The role of primary cilia in adipose tissue
The role of primary cilia in adipose tissue
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DissertationDate of Exam
18.06.2025Date of Publication
04.07.2025Advisor
Wachten, DagmarCo-Referee
Mass, ElviraMetadata
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Abstract
The primary cilium serves as a cellular antenna, transducing extracellular stimuli into an intracellular response. In white adipose tissue (WAT), adipocyte precursor cells (APCs) but not mature adipocytes display a primary cilium. APCs replenish the adipocyte pool by undergoing adipogenesis. Advances in single-cell analysis have revealed the heterogeneity of APCs as they consist of multiple functionally distinct subpopulations in the WAT. The regulation of cell fate and differentiation of APCs is key to maintaining WAT homeostasis. Primary cilia have been proposed to regulate APC function and, thereby, WAT physiology. The role of cilia in regulating whole-body energy metabolism is also reflected in the Bardet-Biedl syndrome (BBS), where primary cilia dysfunction leads to obesity due to hyperphagia and WAT remodeling. However, how ciliary signaling might impact APC fate decision making is not known.
To address that, I comprehensively investigated the APC subpopulations in WAT under physiological conditions and during primary cilia dysfunction in a BBS mouse model before the onset of obesity. In mice that recapitulated the ciliopathy BBS (Bbs8-/-), I demonstrated that loss of BBS8 reduced the stem cell-like P1 APC subpopulation due to a phenotypic switch towards a fibrogenic phenotype. This was accompanied by extracellular matrix remodeling of the WAT and an increase of the profibrotic CD9high APC subpopulation. Single-cell RNA sequencing revealed an altered trajectory of Bbs8-/- cells, as they directly transitioned into fibrogenic progenitors, bypassing the committed P2 APCs. Ciliary hedgehog (Hh) signaling emerged as a central driver of the molecular changes in Bbs8-/- APCs. Controlled activation of the Hh pathway is essential for maintaining stem cell fates. However, loss of BBS8 promoted ectopic Hh activation in APCs and, in turn, induced the fibrogenic fate change.
These findings reveal a novel role of primary cilia in APC fate determination, balancing adipogenesis and fibrogenesis. The identified molecular mechanisms can serve as a basis to refine potential therapeutic targets for obesity.
To address that, I comprehensively investigated the APC subpopulations in WAT under physiological conditions and during primary cilia dysfunction in a BBS mouse model before the onset of obesity. In mice that recapitulated the ciliopathy BBS (Bbs8-/-), I demonstrated that loss of BBS8 reduced the stem cell-like P1 APC subpopulation due to a phenotypic switch towards a fibrogenic phenotype. This was accompanied by extracellular matrix remodeling of the WAT and an increase of the profibrotic CD9high APC subpopulation. Single-cell RNA sequencing revealed an altered trajectory of Bbs8-/- cells, as they directly transitioned into fibrogenic progenitors, bypassing the committed P2 APCs. Ciliary hedgehog (Hh) signaling emerged as a central driver of the molecular changes in Bbs8-/- APCs. Controlled activation of the Hh pathway is essential for maintaining stem cell fates. However, loss of BBS8 promoted ectopic Hh activation in APCs and, in turn, induced the fibrogenic fate change.
These findings reveal a novel role of primary cilia in APC fate determination, balancing adipogenesis and fibrogenesis. The identified molecular mechanisms can serve as a basis to refine potential therapeutic targets for obesity.
Subjects
Fettgewebe, Primäres Zilium, Präadipozyten, Fibrose, Hedgehog Signalweg, BBS, Adipose Tissue, Primary Cilium, Hedeghog Signaling, Preadipocytes, Fibrosis
Classification (DDC)
610 Medizin, GesundheitSieckmann, Maria Katharina: The role of primary cilia in adipose tissue. - Bonn, 2025. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-83561
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-83561
@phdthesis{handle:20.500.11811/13184,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-83561,
author = {{Maria Katharina Sieckmann}},
title = {The role of primary cilia in adipose tissue},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2025,
month = jul,
note = {The primary cilium serves as a cellular antenna, transducing extracellular stimuli into an intracellular response. In white adipose tissue (WAT), adipocyte precursor cells (APCs) but not mature adipocytes display a primary cilium. APCs replenish the adipocyte pool by undergoing adipogenesis. Advances in single-cell analysis have revealed the heterogeneity of APCs as they consist of multiple functionally distinct subpopulations in the WAT. The regulation of cell fate and differentiation of APCs is key to maintaining WAT homeostasis. Primary cilia have been proposed to regulate APC function and, thereby, WAT physiology. The role of cilia in regulating whole-body energy metabolism is also reflected in the Bardet-Biedl syndrome (BBS), where primary cilia dysfunction leads to obesity due to hyperphagia and WAT remodeling. However, how ciliary signaling might impact APC fate decision making is not known.
To address that, I comprehensively investigated the APC subpopulations in WAT under physiological conditions and during primary cilia dysfunction in a BBS mouse model before the onset of obesity. In mice that recapitulated the ciliopathy BBS (Bbs8-/-), I demonstrated that loss of BBS8 reduced the stem cell-like P1 APC subpopulation due to a phenotypic switch towards a fibrogenic phenotype. This was accompanied by extracellular matrix remodeling of the WAT and an increase of the profibrotic CD9high APC subpopulation. Single-cell RNA sequencing revealed an altered trajectory of Bbs8-/- cells, as they directly transitioned into fibrogenic progenitors, bypassing the committed P2 APCs. Ciliary hedgehog (Hh) signaling emerged as a central driver of the molecular changes in Bbs8-/- APCs. Controlled activation of the Hh pathway is essential for maintaining stem cell fates. However, loss of BBS8 promoted ectopic Hh activation in APCs and, in turn, induced the fibrogenic fate change.
These findings reveal a novel role of primary cilia in APC fate determination, balancing adipogenesis and fibrogenesis. The identified molecular mechanisms can serve as a basis to refine potential therapeutic targets for obesity.},
url = {https://hdl.handle.net/20.500.11811/13184}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-83561,
author = {{Maria Katharina Sieckmann}},
title = {The role of primary cilia in adipose tissue},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2025,
month = jul,
note = {The primary cilium serves as a cellular antenna, transducing extracellular stimuli into an intracellular response. In white adipose tissue (WAT), adipocyte precursor cells (APCs) but not mature adipocytes display a primary cilium. APCs replenish the adipocyte pool by undergoing adipogenesis. Advances in single-cell analysis have revealed the heterogeneity of APCs as they consist of multiple functionally distinct subpopulations in the WAT. The regulation of cell fate and differentiation of APCs is key to maintaining WAT homeostasis. Primary cilia have been proposed to regulate APC function and, thereby, WAT physiology. The role of cilia in regulating whole-body energy metabolism is also reflected in the Bardet-Biedl syndrome (BBS), where primary cilia dysfunction leads to obesity due to hyperphagia and WAT remodeling. However, how ciliary signaling might impact APC fate decision making is not known.
To address that, I comprehensively investigated the APC subpopulations in WAT under physiological conditions and during primary cilia dysfunction in a BBS mouse model before the onset of obesity. In mice that recapitulated the ciliopathy BBS (Bbs8-/-), I demonstrated that loss of BBS8 reduced the stem cell-like P1 APC subpopulation due to a phenotypic switch towards a fibrogenic phenotype. This was accompanied by extracellular matrix remodeling of the WAT and an increase of the profibrotic CD9high APC subpopulation. Single-cell RNA sequencing revealed an altered trajectory of Bbs8-/- cells, as they directly transitioned into fibrogenic progenitors, bypassing the committed P2 APCs. Ciliary hedgehog (Hh) signaling emerged as a central driver of the molecular changes in Bbs8-/- APCs. Controlled activation of the Hh pathway is essential for maintaining stem cell fates. However, loss of BBS8 promoted ectopic Hh activation in APCs and, in turn, induced the fibrogenic fate change.
These findings reveal a novel role of primary cilia in APC fate determination, balancing adipogenesis and fibrogenesis. The identified molecular mechanisms can serve as a basis to refine potential therapeutic targets for obesity.},
url = {https://hdl.handle.net/20.500.11811/13184}
}
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