Dan Wei1, Lin Liao2, Huanjun Wang2, Wei Zhang2, Tingting Wang2, Zhipeng Xu3. 1. Department of Endocrinology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China; Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China. Electronic address: 77weidan@163.com. 2. Department of Endocrinology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China; Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China. 3. Department of Urology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China; Department of Urology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China. Electronic address: scofield_xzp@163.com.
Abstract
AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reported to significantly reduce body weight. This study investigated whether SGLT2 inhibitors directly affect adipose tissues and the underlying mechanisms in vivo and in vitro. MAIN METHODS: Male C57BL/6 mice were fed a normal diet, high-fat diet (HFD), or HFD with canagliflozin for 14 weeks. 3T3-L1 adipocytes were treated with canagliflozin. Metabolic parameters were measured. KEY FINDINGS: Canagliflozin reduced body weight, fat mass, and white adipose tissue (WAT) weight and inhibited adipocyte hypertrophy. Canagliflozin improved glucose and lipid metabolic disorders induced by HFD. Furthermore, canagliflozin treatment reversed the suppressed mRNA and protein expression of PGC-1α, NRF1, tfam and CPT1b, which are markers of mitochondrial biogenesis, function and fatty acid oxidation in mice with obesity. In vitro, canagliflozin increased mitochondrial DNA to nuclear DNA and upregulated the expression of PGC-1α, NRF1, tfam, COX5b, COX8b, Atp5o, and CPT1b mRNA and PGC-1α, NRF1, tfam, COX5b, CPT1b protein in 3T3-L1 adipocytes in a dose-dependent manner, while these increases were inhibited by GW6471, a PPARα antagonist. SIGNIFICANCE: Our study showed that canagliflozin protected against HFD-induced obesity and obesity-related metabolic disorders by improving mitochondrial function and fatty acid oxidation in adipose tissue and adipocytes. Such energy-dissipating effects of canagliflozin may be mediated by PPARα.
AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reported to significantly reduce body weight. This study investigated whether SGLT2 inhibitors directly affect adipose tissues and the underlying mechanisms in vivo and in vitro. MAIN METHODS: Male C57BL/6 mice were fed a normal diet, high-fat diet (HFD), or HFD with canagliflozin for 14 weeks. 3T3-L1 adipocytes were treated with canagliflozin. Metabolic parameters were measured. KEY FINDINGS:Canagliflozin reduced body weight, fat mass, and white adipose tissue (WAT) weight and inhibited adipocyte hypertrophy. Canagliflozin improved glucose and lipid metabolic disorders induced by HFD. Furthermore, canagliflozin treatment reversed the suppressed mRNA and protein expression of PGC-1α, NRF1, tfam and CPT1b, which are markers of mitochondrial biogenesis, function and fatty acid oxidation in mice with obesity. In vitro, canagliflozin increased mitochondrial DNA to nuclear DNA and upregulated the expression of PGC-1α, NRF1, tfam, COX5b, COX8b, Atp5o, and CPT1b mRNA and PGC-1α, NRF1, tfam, COX5b, CPT1b protein in 3T3-L1 adipocytes in a dose-dependent manner, while these increases were inhibited by GW6471, a PPARα antagonist. SIGNIFICANCE: Our study showed that canagliflozin protected against HFD-induced obesity and obesity-related metabolic disorders by improving mitochondrial function and fatty acid oxidation in adipose tissue and adipocytes. Such energy-dissipating effects of canagliflozin may be mediated by PPARα.
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