Sodium-glucose co-transporter 2 inhibitor-induced increase in adenosine promotes lipolysis and weight reduction by activating reno-adipose autonomic neurocircuitry

Sodium-glucose co-transporter 2 (SGLT2) inhibitors promote weight loss in patients with type 2 diabetes mellitus; however, the underlying mechanisms remain unknown. This study investigated the role of renal autonomic nerves in SGLT2 inhibitor-induced lipolysis and body weight reduction by utilizing the renal denervation technique. The results indicated that renal autonomic nerves mediated lipolysis in mice fed a high-fat diet following treatment with tofogliflozin, an SGLT2 inhibitor. The effect was attenuated by renal denervation or β3-adrenergic blockade. Metabolomic analysis revealed that treatment with tofogliflozin elevated renal adenosine, which in turn activated adipose sympathetic nerves, as evidenced by increased norepinephrine concentrations in adipose tissue, thereby promoting lipolysis. These findings uncover a novel reno-adipose neurocircuitry linking renal energy depletion to systemic fatty acid oxidation, providing insights into the sustained weight-reducing effects of SGLT2 inhibitors. A scheme illustrating SGLT2 inhibitor-induced activation of reno-adipose autonomic neurocircuitry, which promotes lipolysis and weight reduction.