SUMOylation-deficient TRPV1 in sensory neurons confers resistance to high-fat diet-induced obesity via enhanced sympathetic adipose innervation

• SUMOylation-deficient TRPV1 prevents high-fat diet obesity and boosts energy use. • SUMOylation-deficient TRPV1 in DRG neurons elevates sympathetic drive and lipolysis. • SUMOylation-deficient TRPV1 in DRG neurons ameliorates obesity-associated metabolic dysfunction. • DRG TRPV1 SUMOylation controls HFD obesity via adipose sympathetic innervation. Sensory neurons have emerged as modulators of adipose metabolism and systemic energy balance, with implications for obesity. TRPV1, a nociceptive ion channel, also participates in metabolic regulation, but its precise role remains unclear. While our prior work showed that TRPV1 SUMOylation in sensory neurons is critical for nociception and itch, its contribution to obesity through neuro–metabolic crosstalk is unknown. To define the role and mechanism of TRPV1 SUMOylation in dorsal root ganglion (DRG) sensory neurons in the regulation of diet-induced obesity. We generated TRPV1 SUMOylation-deficient knock-in mice and employed AAV-mediated DRG-specific disruption of TRPV1 SUMOylation. Mice were subjected to a 12-week high-fat diet (HFD) to induce obesity. The role of DRG TRPV1 SUMOylation in regulating obesity was subsequently elucidated using a combination of metabolic phenotyping, indirect calorimetry, RNA sequencing, viral neuronal tracing, three-dimensional sympathetic imaging, and molecular analyses. SUMOylation-deficient TRPV1 conferred robust protection against HFD–induced weight gain, improved glucose and lipid homeostasis, and alleviated hepatic steatosis. Critically, DRG-targeted disruption of TRPV1 SUMOylation produced similar improvements in obesity and related metabolic parameters. Mechanistic analyses revealed that SUMOylation-deficient TRPV1 elevated sympathetic innervation, leading to enhanced lipolysis and increased energy expenditure under metabolic stress. Ablation of sympathetic nerves abolished these anti-obesity effects, confirming the requirement for the DRG–sympathetic–adipose axis. Our findings indicate that SUMOylation-deficient TRPV1 in DRG sensory neurons enhances sympathetic drive to adipose tissue and thereby regulates systemic energy balance via a newly identified neuro–adipose circuit. The identification of TRPV1 SUMOylation as a critical regulator of neuro–metabolic crosstalk highlights its potential as a therapeutic target for obesity and related metabolic disorders