Effects of Dapagliflozin on Adipose and Liver Fatty Acid Composition and
mRNA Expression Involved in Lipid Metabolism in High-Fat-Fed Rats

Daisuke      Sato; Takao      Nakamura; Jota      Amarume; Mizuna      Yano; Yuta      Umehara; Atsuyoshi      Nishina; Kazuhiko      Tsutsumi; Zhonggang      Feng; Masataka      Kusunoki

doi:10.2174/1871530322666220307153618

Abstract

Background: SGLT2 inhibitor enhances not only glucose excretion but also fatty acid utilization. Those facts suggest that SGLT2 inhibitor affects fat accumulation and lipid storage.

Objective: In the present study, we evaluated the effects of dapagliflozin on fatty acid composition and gene expression involved in fatty acid metabolism in rat adipose and liver tissues.

Methods: We administered 1 mg/kg/day dapagliflozin for 7 weeks to male high-fat-fed rats (DAPA group), and then weights and 22 fatty acid contents in the epididymal (EPI), mesenteric (MES), retroperitoneal (RET), and subcutaneous (SUB) adipose tissues, and the liver were compared with the vehicle-administered control group.

Results: In the EPI, RET, and SUB in the DAPA group, contents of several fatty acids were lower (P<0.05) than those in the control group, while no significant difference was detected in tissue weight. In the MES, tissue weight and a wide variety of fatty acid contents, including saturated, monounsaturated, and polyunsaturated fatty acids, were lower (P<0.05). As for the liver tissue, no significant difference was observed in fatty acid contents between the groups. mRNA expression of Srebp1c in EPI was significantly higher (P<0.05) in the DAPA group than in the control group, while Scd1 expression in the liver was lower (P<0.01).

Conclusion: These results suggest that dapagliflozin might suppress lipid accumulation especially in the MES, and could reduce contents of fatty acids not in the liver but in adipose tissues in high-fat-fed rats. In addition, dapagliflozin could influence mRNA expression involved in lipogenesis in the EPI and liver.

Keywords: SGLT2 inhibitor, fatty acid composition, lipid metabolism, insulin resistance, high-fat diet, adipose tissue, liver.

« Previous Next »

Graphical Abstract

[1] 
Kamei, S.; Iwamoto, M.; Kameyama, M.; Shimoda, M.; Kinoshita, T.; Obata, A.; Kimura, T.; Hirukawa, H.; Tatsumi, F.; Kohara, K.; Nakanishi, S.; Mune, T.; Kaku, K.; Kaneto, H. Effect of tofogliflozin on body composition and glycemic control in Japanese subjects with type 2 diabetes mellitus. J. Diabetes Res.,  2018, 2018, 6470137.
[http://dx.doi.org/10.1155/2018/6470137] [PMID:  29507863] 
[2] 
Kashiwagi, A.; Kazuta, K.; Takinami, Y.; Yoshida, S.; Utsuno, A.; Nagase, I. Ipragliflozin improves glycemic control in Japanese patients with type 2 diabetes mellitus: The BRIGHTEN study. Diabetol. Int.,  2014, 6(1), 8-18.
[http://dx.doi.org/10.1007/s13340-014-0164-0] 
[3] 
Johnston, R.; Uthman, O.; Cummins, E.; Clar, C.; Royle, P.; Colquitt, J.; Tan, B.K.; Clegg, A.; Shantikumar, S.; Court, R.; O’Hare, J.P.; McGrane, D.; Holt, T.; Waugh, N. Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: Systematic review and economic evaluation. Health Technol. Assess.,  2017, 21(2), 1-218.
[http://dx.doi.org/10.3310/hta21020] [PMID:  28105986] 
[4] 
Seino, Y.; Sasaki, T.; Fukatsu, A.; Ubukata, M.; Sakai, S.; Samukawa, Y. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, phase 3 study. Curr. Med. Res. Opin.,  2014, 30(7), 1245-1255.
[http://dx.doi.org/10.1185/03007995.2014.912983] [PMID:  24708292] 
[5] 
Kern, M.; Klöting, N.; Mark, M.; Mayoux, E.; Klein, T.; Blüher, M. The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin. Metabolism,  2016, 65(2), 114-123.
[http://dx.doi.org/10.1016/j.metabol.2015.10.010] [PMID:  26773934] 
[6] 
Merovci, A.; Solis-Herrera, C.; Daniele, G.; Eldor, R.; Fiorentino, T.V.; Tripathy, D.; Xiong, J.; Perez, Z.; Norton, L.; Abdul-Ghani, M.A.; DeFronzo, R.A. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest.,  2014, 124(2), 509-514.
[http://dx.doi.org/10.1172/JCI70704] [PMID:  24463448] 
[7] 
Kennedy, A.; Martinez, K.; Chuang, C.C.; LaPoint, K.; McIntosh, M. Saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: Mechanisms of action and implications. J. Nutr.,  2009, 139(1), 1-4.
[http://dx.doi.org/10.3945/jn.108.098269] [PMID:  19056664] 
[8] 
Kusunoki, M.; Natsume, Y.; Miyata, T.; Tsutsumi, K.; Oshida, Y. Effects of concomitant administration of a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes showing relatively good glycemic control under treatment with a sodium glucose co-transporter 2 inhibitor. Drug Res. (Stuttg.),  2018, 68(12), 704-709.
[http://dx.doi.org/10.1055/a-0585-0145] [PMID:  29966149] 
[9] 
Yokono, M.; Takasu, T.; Hayashizaki, Y.; Mitsuoka, K.; Kihara, R.; Muramatsu, Y.; Miyoshi, S.; Tahara, A.; Kurosaki, E.; Li, Q.; Tomiyama, H.; Sasamata, M.; Shibasaki, M.; Uchiyama, Y. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur. J. Pharmacol.,  2014, 727, 66-74.
[http://dx.doi.org/10.1016/j.ejphar.2014.01.040] [PMID:  24486393] 
[10] 
Eriksson, J.W.; Lundkvist, P.; Jansson, P.A.; Johansson, L.; Kvarnström, M.; Moris, L.; Miliotis, T.; Forsberg, G.B.; Risérus, U.; Lind, L.; Oscarsson, J. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: A double-blind randomised placebo-controlled study. Diabetologia,  2018, 61(9), 1923-1934.
[http://dx.doi.org/10.1007/s00125-018-4675-2] [PMID:  29971527] 
[11] 
Sato, D.; Nakamura, T.; Tsutsumi, K.; Shinzawa, G.; Karimata, T.; Okawa, T.; Feng, Z.; Kusunoki, M. Site dependency of fatty acid composition in adipose triacylglycerol in rats and its absence as a result of high-fat feeding. Metabolism,  2012, 61(1), 92-98.
[http://dx.doi.org/10.1016/j.metabol.2011.05.012] [PMID:  21696790] 
[12] 
Sato, D.; Oda, K.; Kusunoki, M.; Nishina, A.; Takahashi, K.; Feng, Z.; Tsutsumi, K.; Nakamura, T. PPARγ activation alters fatty acid composition in adipose triglyceride, in addition to proliferation of small adipocytes, in insulin resistant high-fat fed rats. Eur. J. Pharmacol.,  2016, 773, 71-77.
[http://dx.doi.org/10.1016/j.ejphar.2016.01.012] [PMID:  26825545] 
[13] 
Matsuzaka, T.; Shimano, H.; Yahagi, N.; Kato, T.; Atsumi, A.; Yamamoto, T.; Inoue, N.; Ishikawa, M.; Okada, S.; Ishigaki, N.; Iwasaki, H.; Iwasaki, Y.; Karasawa, T.; Kumadaki, S.; Matsui, T.; Sekiya, M.; Ohashi, K.; Hasty, A.H.; Nakagawa, Y.; Takahashi, A.; Suzuki, H.; Yatoh, S.; Sone, H.; Toyoshima, H.; Osuga, J.; Yamada, N. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nat. Med.,  2007, 13(10), 1193-1202.
[http://dx.doi.org/10.1038/nm1662] [PMID:  17906635] 
[14] 
Sampath, H.; Ntambi, J.M. The role of stearoyl-CoA desaturase in obesity, insulin resistance, and inflammation. Ann. N. Y. Acad. Sci.,  2011, 1243(1), 47-53.
[http://dx.doi.org/10.1111/j.1749-6632.2011.06303.x] [PMID:  22211892] 
[15] 
Hayashizaki-Someya, Y.; Kurosaki, E.; Takasu, T.; Mitori, H.; Yamazaki, S.; Koide, K.; Takakura, S. Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats. Eur. J. Pharmacol.,  2015, 754, 19-24.
[http://dx.doi.org/10.1016/j.ejphar.2015.02.009] [PMID:  25701721] 
[16] 
Honda, Y.; Imajo, K.; Kato, T.; Kessoku, T.; Ogawa, Y.; Tomeno, W.; Kato, S.; Mawatari, H.; Fujita, K.; Yoneda, M.; Saito, S.; Nakajima, A. The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice. PLoS One,  2016, 11(1), e0146337.
[http://dx.doi.org/10.1371/journal.pone.0146337] [PMID:  26731267] 
[17] 
Kusunoki, M.; Natsume, Y.; Sato, D.; Tsutsui, H.; Miyata, T.; Tsutsumi, K.; Suga, T.; Oshida, Y. Luseogliflozin, a sodium glucose co-transporter 2 inhibitor, alleviates hepatic impairment in Japanese patients with type 2 diabetes. Drug Res. (Stuttg.),  2016, 66(11), 603-606.
[http://dx.doi.org/10.1055/s-0042-111515] [PMID:  27626603] 
[18] 
Sato, D.; Kusunoki, M.; Seino, N.; Nishina, A.; Feng, Z.; Tsutsumi, K.; Nakamura, T. Black soybean extract reduces fatty acid contents in subcutaneous, but not in visceral adipose triglyceride in high-fat fed rats. Int. J. Food Sci. Nutr.,  2015, 66(5), 539-545.
[http://dx.doi.org/10.3109/09637486.2015.1028907] [PMID:  25830948] 
[19] 
Schmitz, G.; Ecker, J. The opposing effects of n-3 and n-6 fatty acids. Prog. Lipid Res.,  2008, 47(2), 147-155.
[http://dx.doi.org/10.1016/j.plipres.2007.12.004] [PMID:  18198131] 
[20] 
Chen, H.; Yuan, R.; Zhang, Y.; Zhang, X.; Chen, L.; Zhou, X.; Yuan, Z.; Nie, Y.; Li, M.; Mo, D.; Chen, Y. ATF4 regulates SREBP1c expression to control fatty acids synthesis in 3T3-L1 adipocytes differentiation. Biochim. Biophys. Acta,  2016, 1859(11), 1459-1469.
[http://dx.doi.org/10.1016/j.bbagrm.2016.07.010] [PMID:  27452504] 
[21] 
Luiken, J.J.; Coort, S.L.; Willems, J.; Coumans, W.A.; Bonen, A.; Glatz, J.F. Dipyridamole alters cardiac substrate preference by inducing translocation of FAT/CD36, but not that of GLUT4. Mol. Pharmacol.,  2004, 65(3), 639-645.
[http://dx.doi.org/10.1124/mol.65.3.639] [PMID:  14978242] 
[22] 
Kanda, Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant.,  2013, 48(3), 452-458.
[http://dx.doi.org/10.1038/bmt.2012.244] [PMID:  23208313] 
[23] 
Devenny, J.J.; Godonis, H.E.; Harvey, S.J.; Rooney, S.; Cullen, M.J.; Pelleymounter, M.A. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring),  2012, 20(8), 1645-1652.
[http://dx.doi.org/10.1038/oby.2012.59] [PMID:  22402735] 
[24] 
Masuda, T.; Muto, S.; Fukuda, K.; Watanabe, M.; Ohara, K.; Koepsell, H.; Vallon, V.; Nagata, D. Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume. Physiol. Rep.,  2020, 8(2), e14360.
[http://dx.doi.org/10.14814/phy2.14360] [PMID:  31994353] 
[25] 
Xu, L.; Nagata, N.; Nagashimada, M.; Zhuge, F.; Ni, Y.; Chen, G.; Mayoux, E.; Kaneko, S.; Ota, T. SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice. EBioMedicine,  2017, 20, 137-149.
[http://dx.doi.org/10.1016/j.ebiom.2017.05.028] [PMID:  28579299] 
[26] 
Wei, D.; Liao, L.; Wang, H.; Zhang, W.; Wang, T.; Xu, Z. 
            Canagliflozin ameliorates obesity by improving mitochondrial function and fatty acid oxidation 
            via
             PPARα 
            in vivo
             and 
            in vitro
.
           Life Sci.,  2020, 247, 117414.
[http://dx.doi.org/10.1016/j.lfs.2020.117414] [PMID:  32035928] 
[27] 
Yang, X.; Liu, Q.; Li, Y.; Tang, Q.; Wu, T.; Chen, L.; Pu, S.; Zhao, Y.; Zhang, G.; Huang, C.; Zhang, J.; Zhang, Z.; Huang, Y.; Zou, M.; Shi, X.; Jiang, W.; Wang, R.; He, J. 
            The diabetes medication canagliflozin promotes mitochondrial remodelling of adipocyte 
            via
             the AMPK-Sirt1-Pgc-1α signalling pathway.
           Adipocyte,  2020, 9(1), 484-494.
[http://dx.doi.org/10.1080/21623945.2020.1807850] [PMID:  32835596] 
[28] 
Osataphan, S.; Macchi, C.; Singhal, G.; Chimene-Weiss, J.; Sales, V.; Kozuka, C.; Dreyfuss, J.M.; Pan, H.; Tangcharoenpaisan, Y.; Morningstar, J.; Gerszten, R.; Patti, M.E. 
            SGLT2 inhibition reprograms systemic metabolism 
            via
             FGF21-dependent and -independent mechanisms.
           JCI Insight,  2019, 4(5), e123130.
[http://dx.doi.org/10.1172/jci.insight.123130] [PMID:  30843877] 
[29] 
Imamura, F.; Micha, R.; Wu, J.H.; de Oliveira Otto, M.C.; Otite, F.O.; Abioye, A.I.; Mozaffarian, D. Effects of saturated fat, polyunsaturated fat, monounsaturated fat, and carbohydrate on glucose-insulin homeostasis: A systematic review and meta-analysis of randomised controlled feeding trials. PLoS Med.,  2016, 13(7), e1002087.
[http://dx.doi.org/10.1371/journal.pmed.1002087] [PMID:  27434027] 
[30] 
Presler, M.; Wojtczyk-Miaskowska, A.; Schlichtholz, B.; Kaluzny, A.; Matuszewski, M.; Mika, A.; Sledzinski, T.; Swierczynski, J. Increased expression of the gene encoding stearoyl-CoA desaturase 1 in human bladder cancer. Mol. Cell. Biochem.,  2018, 447(1-2), 217-224.
[http://dx.doi.org/10.1007/s11010-018-3306-z] [PMID:  29396722] 
[31] 
Aljohani, A.; Khan, M.I.; Bonneville, A.; Guo, C.; Jeffery, J.; O’Neill, L.; Syed, D.N.; Lewis, S.A.; Burhans, M.; Mukhtar, H.; Ntambi, J.M. Hepatic stearoyl CoA desaturase 1 deficiency increases glucose uptake in adipose tissue partially through the PGC-1α-FGF21 axis in mice. J. Biol. Chem.,  2019, 294(51), 19475-19485.
[http://dx.doi.org/10.1074/jbc.RA119.009868] [PMID:  31690632] 

Rights & Permissions Print Cite

Article Metrics

19

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1871530322666220307153618	Print ISSN 1871-5303
Publisher Name Bentham Science Publisher	Online ISSN 2212-3873

Endocrine, Metabolic & Immune Disorders - Drug Targets

Effects of Dapagliflozin on Adipose and Liver Fatty Acid Composition and mRNA Expression Involved in Lipid Metabolism in High-Fat-Fed Rats

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract