Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway

Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the ef...

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Autores principales:	Ji-Yeon Lee, Minyoung Lee, Ji Young Lee, Jaehyun Bae, Eugene Shin, Yong-ho Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha
Formato:	article
Lenguaje:	EN
Publicado:	Korean Diabetes Association 2021
Materias:	adipose tissue obesity sodium-glucose transporter 2 inhibitors thermogenesis Diseases of the endocrine glands. Clinical endocrinology RC648-665
Acceso en línea:	https://doaj.org/article/8078313d0e374aa6aff5faf55d06cfe9
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spelling	oai:doaj.org-article:8078313d0e374aa6aff5faf55d06cfe92021-12-01T05:07:51ZIpragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway2233-60792233-608710.4093/dmj.2020.0187https://doaj.org/article/8078313d0e374aa6aff5faf55d06cfe92021-11-01T00:00:00Zhttp://www.e-dmj.org/upload/pdf/dmj-2020-0187.pdfhttps://doaj.org/toc/2233-6079https://doaj.org/toc/2233-6087Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism. Methods Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks. Results The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue. Conclusion SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.Ji-Yeon LeeMinyoung LeeJi Young LeeJaehyun BaeEugene ShinYong-ho LeeByung-Wan LeeEun Seok KangBong-Soo ChaKorean Diabetes Associationarticleadipose tissueobesitysodium-glucose transporter 2 inhibitorsthermogenesisDiseases of the endocrine glands. Clinical endocrinologyRC648-665ENDiabetes & Metabolism Journal, Vol 45, Iss 6, Pp 921-932 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	adipose tissue obesity sodium-glucose transporter 2 inhibitors thermogenesis Diseases of the endocrine glands. Clinical endocrinology RC648-665
spellingShingle	adipose tissue obesity sodium-glucose transporter 2 inhibitors thermogenesis Diseases of the endocrine glands. Clinical endocrinology RC648-665 Ji-Yeon Lee Minyoung Lee Ji Young Lee Jaehyun Bae Eugene Shin Yong-ho Lee Byung-Wan Lee Eun Seok Kang Bong-Soo Cha Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway
description	Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism. Methods Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks. Results The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue. Conclusion SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.
format	article
author	Ji-Yeon Lee Minyoung Lee Ji Young Lee Jaehyun Bae Eugene Shin Yong-ho Lee Byung-Wan Lee Eun Seok Kang Bong-Soo Cha
author_facet	Ji-Yeon Lee Minyoung Lee Ji Young Lee Jaehyun Bae Eugene Shin Yong-ho Lee Byung-Wan Lee Eun Seok Kang Bong-Soo Cha
author_sort	Ji-Yeon Lee
title	Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway
title_short	Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway
title_full	Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway
title_fullStr	Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway
title_full_unstemmed	Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway
title_sort	ipragliflozin, an sglt2 inhibitor, ameliorates high-fat diet-induced metabolic changes by upregulating energy expenditure through activation of the ampk/ sirt1 pathway
publisher	Korean Diabetes Association
publishDate	2021
url	https://doaj.org/article/8078313d0e374aa6aff5faf55d06cfe9
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Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway

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