Helen Louise
AU  - Zurkovic, Jelena
AU  - Thiele, Christoph
AU  - Thurley, Kevin
AU  - Sorokin, Lydia
AU  - Ruiz de Almodovar, Carmen
AU  - Mass, Elvira
AU  - Wachten, Dagmar
TI  - BBS8-dependent ciliary Hedgehog signaling governs cell fate in the white adipose tissue.
JO  - The EMBO journal
VL  - 44
IS  - 19
SN  - 0261-4189
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2025-01153
SP  - 5315 - 5336
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Adipose Tissue, White: metabolism
KW  - Adipose Tissue, White: cytology
KW  - Adipose Tissue, White: pathology
KW  - Mice
KW  - Hedgehog Proteins: metabolism
KW  - Hedgehog Proteins: genetics
KW  - Signal Transduction
KW  - Cilia: metabolism
KW  - Mice, Knockout
KW  - Cell Differentiation
KW  - Adipogenesis
KW  - Bardet-Biedl Syndrome: metabolism
KW  - Bardet-Biedl Syndrome: genetics
KW  - Bardet-Biedl Syndrome: pathology
KW  - Obesity: metabolism
KW  - Obesity: genetics
KW  - Obesity: pathology
KW  - Adipocytes: metabolism
KW  - Adipocytes: cytology
KW  - Microtubule-Associated Proteins: metabolism
KW  - Microtubule-Associated Proteins: genetics
KW  - Adipose Tissue (Other)
KW  - BBS (Other)
KW  - Cell Fate (Other)
KW  - Cilia (Other)
KW  - Hedgehog Proteins (NLM Chemicals)
KW  - Microtubule-Associated Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40836034
C2  - pmc:PMC12489102
DO  - DOI:10.1038/s44318-025-00524-y
UR  - https://pub.dzne.de/record/281535
ER  -