A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation

Yu Wang; Yunxiao Zhang; Verina H. Leung; Saba Heydari Seradj; Utku Sonmez; M. Rocio Servin-Vences; Shuke Xiao; Xiangyu Ren; Leon Wang; Sassan A. Mishkanian; Sejal A. Kini; Jonathan Z. Long; Darren J. Lipomi; Li Ye; Ardem Patapoutian

doi:10.1016/j.cmet.2025.02.004

A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation

Yu Wang, Yunxiao Zhang, Verina H. Leung, Saba Heydari Seradj, Utku Sonmez, M. Rocio Servin-Vences, Shuke Xiao, Xiangyu Ren, Leon Wang, Sassan A. Mishkanian, Sejal A. Kini, Jonathan Z. Long, Darren J. Lipomi, Li Ye^*, Ardem Patapoutian^*

^*Corresponding author for this work

Medicine, Gastroenterology Division

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Compared with the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work has revealed the anatomical and physiological significance of adipose sensory innervation; however, its molecular underpinning remains unclear. Here, using organ-targeted single-cell RNA sequencing, we identified the mechanoreceptor PIEZO2 as one of the most prevalent receptors in fat-innervating dorsal root ganglia (DRG) neurons. PIEZO2 deletion in fat-innervating neurons induced transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation. Conversely, a gain-of-function PIEZO2 mutant shifted the adipose phenotypes in the opposite direction. These results indicate that PIEZO2 plays a major role in the sensory regulation of adipose tissues. This discovery opens new avenues for exploring mechanosensation in organs not traditionally considered mechanically active, such as adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis.

Original language	English (US)
Pages (from-to)	1001-1011.e7
Journal	Cell Metabolism
Volume	37
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2025.02.004
State	Published - Apr 1 2025

Funding

We thank all members of the Patapoutian and Ye lab for their support and feedback. We thank Drs Jeffery Friedman, Enrique Saez, and Kara Marshall for their input; Shang Ma, Adrienne Dubin, and Meaghan Loud for generating and characterizing the PIEZO2 GOF mouse line; Alexandra Selke for assisting with experiments; Jeffery Stirman for the imaging support; and the staff at Scripps FACS core and genomics core for sample preparation. This work was supported by the Howard Hughes Medical Institute (to A.P. and L.Y.), NIH grants R01AT012051 (to A.P.), and NIH Director's New Innovator Award DP2DK128800 (to L.Y.). L.Y. was also supported by the NIDDK, NIDA, NIMH, NCI, BRAIN Initiative, the Chan Zuckerberg Initiative, and the Dana, Whitehall, Baxter, and Abide-Vividion Foundations. J.Z.L. was supported by NIH (DK124265 and DK130541) and also supported by the Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, the Ono Pharma Foundation. Y.W. was supported by the Dorris Scholar Award; Y.Z. is a Merck Fellow of the Damon Runyon Cancer Research Foundation, DRG-2405-20; and S.X is supported by an American Heart Association postdoctoral fellowship (24POST1200064). U.S. and D.J.L. acknowledge support from the National Science Foundation, grant number CMMI-2135428.

Keywords

adipose
mechanosensation

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2025.02.004

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title = "A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation",

abstract = "Compared with the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work has revealed the anatomical and physiological significance of adipose sensory innervation; however, its molecular underpinning remains unclear. Here, using organ-targeted single-cell RNA sequencing, we identified the mechanoreceptor PIEZO2 as one of the most prevalent receptors in fat-innervating dorsal root ganglia (DRG) neurons. PIEZO2 deletion in fat-innervating neurons induced transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation. Conversely, a gain-of-function PIEZO2 mutant shifted the adipose phenotypes in the opposite direction. These results indicate that PIEZO2 plays a major role in the sensory regulation of adipose tissues. This discovery opens new avenues for exploring mechanosensation in organs not traditionally considered mechanically active, such as adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis.",

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AU - Zhang, Yunxiao

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AU - Seradj, Saba Heydari

AU - Sonmez, Utku

AU - Servin-Vences, M. Rocio

AU - Xiao, Shuke

AU - Ren, Xiangyu

AU - Wang, Leon

AU - Mishkanian, Sassan A.

AU - Kini, Sejal A.

AU - Long, Jonathan Z.

AU - Lipomi, Darren J.

AU - Ye, Li

AU - Patapoutian, Ardem

PY - 2025/4/1

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N2 - Compared with the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work has revealed the anatomical and physiological significance of adipose sensory innervation; however, its molecular underpinning remains unclear. Here, using organ-targeted single-cell RNA sequencing, we identified the mechanoreceptor PIEZO2 as one of the most prevalent receptors in fat-innervating dorsal root ganglia (DRG) neurons. PIEZO2 deletion in fat-innervating neurons induced transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation. Conversely, a gain-of-function PIEZO2 mutant shifted the adipose phenotypes in the opposite direction. These results indicate that PIEZO2 plays a major role in the sensory regulation of adipose tissues. This discovery opens new avenues for exploring mechanosensation in organs not traditionally considered mechanically active, such as adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis.

AB - Compared with the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work has revealed the anatomical and physiological significance of adipose sensory innervation; however, its molecular underpinning remains unclear. Here, using organ-targeted single-cell RNA sequencing, we identified the mechanoreceptor PIEZO2 as one of the most prevalent receptors in fat-innervating dorsal root ganglia (DRG) neurons. PIEZO2 deletion in fat-innervating neurons induced transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation. Conversely, a gain-of-function PIEZO2 mutant shifted the adipose phenotypes in the opposite direction. These results indicate that PIEZO2 plays a major role in the sensory regulation of adipose tissues. This discovery opens new avenues for exploring mechanosensation in organs not traditionally considered mechanically active, such as adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis.

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A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation

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