Too much fat can be harmful, and the way fat cells (adipocytes) form is critical for maintaining healthy fat tissue. A team led by researchers from the University Hospital Bonn (UKB) and the University of Bonn has studied how dysfunction in primary cilia—the antenna-like structures on precursor cells—affects fat cell development in mice.

The study, published in The EMBO Journal, reveals that overactivation of the Hedgehog signaling pathway leads precursor cells to develop into connective tissue-like cells instead of white fat cells.

“White adipose tissue stores energy and regulates important metabolic processes in the body. It constantly grows or shrinks, depending on how much energy we consume or burn. Specialized ‘stem cell-like’ precursor cells play a key role in this process because they have the ability to form new fat tissue,” explains corresponding author Prof. Dagmar Wachten, co-director of the Institute of Innate Immunity at the UKB.

Unlike mature fat cells, precursor cells possess primary cilia that help regulate signaling pathways, determining whether these cells form fat cells or connective tissue-like cells. “The regulation of these precursor cells is crucial for the health of white adipose tissue in obesity. We therefore wanted to find out how cilia control the development of precursor cells into fat cells,” Prof. Wachten adds.

Early Remodeling in Fat Tissue – Even Before Obesity

The team studied precursor cells in mice with Bardet-Biedl syndrome (BBS), a genetic disorder that impairs cilia function and often leads to obesity. They found that when an important cilia protein (BBS8) is missing, white adipose tissue begins to remodel before obesity develops.

In these mice, precursor cells diminished because many transformed into connective tissue-like cells. Such cells, typically found in scar tissue, contribute to tissue stiffening. Their exact role in lean adipose tissue, however, remains unclear.

Hedgehog Pathway as the Key Driver

The researchers identified the Hedgehog signaling pathway as central to this abnormal development.

“We have identified the Hedgehog signaling pathway as a key factor in the malformation. Its activation is normally strictly regulated by primary cilia,” says co-first author Katharina Sieckmann, a doctoral student at the University of Bonn.

Alumna and co-first author Nora Winnerling adds: “If cilia function is disrupted, as in BBS, this pathway becomes overactive and drives the cells in an undesirable direction: away from their actual function in forming fat cells. Thus, the Hedgehog signaling pathway controls cell fate in white adipose tissue.”

Implications for Obesity Research

The findings suggest that primary cilia play an active role in determining whether fat precursor cells form healthy fat cells or malfunction into connective tissue-like cells.

“These mechanisms could play a central role in the development of obesity. This discovery opens up new possibilities for targeted intervention in fat cell regulation and, in turn, for the development of more targeted therapies against pathological changes during obesity,” concludes Prof. Wachten.

Participating Institutions and Funding

This research was part of the DFG Collaborative Research Center SFB1454 “Metaflammation and Cellular Programming” and the Research Group FOR5547 “Primary cilia dynamics.” Prof. Wachten serves as spokesperson for SFB1454 and co-spokesperson for FOR5547.

Collaborating institutions included:

• University Hospital Bonn (UKB)
• University of Bonn
• Universities of Mainz and Münster
• German Center for Degenerative Diseases (DZNE)

Summary of Key Findings

• Primary cilia regulate fat precursor cell development through signaling pathways.
• Disrupted cilia function (e.g., in Bardet-Biedl syndrome) causes precursor cells to turn into connective tissue-like cells rather than fat cells.
• Hedgehog signaling pathway overactivation drives this abnormal cell fate.
• Early fat tissue remodeling occurs before obesity develops.
• Findings open new therapeutic possibilities for obesity-related disorders.

Original Publication
Authors: Katharina Sieckmann, Nora Winnerling, Dalila Juliana Silva Ribeiro, Seniz Yüksel, Ronja Kardinal, Lisa Maria Steinheuer, Fabian Frechen, Luis Henrique Corrêa, Geza Schermann, Christina Klausen, Nelli Blank-Stein, Jonas Schulte-Schrepping, Collins Osei-Sarpong, Matthias Becker, Lorenzo Bonaguro, Marc Beyer, Helen Louise May-Simera, Jelena Zurkovic, Christoph Thiele, Kevin Thurley, Lydia Sorokin, Carmen Ruiz de Almodovar, Elvira Mass and Dagmar Wachten.
Journal: The EMBO Journal
DOI: 10.1038/s44318-025-00524-y
Article Title: BBS8-dependent ciliary Hedgehog signaling governs cell fate in the white adipose tissue
Article Publication Date: 20-Aug-2025

Original Source: https://doi.org/10.1038/s44318-025-00524-y

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