PMID- 36965744 OWN - NLM STAT- MEDLINE DCOM- 20230411 LR - 20230411 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 947 DP - 2023 May 15 TI - Combined treatment with teneligliptin and canagliflozin additively suppresses high-fat diet-induced body weight gain in mice with modulation of lipid metabolism-related gene expression. PG - 175682 LID - S0014-2999(23)00193-0 [pii] LID - 10.1016/j.ejphar.2023.175682 [doi] AB - In the treatment of type 2 diabetes mellitus (T2DM), comprehensive management of multiple risk factors, such as blood glucose, body weight, and lipids, is important to prevent disease progression. Although the combination of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter 2 (SGLT2) inhibitor is often used clinically, the effects of this combination, other than glucose metabolism, have yet to be thoroughly investigated. In this study, we evaluated the effects of combined treatment with a DPP-4 inhibitor, teneligliptin, and an SGLT2 inhibitor, canagliflozin, on the body weight and lipid metabolism in high-fat diet (HFD)-induced obese mice. We found that monotherapy with teneligliptin or canagliflozin showed suppressive effects on high-fat diet-induced body weight gain and reduced inguinal white adipose tissue (iWAT) mass, and combined treatment additively reduced body weight gain and iWAT mass. Teneligliptin significantly increased oxygen consumption during the light phase, and this effect was preserved in the combined treatment. The combined treatment did not alter the mRNA expression levels of thermogenesis-related genes in adipose tissue but showed the tendency to additively induce mRNA of fatty acid oxidation-related genes in brown adipose tissue and tended to additively decrease mRNA of fatty acid synthesis-related genes in iWAT and liver tissues. These results suggest that combined treatment with teneligliptin and canagliflozin additively suppresses HFD-induced body weight gain with increasing oxygen consumption and modulating the expression of lipid metabolism-related genes. This combination therapy may provide effective body weight management for patients with T2DM and obesity. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Kawarasaki, Satoko AU - Kawarasaki S AD - Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan. FAU - Sawazaki, Honami AU - Sawazaki H AD - Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan. FAU - Iijima, Hiroaki AU - Iijima H AD - Medical Affairs Department, Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. FAU - Takahashi, Haruya AU - Takahashi H AD - Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan. FAU - Nomura, Wataru AU - Nomura W AD - Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, 606-8317, Japan. FAU - Inoue, Kazuo AU - Inoue K AD - Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, 606-8317, Japan. FAU - Kawada, Teruo AU - Kawada T AD - Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, 606-8317, Japan. FAU - Goto, Tsuyoshi AU - Goto T AD - Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan; Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, 606-8317, Japan. Electronic address: goto.tsuyoshi.6x@kyoto-u.ac.jp. LA - eng PT - Journal Article DEP - 20230324 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0SAC974Z85 (Canagliflozin) RN - 0 (3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (RNA, Messenger) RN - 0 (Fatty Acids) SB - IM MH - Mice MH - Animals MH - Canagliflozin/pharmacology/therapeutic use MH - *Diabetes Mellitus, Type 2/metabolism MH - Lipid Metabolism MH - Diet, High-Fat/adverse effects MH - *Sodium-Glucose Transporter 2 Inhibitors/pharmacology MH - Hypoglycemic Agents/pharmacology/therapeutic use MH - Weight Gain MH - Body Weight MH - *Dipeptidyl-Peptidase IV Inhibitors/pharmacology/therapeutic use MH - RNA, Messenger/metabolism MH - Fatty Acids MH - Gene Expression OTO - NOTNLM OT - Canagliflozin OT - Combined treatment OT - Lipid metabolism OT - Teneligliptin COIS- Declaration of competing interest H. Iijima is an employee of Mitsubishi Tanabe Pharma Corporation. The company person was not involved in the experiment or result analysis but contributed to interpreting the results based on his knowledge of medicine and pharmacology. No other authors have potential conflicts of interest. EDAT- 2023/03/26 06:00 MHDA- 2023/04/11 06:42 CRDT- 2023/03/25 20:31 PHST- 2023/01/28 00:00 [received] PHST- 2023/03/20 00:00 [revised] PHST- 2023/03/22 00:00 [accepted] PHST- 2023/04/11 06:42 [medline] PHST- 2023/03/26 06:00 [pubmed] PHST- 2023/03/25 20:31 [entrez] AID - S0014-2999(23)00193-0 [pii] AID - 10.1016/j.ejphar.2023.175682 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 May 15;947:175682. doi: 10.1016/j.ejphar.2023.175682. Epub 2023 Mar 24.