A dominant CIDEC variant segregates with familial obesity by increasing lipid droplet size in adipocytes Article Swipe
Franziska Paul
,
Hui Wang
,
Jianqin Wang
,
Liang Juin Tan
,
Crystal Y. Chia
,
Li Sun
,
Hui Jen Goh
,
Mark Kelly
,
Suresh Anand Sadananthan
,
Gunaseelan Narayanan
,
Lawrence M. Lifshitz
,
S. Sendhil Velan
,
Sarah M. Nicoloro
,
Sumanty Tohari
,
Alvin Yu Jin Ng
,
Byrappa Venkatesh
,
Poh San Lai
,
Carine Bonnard
,
Kamille Airyel T. Enriquez-Satuito
,
Perie Adorable-Wagan
,
Elizabeth Paz-Pacheco
,
Eva Maria C. Cutiongco–de la Paz
,
Qi-Jing Li
,
Melvin Khee‐Shing Leow
,
Li Xu
,
Peng Li
,
Michael Czech
,
Bruno Reversade
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.07.28.25332029
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.07.28.25332029
Adipose tissue dysfunction in obesity is a major global public health risk, contributing to insulin resistance and chronic diseases such as diabetes and cardiovascular disorders. Here, we identify a dominant c.37A>G p.(Arg13Gly) variant in the long isoform of CIDEC (CIDEC-L), a key regulator of lipid droplet (LD) size, as the underlying cause of familial obesity. Affected individuals display marked subcutaneous fat accumulation in white adipose tissue (WAT), elevated fat content in brown adipose tissue (BAT) and insulin resistance. Accordingly, patient-derived iPSCs differentiated into white adipocytes exhibit accelerated LD growth, a phenotype mirrored by CIDEC-L R13G overexpression. Mechanistically, we find that the p.Arg13Gly variant disrupts the N-terminal structural order of CIDEC-L, shifting its phase separation properties to enable, rather than restrict, lipid exchange through condensation plates between LDs. Notably, knock-in mice with the analogous Cidec-L p.(Arg10Gly) mutation recapitulate the human BAT hypertrophy and exhibit impaired thermogenesis. These findings establish the CIDEC-L R13G variant as the first example of a dominantly inherited monogenic obesity driven by a dysfunctional adipocyte LD protein, revealing a critical role for CIDEC-L in restraining fat accumulation and maintaining metabolic health.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.07.28.25332029
- https://www.medrxiv.org/content/medrxiv/early/2025/07/29/2025.07.28.25332029.full.pdf
- OA Status
- green
- References
- 67
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4412767162
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4412767162Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.07.28.25332029Digital Object Identifier
- Title
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A dominant CIDEC variant segregates with familial obesity by increasing lipid droplet size in adipocytesWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-07-29Full publication date if available
- Authors
-
Franziska Paul, Hui Wang, Jianqin Wang, Liang Juin Tan, Crystal Y. Chia, Li Sun, Hui Jen Goh, Mark Kelly, Suresh Anand Sadananthan, Gunaseelan Narayanan, Lawrence M. Lifshitz, S. Sendhil Velan, Sarah M. Nicoloro, Sumanty Tohari, Alvin Yu Jin Ng, Byrappa Venkatesh, Poh San Lai, Carine Bonnard, Kamille Airyel T. Enriquez-Satuito, Perie Adorable-Wagan, Elizabeth Paz-Pacheco, Eva Maria C. Cutiongco–de la Paz, Qi-Jing Li, Melvin Khee‐Shing Leow, Li Xu, Peng Li, Michael Czech, Bruno ReversadeList of authors in order
- Landing page
-
https://doi.org/10.1101/2025.07.28.25332029Publisher landing page
- PDF URL
-
https://www.medrxiv.org/content/medrxiv/early/2025/07/29/2025.07.28.25332029.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.medrxiv.org/content/medrxiv/early/2025/07/29/2025.07.28.25332029.full.pdfDirect OA link when available
- Concepts
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Lipid droplet, Obesity, Adipocyte, Chemistry, Biology, Cell biology, Endocrinology, Adipose tissueTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- References (count)
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67Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| countries_distinct_count | 6 |
| institutions_distinct_count | 28 |
| corresponding_institution_ids | https://openalex.org/I115228651, https://openalex.org/I1351752, https://openalex.org/I165932596, https://openalex.org/I166722992, https://openalex.org/I38877650, https://openalex.org/I4210160507, https://openalex.org/I66068411, https://openalex.org/I71920554, https://openalex.org/I75573869, https://openalex.org/I99065089 |
| citation_normalized_percentile.value | 0.31330396 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |