Abstract
Insulin resistance is a worldwide health problem. This study investigated the acute effects of eicosapentanoic acid (EPA) on glucose homeostasis focusing on the role of free fatty acid receptor 1 (FFAR1) and the chronic effects of fish oil omega-3 fatty acids on insulin resistance. Insulin resistance was induced by feeding mice high-fructose, high-fat diet (HFrHFD) for 16 weeks. In the first part, the acute effects of EPA alone and in combination with GW1100 and DC260126 (FFAR1 blockers) on glucose homeostasis and hepatic phosphatidyl-inositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) were investigated in standard chow diet (SCD)- and HFrHFD-fed mice. In the second part, mice were treated with fish oil omega-3 fatty acids for 4 weeks starting at the week 13 of feeding HFrHFD. Changes in the blood- and liver tissue-insulin resistance markers and FFAR1 downstream signals were recorded at the end of experiment. Results showed that EPA increased 0 and 30 min blood glucose levels after glucose load in SCD-fed mice but improved glucose tolerance in HFrHFD-fed mice. Moreover, FFAR1 blockers reduced EPA effects on glucose tolerance and hepatic PIP2 and DAG levels. On the other hand, chronic use of fish oil omega-3 fatty acids increased FBG levels and decreased serum insulin and triglycerides levels without improving the index of insulin resistance. Also, they increased hepatic β-arrestin-2, PIP2, and pS473 Akt levels but decreased DAG levels. In conclusion, EPA acutely improved glucose homeostasis in HFrHFD-fed mice by modulating the activity of FFAR1. However, the chronic use of fish oil omega-3 fatty acids did not improve the insulin resistance.
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References
Ahmadian M, Duncan RE, Sul HS (2007) Triacylglycerol metabolism in adipose tissue. Future Lipidol 2:229–237
Akinkuolie AO, Ngwa JS, Djoussé L (2011) Omega-3 polyunsaturated fatty acid and insulin sensitivity: a meta-analysis of randomized controlled trials. Clin Nutr 30:702–707
Albert BB, Derraik JG, Brennan CM, Biggs JB, Smith GC, Garg ML et al (2014) Higher omega-3 index is associated with increased insulin sensitivity and more favourable metabolic profile in middle-aged overweight men. Sci Rep 4:6697
Baker PW, Gibbons GF (2000) Effect of dietary fish oil on the sensitivity of hepatic lipid metabolism to regulation by insulin. J Lipid Res 41:719–726
Basciano H, Federico L, Adeli K (2005) Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab. 2:5
Bauer S, Wennberg Huldt C, Kanebratt K, Durieux I, Gunne D, Andersson S et al (2017) Functional coupling of human pancreatic islets and liver spheroids on-a-chip: towards a novel human ex vivo type 2 diabetes model. Sci Rep 7:14620
Behme MT (1996) Dietary fish oil enhances insulin sensitivity in miniature pigs. J Nutr 126:1549–1553
Boden G (2011) Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes 18:139–143
Borkman M, Chisholm DJ, Furler SM, Storlien LH, Kraegen EW, Simons LA, Chesterman CN (1989) Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM. Diabetes. 38:1314–1319
Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR Jr, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI (2003) The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 278:11303–11311
Burant CF (2013) Activation of GPR40 as a therapeutic target for the treatment of type 2 diabetes. Diabetes Care 36:S175–S179
Choi K, Kim YB (2010) Molecular mechanism of insulin resistance in obesity and type 2 diabetes. Korean J Intern Med 25:119–129
Deisl C, Anderegg M, Albano G, Lüscher BP, Cerny D, Soria R, Bouillet E, Rimoldi S, Scherrer U, Fuster DG (2016) Loss of sodium/hydrogen exchanger NHA2 exacerbates obesity-and aging-induced glucose intolerance in mice. PLoS One 11:e0163568
Figueras M, Olivan M, Busquets S, López-Soriano FJ, Argilés JM (2011) Effects of eicosapentaenoic acid (EPA) treatment on insulin sensitivity in an animal model of diabetes: improvement of the inflammatory status. Obesity. 19:362–369
Franekova V, Angin Y, Hoebers NT, Coumans WA, Simons PJ, Glatz JF et al (2014) Marine omega-3 fatty acids prevent myocardial insulin resistance and metabolic remodeling as induced experimentally by high insulin exposure. Am J Physiol Cell Physiol 308:C297–C307
Gao H, Geng T, Huang T, Zhao Q (2017) Fish oil supplementation and insulin sensitivity: a systematic review and meta-analysis. Lipids Health Dis 16:131
Giacco R, Cuomo V, Vessby B, Uusitupa M, Hermansen K, Meyer BJ, Riccardi G, Rivellese AA, KANWU Study Group (2007) Fish oil, insulin sensitivity, insulin secretion and glucose tolerance in healthy people: is there any effect of fish oil supplementation in relation to the type of background diet and habitual dietary intake of n-6 and n-3 fatty acids? Nutr Metab Cardiovasc Dis 17:572–580
Gross C, Chang CW, Kelly SM, Bhattacharya A, McBride SM, Danielson SW et al (2015) Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep 11:727–736
Haber EP, Ximenes HM, Procópio J, Carvalho CR, Curi R, Carpinelli AR (2003) Pleiotropic effects of fatty acids on pancreatic β-cells. J Cell Physiol 194:1–12
Heldmaier G (1974) Temperature adaptation and brown adipose tissue in hairless and albino mice. J Comp Physiol 92(3):281–292
Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11:90–94
Holness MJ, Smith ND, Greenwood GK, Sugden MC (2004) Acute ω-3 fatty acid enrichment selectively reverses high-saturated fat feeding-induced insulin hypersecretion but does not improve peripheral insulin resistance. Diabetes. 53:S166–S171
Home PD, Pacini G (2008) Hepatic dysfunction and insulin insensitivity in type 2 diabetes mellitus: a critical target for insulin-sensitizing agents. Diabetes Obes Metab 10:699–718
Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, Komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M (2003) Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature. 422:173–176
Jornayvaz FR, Shulman GI (2012) Diacylglycerol activation of protein kinase Cε and hepatic insulin resistance. Cell Metab 15:574–584
Kalupahana NS, Claycombe K, Newman SJ, Stewart T, Siriwardhana N, Matthan N, Lichtenstein AH, Moustaid-Moussa N (2010) Eicosapentaenoic acid prevents and reverses insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation. J Nutr 140:1915–1922
Kato M, Nishikawa S, Ikehata A, Dochi K, Tani T, Takahashi T, Imaizumi A, Tsuda T (2017) Curcumin improves glucose tolerance via stimulation of glucagon-like peptide-1 secretion. Mol Nutr Food Res 61:1600471
Kim Y, Shin D (2014) Effect of omega-3 polyunsaturated fatty acids on insulin resistance in type 2 diabetes. Bioscientifica. 35
Kristinsson H, Bergsten P, Sargsyan E (2015) Free fatty acid receptor 1 (FFAR1/GPR40) signaling affects insulin secretion by enhancing mitochondrial respiration during palmitate exposure. Biochim Biophys Acta 1853:3248–3257
Lark DS, Fisher-Wellman KH, Neufer PD (2012) High-fat load: mechanism (s) of insulin resistance in skeletal muscle. Int J Obes Suppl 2:S31–S36
Li J, He J, Du Y, Cui J, Ma Y, Zhang X (2014) Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via angiotensin II its receptors-mediated mechanism in rats. BMC Complement Altern Med 14:441
Liu X, Cervantes C, Liu F (2017) Common and distinct regulation of human and mouse brown and beige adipose tissues: a promising therapeutic target for obesity. Protein Cell 8(6):446–454
Luan B, Zhao J, Wu H, Duan B, Shu G, Wang X, Li D, Jia W, Kang J, Pei G (2009) Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance. Nature. 457:1146–1149
Luttrell LM, Lefkowitz RJ (2002) The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 115:455–465
Manosalva C, Mena J, Velasquez Z, Colenso CK, Brauchi S, Burgos RA, Hidalgo MA (2015) Cloning, identification and functional characterization of bovine free fatty acid receptor-1 (FFAR1/GPR40) in neutrophils. PLoS One 10:e0119715
Matthews DR, Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 28:412–419
Meyers AM, Mourra D, Beeler JA (2017) High fructose corn syrup induces metabolic dysregulation and altered dopamine signaling in the absence of obesity. PLoS One 12:e0190206
Moller DE, Kaufman KD (2005) Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 56:45–62
Mori Y, Murakawa Y, Katoh S, Hata S, Yokoyama J, Tajima N, Ikeda Y, Nobukata H, Ishikawa T, Shibutani Y (1997) Influence of highly purified eicosapentaenoic acid ethyl ester on insulin resistance in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous non-insulin-dependent diabetes mellitus. Metabolism. 46:1458–1464
Musselman LP, Fink JL, Narzinski K, Ramachandran PV, Hathiramani SS, Cagan RL et al (2011) A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila. Dis Model Mech 4:842–849
Muurling M, Mensink RP, Pijl H, Romijn JA, Havekes LM, Voshol PJ (2003) A fish oil diet does not reverse insulin resistance despite decreased adipose tissue TNF-α protein concentration in ApoE-3* Leiden mice. J Nutr 133:3350–3355
Nagasumi K, Esaki R, Iwachidow K, Yasuhara Y, Ogi K, Tanaka H, Nakata M, Yano T, Shimakawa K, Taketomi S, Takeuchi K, Odaka H, Kaisho Y (2009) Overexpression of GPR40 in pancreatic β-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes. 58:1067–1076
Nakamoto K, Nishinaka T, Sato N, Mankura M, Koyama Y, Kasuya F, Tokuyama S (2013) Hypothalamic GPR40 signaling activated by free long chain fatty acids suppresses CFA-induced inflammatory chronic pain. PLoS One 8:e81563
Oda Y, Tadokoro S, Takase M, Kanahara N, Watanabe H, Shirayama Y, Hashimoto K, Iyo M (2015) G protein-coupled receptor kinase 6/β-arrestin 2 system in a rat model of dopamine supersensitivity psychosis. J Psychopharmacol 29:1308–1313
Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 142:687–698
Oh PC, Koh KK, Sakuma I, Lim S, Lee Y, Lee S, Lee K, Han SH, Shin EK (2014) Omega-3 fatty acid therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation, however, did not significantly improve insulin sensitivity in patients with hypertriglyceridemia. Int J Cardiol 176:696–702
Panchal SK, Poudyal H, Iyer A, Nazer R, Alam A, Diwan V, Kauter K, Sernia C, Campbell F, Ward L, Gobe G, Fenning A, Brown L (2011) High-carbohydrate high-fat diet–induced metabolic syndrome and cardiovascular remodeling in rats. J Cardiovasc Pharmacol 57:51–64
Rivellese AA, Maffettone A, Iovine C, Di Marino L, Annuzzi G, Mancini M et al (1996) Long-term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care 19:1207–1213
Salehi A, Flodgren E, Nilsson NE, Jimenez-Feltstrom J, Miyazaki J, Owman C, Olde B (2005) Free fatty acid receptor 1 (FFA 1 R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion. Cell Tissue Res 322:207–215
Sarbolouki S, Javanbakht MH, Derakhshanian H, Hosseinzadeh P, Zareei M, Hashemi SB, Dorosty AR, Eshraghian MR, Djalali M (2013) Eicosapentaenoic acid improves insulin sensitivity and blood sugar in overweight type 2 diabetes mellitus patients: a double-blind randomised clinical trial. Singap Med J 54:387–390
Scorletti E, Byrne CD (2013) Omega-3 fatty acids, hepatic lipid metabolism, and nonalcoholic fatty liver disease. Annu Rev Nutr 33:231–248
Weir GC, Bonner-Weir S (2004) Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes. 53(suppl 3):S16–S21
Xu P, Wang H, Kayoumu A, Wang M, Huang W, Liu G (2015) Diet rich in docosahexaenoic acid/eicosapentaenoic acid robustly ameliorates hepatic steatosis and insulin resistance in seipin deficient lipodystrophy mice. Nutr Metab 12:58
Yamada H, Yoshida M, Ito K, Dezaki K, Yada T, Ishikawa SE et al (2016) Potentiation of glucose-stimulated insulin secretion by the GPR40–PLC–TRPC pathway in pancreatic β-cells. Sci Rep 6:25912
Yaney GC, Corkey BE (2003) Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia. 46:1297–1312
Zarei M, Fakher S, Djalali M (2016) Effects of vitamin A, C and E, or omega-3 fatty acid supplementation on the level of paraoxonase and arylesterase activity in streptozotocin-induced diabetic rats: an investigation of activities in plasma, and heart and liver homogenates. Singap Med J 57:153–156
Zhang X, Yan G, Li Y, Zhu W, Wang H (2010) DC260126, a small-molecule antagonist of GPR40, improves insulin tolerance but not glucose tolerance in obese Zucker rats. Biomed Pharmacother 64:647–651
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SF performed the experiments. All authors contributed equally to all other parts of this study (experiment design, data analysis, manuscript writing and revision), approved the final version, and agreed for publication.
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All procedures were conducted in accordance with the accepted principles for care and use of laboratory animals and were approved by the animal ethics committee of Faculty of Pharmacy, Zagazig University (Protocol no. P20/12/2017).
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El-Fayoumi, S.H., Mahmoud, A.A.A., Fahmy, A. et al. Effect of omega-3 fatty acids on glucose homeostasis: role of free fatty acid receptor 1. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1797–1808 (2020). https://doi.org/10.1007/s00210-020-01883-5
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DOI: https://doi.org/10.1007/s00210-020-01883-5