Inhibition of the sodium–glucose co‐transporter SGLT2 by canagliflozin ameliorates diet‐induced obesity by increasing intra‐adipose sympathetic innervation

• DOI: 10.1111/bph.15381
• Publication Date: 2021-01-22T23:10:33Z
• Authors: Xuping Yang; Qinhui Liu; Yanping Li; Yi Ding; Yan Zhao; Qin Tang; Tong Wu; Lei Chen; Shiyun Pu; Shihai Cheng; Jinhang Zhang; Zijing Zhang; Ya Huang; Rui Li; Yingnan Zhao; Min Zou; Xiongjie Shi; Wei Jiang; Rui Wang; Jinhan He
• Keywords: Male; 0301 basic medicine; 2. Zero hunger; Sodium; Diet, High-Fat; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Glucose; Adipose Tissue; Sodium-Glucose Transporter 2; Positron Emission Tomography Computed Tomography; Animals; Obesity; Canagliflozin

Background and PurposeInhibition of the sodium–glucose cotransporter 2 (SGLT2) induces hypoglycaemia by increasing urinary glucose excretion and increasing the use of fat. However, the underlying mechanism is poorly understood. This study was aimed to determine the effects of canagliflozin, a selective SGLT2 inhibitor, on diet‐induced obesity and the underlying mechanism(s).Experimental ApproachAdult C57BL/6J male mice were fed with a standard chow diet or high‐fat diet supplemented with vehicle or canagliflozin. Whole body energy expenditure was monitored by metabolic cages, noradrenaline levels were measured by HPLC, glucose uptake was measured by PET/CT, and mRNA and protein expression were measured by RT‐PCR and western blotting analysis.Key ResultsMice treated with canagliflozin were resistant to high‐fat diet‐induced obesity and its metabolic consequences. Canagliflozin treatment decreased fat mass and increased energy expenditure via increasing thermogenesis and lipolysis in adipose tissue. Mechanistically, SGLT2 inhibition by canagliflozin elevated adipose sympathetic innervation and fat mobilization via a β3‐adrenoceptor‐cAMP‐PKA signalling pathway. Finally, we showed that canagliflozin improved insulin resistance and hepatic steatosis in mice fed with a high‐fat diet.Conclusions and ImplicationsChronic inhibition of SGLT2 increased energy consumption by increasing intra‐adipose sympathetic innervation to counteract diet‐induced obesity. The present study reveals a new therapeutic function for SGLT2 inhibitors in regulating energy homeostasis.