4.7 Article

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

期刊

BRITISH JOURNAL OF PHARMACOLOGY
卷 178, 期 8, 页码 1756-1771

出版社

WILEY
DOI: 10.1111/bph.15381

关键词

beige fat; lipolysis; obesity; SGLT2 inhibitors; sympathetic innervation

资金

  1. National Natural Science Foundation of China [81471068, 81603035, 81870599, 81873662, 82025007, 81930020]
  2. Natural Science Foundation of Shanghai [18ZR1435900]
  3. Postdoctoral Fellowship of Sichuan University [2017SCU12036]
  4. Young Scientist Fellowship of Sichuan University [2017SCU11026]
  5. China Postdoctoral Fellowship [2017M612981]

向作者/读者索取更多资源

The study shows that treatment with canagliflozin helps resist high-fat diet-induced obesity and its metabolic consequences by reducing fat mass and increasing energy expenditure through enhancing thermogenesis and lipolysis in adipose tissue. Canagliflozin also improves insulin resistance and hepatic steatosis via elevating adipose sympathetic innervation and fat mobilization through a beta(3)-adrenoceptor-cAMP-PKA signaling pathway.
Background and Purpose Inhibition 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 Approach Adult 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 Results Mice 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 beta(3)-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 Implications Chronic 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.

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