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

Authors

Abbey Diener Blake, Zhixuan Zhang, Coralie Alexandre, Anne Gorayeb, Mrinaalini Jain, Qi Liu, Rithu Pattali, Alicja Bednarska, Parleen Kaur Pandher, Sumei Zhang, Xinyu Yue, James Nuñez, Christian Vaisse

Published in

Molecular metabolism. Pages 102454. Oct 06, 2026. Epub Oct 06, 2026.

Abstract

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.
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.
CRISPRi-mediated repression of Mc4r in adult PVN^MC4R neurons reduced transcript and protein levels and induced progressive obesity, validating the approach. Downregulation of the ciliary adenylyl cyclase Adcy3 specifically in adult PVN^MC4R 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.
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.

PMID:
42838451
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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