Piezo2 in sensory neurons influences systemic and adipose tissue metabolism

Summary Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons regulate morphological and physiological properties of brown and beige fat and prevent systemic hypermetabolism. Targeting Runx3/PV sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat diet-induced obesity and caused adipose tissue browning and beiging, likely driven by elevated norepinephrine levels. Finding that brown and beige fat are innervated by Runx3/PV sensory neurons expressing Piezo2, suggests a model where mechanical signals sensed by Piezo2 in sensory neurons protect energy storages and prevent a systemic metabolic phenotype. Highlights Lack of Runx3/PV sensory neurons reduces body fat and fasting glucose levels and increases glucose tolerance in mice Mechanosensitive ion channel PIEZO2 in PV sensory neurons plays an important role in systemic metabolism under physiological and pathological conditions PIEZO2 in PV sensory neurons regulates thermogenic programs and glucose uptake in brown and beige adipose tissues Brown and beige adipose tissues are innervated by Runx3/PV sensory neurons