Effect of dietary fish oil on enhanced inflammation and disturbed lipophagy in white adipose tissue caused by a high fat diet


Fish oil containing omega-3 polyunsaturated fatty acids (PUFA) attenuates chronic inflammation found in obesity, leading to a reduction in insulin resistance. The effect of fish oils containing omega-3 PUFA in the lipophagy pathway is unknown. In the present study, we examined whether omega-3 PUFA affects anti-inflammatory or lipophagy pathways in high fat diet-induced obesity. There was a significant increase in body weight gain in mice fed a high fat diet (HFD) or HFD with fish oil (HFD-FO), but not in mice fed a normal diet (ND). Although there was no significant difference between body weight gain and plasma insulin levels in the HFD and HFD-FO mice, the intake of HFD-FO prevented glucose intolerance and peripheral insulin resistance induced by HFD. In addition, macrophage infiltration and cytokine levels in white adipose tissue (WAT) in HFD-FO mice were decreased, compared with HFD mice. There were no significant differences between lipophagy related proteins and their mRNA levels in the HFD-FO and HFD groups. These results suggest that supplementation with fish oil might be beneficial in preventing insulin resistance caused by a high fat diet through an anti-inflammatory effect, but not lipophagy activation.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4



A disintegrin-like and metalloproteinase 8


Cross-sectional areas


Crown-like structures


G protein-coupled protein 120


Glucose tolerance test




Insulin tolerance test


Lipid droplet


Monocyte chemoattractant protein-1


Phospholipase D1




Polyunsaturated fatty acids


Toll like receptor


Tumor necrosis factor


White adipose tissue


  1. Abe T, Hirasaka K, Kagawa S, Kohno S, Ochi A, Utsunomiya K, Sakai A, Ohno A, Teshima-Kondo S, Okumura Y, Oarada M, Maekawa Y, Terao J, Mills EM, Nikawa T (2013) Cbl-b is a critical regulator of macrophage activation associated with obesity-induced insulin resistance in mice. Diabetes 62:1957–1969

  2. Bessone F, Dirchwolf M, Rodil MA, Razori MV, Roma MG (2018) Review article: drug-induced liver injury in the context of nonalcoholic fatty liver disease - a physiopathological and clinical integrated view. Aliment Pharmacol Ther 48:892–913

  3. Bhaskaran S, Unnikrishnan A, Ranjit R, Qaisar R, Pharaoh G, Matyi S, Kinter M, Deepa SS (2017) A fish oil diet induces mitochondrial uncoupling and mitochondrial unfolded protein response in epididymal white adipose tissue of mice. Free Radic Biol Med 108:704–714

  4. Camastra S, Vitali A, Anselmino M, Gastaldelli A, Bellini R, Berta R, Severi I, Baldi S, Astiarraga B, Barbatelli G, Cinti S, Ferrannini E (2017) Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery. Sci Rep 7:9007

  5. Chen K, Yuan R, Zhang Y, Geng S, Li L (2017) Tollip deficiency alters atherosclerosis and steatosis by disrupting lipophagy. J Am Heart Assoc 6:e004078

  6. de Luca C, Olefsky JM (2006) Stressed out about obesity and insulin resistance. Nat Med 12:41–42

  7. de Luca C, Olefsky JM (2008) Inflammation and insulin resistance. FEBS Lett 582:97–105

  8. Eraky SM, Abdel-Rahman N, Eissa LA (2018) Modulating effects of omega-3 fatty acids and pioglitazone combination on insulin resistance through toll-like receptor 4 in type 2 diabetes mellitus. Prostaglandins Leukot Essent Fat Acids 136:123–129

  9. Flachs P, Rossmeisl M, Kopecky J (2014) The effect of n-3 fatty acids on glucose homeostasis and insulin sensitivity. Physiol Res 63:S93–S118

  10. Hiramoto S, Yahata N, Saitoh K, Yoshimura T, Wang Y, Taniyama S, Nikawa T, Tachibana K, Hirasaka K (2018) Dietary supplementation with alkylresorcinols prevents muscle atrophy through a shift of energy supply. J Nutr Biochem 61:147–154

  11. Hirasaka K, Kohno S, Goto J, Furochi H, Mawatari K, Harada N, Hosaka T, Nakaya Y, Ishidoh K, Obata T, Ebina Y, Gu H, Takeda S, Kishi K, Nikawa T (2007) Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice. Diabetes 56:2511–2522

  12. Hirasaka K, Saito S, Yamaguchi S, Miyazaki R, Wang Y, Haruna M, Taniyama S, Higashitani A, Terao J, Nikawa T, Tachibana K (2016) Dietary supplementation with isoflavones prevents muscle wasting in tumor-bearing mice. J Nutr Sci Vitaminol 62:178–184

  13. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271:665–668

  14. Huang R, Liu W (2015) Identifying an essential role of nuclear LC3 for autophagy. Autophagy 11:852–853

  15. Kim HS, Montana V, Jang HJ, Parpura V, Kim JA (2013) Epigallocatechin gallate (EGCG) stimulates autophagy in vascular endothelial cells: a potential role for reducing lipid accumulation. J Biol Chem 288:22693–22705

  16. Kim SN, Kwon HJ, Akindehin S, Jeong HW, Lee YH (2017) Effects of epigallocatechin-3-gallate on autophagic lipolysis in adipocytes. Nutrients 9:E680

  17. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149–1163

  18. Li Y, Yang P, Zhao L, Chen Y, Zhang X, Zeng S, Wei L, Varghese Z, Moorhead JF, Chen Y, Ruan XZ (2019) CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway. J Lipid Res 60:844–855

  19. Liu MJ, Bao S, Bolin ER, Burris DL, Xu X, Sun Q, Killilea DW, Shen Q, Ziouzenkova O, Belury MA, Failla ML, Knoell DL (2013) Zinc deficiency augments leptin production and exacerbates macrophage infiltration into adipose tissue in mice fed a high-fat diet. J Nutr 143:1036–1045

  20. Liu C, Liao JZ, Li PY (2017) Traditional Chinese herbal extracts inducing autophagy as a novel approach in therapy of nonalcoholic fatty liver disease. World J Gastroenterol 23:1964–1973

  21. Martínez-Fernández L, Laiglesia LM, Huerta AE, Martínez JA, Moreno-Aliaga MJ (2015) Omega-3 fatty acids and adipose tissue function in obesity and metabolic syndrome. Prostaglandins Other Lipid Mediat 121:24–41

  22. Martins AR, Crisma AR, Masi LN, Amaral CL, Marzuca-Nassr GN, Bomfim LHM, Teodoro BG, Queiroz AL, Serdan TDA, Torres RP, Mancini-Filho J, Rodrigues AC, Alba-Loureiro TC, Pithon-Curi TC, Gorjao R, Silveira LR, Curi R, Newsholme P, Hirabara SM (2018) Attenuation of obesity and insulin resistance by fish oil supplementation is associated with improved skeletal muscle mitochondrial function in mice fed a high-fat diet. J Nutr Biochem 55:76–88

  23. 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

  24. Oliver E, McGillicuddy FC, Harford KA, Reynolds CM, Phillips CM, Ferguson JF, Roche HM (2012) Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC n-3 PUFA. J Nutr Biochem 23:1192–1200

  25. Rogov V, Dötsch V, Johansen T, Kirkin V (2014) Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell 53:167–178

  26. Rotter V, Nagaev I, Smith U (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278:45777–45784

  27. Samane S, Christon R, Dombrowski L, Turcotte S, Charrouf Z, Lavigne C, Levy E, Bachelard H, Amarouch H, Marette A, Haddad PS (2009) Fish oil and argan oil intake differently modulate insulin resistance and glucose intolerance in a rat model of dietary-induced obesity. Metabolism 58:909–919

  28. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025

  29. Spencer M, Finlin BS, Unal R, Zhu B, Morris AJ, Shipp LR, Lee J, Walton RG, Adu A, Erfani R, Campbell M, McGehee RE Jr, Peterson CA, Kern PA (2013) Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes 62:1709–1717

  30. Takahashi K, Mizuarai S, Araki H, Mashiko S, Ishihara A, Kanatani A, Itadani H, Kotani H (2003) Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. J Biol Chem 278:46654–46660

  31. Westerbacka J, Cornér A, Kolak M, Makkonen J, Turpeinen U, Hamsten A, Fisher RM, Yki-Järvinen H (2008) Insulin regulation of MCP-1 in human adipose tissue of obese and lean women. Am J Physiol Endocrinol Metab. 294:E841–E845

  32. White MF, Kahn CR (1994) The insulin signaling system. J Biol Chem 269:1–4

  33. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830

  34. Yang L, Li P, Fu S, Calay ES, Hotamisligil GS (2010) Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 11:467–478

  35. Zeng J, Zhu B, Su M (2018) Autophagy is involved in acetylshikonin ameliorating non-alcoholic steatohepatitis through AMPK/mTOR pathway. Biochem Biophys Res Commun 503:1645–1650

  36. Zeng H, Guo X, Zhou F, Xiao L, Liu J, Jiang C, Xing M, Yao P (2019) Quercetin alleviates ethanol-induced liver steatosis associated with improvement of lipophagy. Food Chem Toxicol 125:21–28

  37. Zhang R, He GZ, Wang YK, Zhou KG, Ma EL (2015) Omega-3 polyunsaturated fatty acids inhibit the increase in cytokines and chemotactic factors induced in vitro by lymph fluid from an intestinal ischemia-reperfusion injury model. Nutrition 31:508–514

  38. Zhou K, Yao P, He J, Zhao H (2019) Lipophagy in nonliver tissues and some related diseases: Pathogenic and therapeutic implications. J Cell Physiol 234:7938–7947

Download references


This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, to K.H. (Grant No. 18KT0093).

Author information

Correspondence to Katsuya Hirasaka.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 18 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saitoh, K., Yoshimura, T., Sun, L. et al. Effect of dietary fish oil on enhanced inflammation and disturbed lipophagy in white adipose tissue caused by a high fat diet. Fish Sci 86, 187–196 (2020) doi:10.1007/s12562-019-01374-4

Download citation


  • Lipophagy
  • Fish oil
  • Macrophage
  • White adipose tissue