A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation [bulk RNA-seq]

Compared to the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work 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. Selective PIEZO2 deletion in fat-innervating neurons led to molecular alternations in adipose tissue similar to 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 the adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis. Overall design: A unilateral retrograde AAV injection expressing Cre was administered into the iWAT of PIEZO2f/f or PIEZO2GOF f/f male mice to knock out PIEZO2 or express the PIEZO2 GOF mutant in fat-innervating DRGs. Mice were then maintained on a chow or high-fat diet (HFD) for three weeks before tissue harvesting.