Skip to content
DraconiticResearch
Search Sources API
194,067 studies31 sourcesUpdated 52 min ago
Peer-reviewedCC BYMolecular metabolism

Cell-type-specific repression reveals MC4R neurons as a site of action for ciliary obesity genes.

  • Abbey Diener Blake1
  • Zhixuan Zhang1
  • Coralie Alexandre2
  • Anne Gorayeb2
  • Mrinaalini Jain2
  • Qi Liu3
  • Rithu Pattali4
  • Alicja Bednarska1
  • Parleen Kaur Pandher1
  • Sumei Zhang2
  • Xinyu Yue1
  • James Nuñez5
1 more authors
  • Christian Vaisse6
6 affiliations
  1. 1Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  2. 2Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
  3. 3Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  4. 4Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  5. 5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Chan Zuckerberg Biohub, San Francisco, San Francisco, CA, USA.
  6. 6Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].
Read full textPDFDOICite

Abstract

Objectives

Understanding how obesity-associated genes function within defined neuronal subpopulations remains a major barrier to translating human genetics into pathophysiological mechanisms. Melanocortin-4 receptor-expressing (MC4R) neurons are key regulators of energy homeostasis and represent a potential site of action for these genes. Here, we investigated whether obesity-associated ciliary genes regulate body weight through MC4R neurons in vivo, using a Cre-dependent CRISPR interference (CRISPRi) strategy that enables temporal, spatial, and cell-type-specific gene repression without permanent DNA modification.Methods

Gene repression was achieved in MC4R neurons using a Cre-dependent CRISPRi system with AAV-delivered sgRNAs, and physiological outcomes, including body weight and body composition, were assessed following gene downregulation.Results

CRISPRi-mediated repression of Mc4r in adult PVNMC4R neurons reduced transcript and protein levels and induced progressive obesity, validating the approach. Downregulation of the ciliary adenylyl cyclase Adcy3 specifically in adult PVNMC4R neurons was sufficient to drive weight gain, establishing a cell-type-specific requirement for ADCY3 in body-weight regulation. An in vivo CRISPRi screen of obesity-associated ciliopathy genes (Bbs10, Inpp5e, Ankrd26) demonstrated that their repression in MC4R neurons is sufficient to promote obesity, identifying these neurons as a convergent site linking human ciliopathies to obesity.Conclusions

These findings define MC4R neurons as a critical neuronal population through which multiple obesity-associated ciliary genes act and establish a direct link between ciliary function in defined neuronal populations and organismal energy balance. This work provides insight into the neural mechanisms underlying obesity and a framework for linking human genetic variations to specific neuronal populations in vivo.

Related

  1. Transcriptomics of independent CRISPR-edited cell lines reveal ciliary-specific ARL13B dependent changes
    O. Morrison, T. Caspary
    bioRxivPreprintAll rights reservedFull textGenetics & genomicsbioRxiv
  2. Cfap410a and Cby work together with tissue-specific requirements to build Drosophila ciliary transition zones
    A. Billon, J. Vieillard, P. Priya +10
    bioRxivPreprintAll rights reservedFull textCell biologybioRxiv
  3. Transcriptomics of independent CRISPR-edited cell lines reveal ciliary-specific ARL13B-dependent changes
    Olivia Morrison, Tamara Caspary
    G3: Genes, Genomes, GeneticsPeer-reviewedCC BY 4.0Full textGenetics & genomicsCrossref
  4. C3a receptor signalling in ObRb-expressing neurons promotes leptin resistance and obesity-associated cardiac remodelling
    E. Rawish, C. Gragoll, M. Schneider +21
    bioRxivPreprintAll rights reservedFull textImmunologybioRxiv
  5. Single-nucleus transcriptomics uncovers region-specific molecular features underlying selective aging vulnerability of cholinergic neurons
    Qianqian Li, Jiale Chen, Xiuli Liu +3
    iSciencePeer-reviewedCC BY-NC 4.0Full textNeuroscienceCell PressCrossrefEurope PMC

Cite

BibTeXRIS
BibTeX
@article{blake2026celltypespecific,
  title = {{Cell-type-specific repression reveals MC4R neurons as a site of action for ciliary obesity genes.}},
  author = {Abbey Diener Blake and Zhixuan Zhang and Coralie Alexandre and Anne Gorayeb and Mrinaalini Jain and Qi Liu and Rithu Pattali and Alicja Bednarska and Parleen Kaur Pandher and Sumei Zhang and Xinyu Yue and James Nuñez and Christian Vaisse},
  journal = {Molecular metabolism},
  year = {2026},
  month = oct,
  doi = {10.1016/j.molmet.2026.102454},
  url = {https://europepmc.org/article/MED/42838451},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cell-type-specific repression reveals MC4R neurons as a site of action for ciliary obesity genes.
AU  - Abbey Diener Blake
AU  - Zhixuan Zhang
AU  - Coralie Alexandre
AU  - Anne Gorayeb
AU  - Mrinaalini Jain
AU  - Qi Liu
AU  - Rithu Pattali
AU  - Alicja Bednarska
AU  - Parleen Kaur Pandher
AU  - Sumei Zhang
AU  - Xinyu Yue
AU  - James Nuñez
AU  - Christian Vaisse
PY  - 2026
DA  - 2026/10/06
JO  - Molecular metabolism
DO  - 10.1016/j.molmet.2026.102454
UR  - https://europepmc.org/article/MED/42838451
AB  - Objectives  Understanding how obesity-associated genes function within defined neuronal subpopulations remains a major barrier to translating human genetics into pathophysiological mechanisms. Melanocortin-4 receptor-expressing (MC4R) neurons are key regulators of energy homeostasis and represent a potential site of action for these genes. Here, we investigated whether obesity-associated ciliary genes regulate body weight through MC4R neurons in vivo, using a Cre-dependent CRISPR interference (CRISPRi) strategy that enables temporal, spatial, and cell-type-specific gene repression without permanent DNA modification.Methods  Gene repression was achieved in MC4R neurons using a Cre-dependent CRISPRi system with AAV-delivered sgRNAs, and physiological outcomes, including body weight and body composition, were assessed following gene downregulation.Results  CRISPRi-mediated repression of Mc4r in adult PVNMC4R neurons reduced transcript and protein levels and induced progressive obesity, validating the approach. Downregulation of the ciliary adenylyl cyclase Adcy3 specifically in adult PVNMC4R neurons was sufficient to drive weight gain, establishing a cell-type-specific requirement for ADCY3 in body-weight regulation. An in vivo CRISPRi screen of obesity-associated ciliopathy genes (Bbs10, Inpp5e, Ankrd26) demonstrated that their repression in MC4R neurons is sufficient to promote obesity, identifying these neurons as a convergent site linking human ciliopathies to obesity.Conclusions  These findings define MC4R neurons as a critical neuronal population through which multiple obesity-associated ciliary genes act and establish a direct link between ciliary function in defined neuronal populations and organismal energy balance. This work provides insight into the neural mechanisms underlying obesity and a framework for linking human genetic variations to specific neuronal populations in vivo.
SN  - 2212-8778
ER  -