Original Article | Published:

Animal Models

Targeted inhibition of galectin 1 by thiodigalactoside dramatically reduces body weight gain in diet-induced obese rats

International Journal of Obesity volume 39, pages 13491358 (2015) | Download Citation

Abstract

Background:

Galectin 1 (GAL1), an animal lectin is well characterized in the context of cancer, tumor environment, but its physiological roles in obesity remain to be demonstrated. In this study, we investigated whether targeted inhibition of GAL1 prevents obesity based on the previous observations that GAL1 is highly expressed in adipose tissues of high-fat diet (HFD)-induced obese rats.

Methods:

Lipogenic capacity of Lgals1 knocked down adipocytes was evaluated by determining the expression levels of major lipogenic markers using real-time PCR and immunoblot analysis. GAL1 partner proteins were identified using co-immunoprecipitation followed by protein mass fingerprinting. Finally, inhibitory effect of GAL1 by thiodigalactoside (TDG) was assessed in adipocytes and HFD-induced obese rats.

Results:

Knockdown of GAL1-encoding gene (Lgals1) attenuated adipogenesis and lipogenesis in both 3T3-L1 and HIB1B adipocytes. Further, direct treatment with TDG, a potent inhibitor of GAL1, to cultured adipocytes in vitro significantly reduced fat accumulation. Our animal experiment revealed that intraperitoneal injection of TDG (5 mg kg−1) once per week for 5 weeks in Sprague-Dawley (SD) rats resulted in dramatic inhibition of HFD-induced body weight gain (27.3% reduction compared with HFD-fed controls) by inhibiting adipogenesis and lipogensis as well as by increasing expression of the proteins associated with thermogenesis and energy expenditure.

Conclusion:

GAL1 has an essential role in HFD-induced obesity development. From a clinical viewpoint, pharmaceutical targeting of GAL1 using TDG and other inhibitor compounds would be a novel therapeutic approach for the treatment of obesity.

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References

  1. 1.

    , . Galectins: a family of animal lectins that decipher glycocodes. J Biochem 1996; 119: 1–8.

  2. 2.

    , , , . Nucleocytoplasmic lectins. Biochim Biophys Acta 2004; 1673: 75–93.

  3. 3.

    , . Galectins as modulators of tumour progression. Nat Rev Cancer 2005; 5: 29–41.

  4. 4.

    , , . On the role of galectin-3 in cancer apoptosis. Apoptosis 2005; 10: 267–275.

  5. 5.

    , , , , , et al. Ablation of a galectin preferentially expressed in adipocytes increases lipolysis, reduces adiposity, and improves insulin sensitivity in mice. Proc Natl Acad Sci USA 2011; 108: 18696–18701.

  6. 6.

    , , , , , et al. Galectin-12, an adipose-expressed galectin-like molecule possessing apoptosis-inducing activity. J Biol Chem 2001; 276: 34089–34097.

  7. 7.

    , , . Endogenous galectins and the control of the host inflammatory response. J Endocrinol 2009; 201: 169–184.

  8. 8.

    , , . Attenuation of Th1 response through galectin-9 and T-cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice. Eur J Immunol 2009; 39: 2403–2411.

  9. 9.

    , , , . Galectins. Structure and function of a large family of animal lectins. J Biol Chem 1994; 269: 20807–20810.

  10. 10.

    , , , . Apoptosis of T cells mediated by galectin-1. Nature 1995; 378: 736–739.

  11. 11.

    , , , , . Galectin-1 induces partial TCR zeta-chain phosphorylation and antagonizes processive TCR signal transduction. J Immunol 2000; 165: 3722–3729.

  12. 12.

    , , , , , . Multiple functional targets of the immunoregulatory activity of galectin-1: control of immune cell trafficking, dendritic cell physiology, and T-cell fate. Methods Enzymol 2010; 480: 199–244.

  13. 13.

    , , , , , et al. Suppression of autoimmune diabetes by soluble galectin-1. J Immunol 2009; 182: 2641–2653.

  14. 14.

    , , , , . Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake. Obesity 2010; 18: 27–34.

  15. 15.

    , , , , , et al. Adipose tissue-specific modulation of galectin expression in lean and obese mice: evidence for regulatory function. Obesity 2013; 21: 310–319.

  16. 16.

    , , , , , et al. Profiling of the secreted proteins during 3T3-L1 adipocyte differentiation leads to the identification of novel adipokines. Cell Mol Life Sci 2004; 61: 2405–2417.

  17. 17.

    , , , , , et al. Changes in expression of skeletal muscle proteins between obesity-prone and obesity-resistant rats induced by a high-fat diet. J Proteome Res 2011; 10: 1281–1292.

  18. 18.

    , , , , , . Profiling of gender-specific rat plasma proteins associated with susceptibility or resistance to diet-induced obesity. J Proteomics 2012; 75: 1386–1400.

  19. 19.

    , , . Gender differences in rat plasma proteome in response to high-fat diet. Proteomics 2012; 12: 269–283.

  20. 20.

    , , , . Sex-dependent expression of caveolin 1 in response to sex steroid hormones is closely associated with development of obesity in rats. PLoS ONE 2014; 9: e90918.

  21. 21.

    , , , , , et al. Unraveling galectin-1 as a novel therapeutic target for cancer. Cancer Treat Rev 2014; 40: 307–319.

  22. 22.

    , , , , , et al. Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model. Cancer Lett 2010; 299: 95–110.

  23. 23.

    , , , , , et al. Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress. Angiogenesis 2011; 14: 293–307.

  24. 24.

    , . Inhibiting galectin-1 reduces murine lung metastasis with increased CD4(+) and CD8 (+) T cells and reduced cancer cell adherence. Clin Exp Metastasis 2012; 29: 561–572.

  25. 25.

    , , , , , et al. Identification of galectin-1 as a critical factor in function of mouse mesenchymal stromal cell-mediated tumor promotion. PLoS ONE 2012; 7: e41372.

  26. 26.

    , , , , , et al. Galectin-inhibitory thiodigalactoside ester derivatives have antimigratory effects in cultured lung and prostate cancer cells. J Med Chem 2008; 51: 8109–8114.

  27. 27.

    , . Bromocriptine inhibits adipogenesis and lipogenesis by agonistic action on alpha2-adrenergic receptor in 3T3-L1 adipocyte cells. Mol Biol Rep 2013; 40: 3783–3792.

  28. 28.

    , , , , . C/EBPbeta reprograms white 3T3-L1 preadipocytes to a Brown adipocyte pattern of gene expression. J Biol Chem 2007; 282: 24660–24669.

  29. 29.

    , , . Isolation and culture of preadipocytes from rodent white adipose tissue. Methods Mol Biol 2008; 456: 201–219.

  30. 30.

    , , , , . TC10 is regulated by caveolin in 3T3-L1 adipocytes. PLoS One 2012; 7: e42451.

  31. 31.

    , , , , , et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 2010; 38: W214–W220.

  32. 32.

    , , , , , et al. STRING 8—a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res 2009; 37: D412–D416.

  33. 33.

    , , , , , et al. Galectin-3 deficiency accelerates high-fat diet-induced obesity and amplifies inflammation in adipose tissue and pancreatic islets. Diabetes 2013; 62: 1932–1944.

  34. 34.

    , , , , , et al. Increased adiposity, dysregulated glucose metabolism and systemic inflammation in Galectin-3 KO mice. PLoS One 2013; 8: e57915.

  35. 35.

    , , , , , et al. Serum galectin-3 is elevated in obesity and negatively correlates with glycosylated hemoglobin in type 2 diabetes. J Clin Endocrinol Metab 2010; 95: 1404–1411.

  36. 36.

    , , , , . Galectin-3 stimulates preadipocyte proliferation and is up-regulated in growing adipose tissue. Obesity 2007; 15: 32–39.

  37. 37.

    , , , , . Galectin-12 is required for adipogenic signaling and adipocyte differentiation. J Biol Chem 2004; 279: 29761–29766.

  38. 38.

    , , , . The effect of galectin-1 on the differentiation of fibroblasts and myoblasts in vitro. J Cell Sci 2002; 115: 355–366.

  39. 39.

    , , . Understanding the biochemical activities of galectin-1 and galectin-3 in the nucleus. Glycoconj J 2004; 19: 499–506.

  40. 40.

    , , , , , . Galectin-1 induces chemokine production and proliferation in pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2006; 290: G729–G736.

  41. 41.

    , , , . Evidence for a role for galectin-1 in pre-mRNA splicing. Mol Cell Biol 1997; 17: 4730–4737.

  42. 42.

    , , , . Met-tRNAfMet binding to 40S ribosomal subunits: a site for the regulation of initiation of protein synthesis by hemin. Proc Natl Acad Sci USA 1974; 71: 2946–2950.

  43. 43.

    , , , , , et al. Serum heat shock protein 70 concentration in relation to polycystic ovary syndrome in a non-obese chinese population. PLoS One 2013; 8: e67727.

  44. 44.

    , , , , , et al. Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance. Diabetes 2010; 59: 6–16.

  45. 45.

    , , , , . Changes in lipid transport-involved proteins of epicardial adipose tissue associated with coronary artery disease. Atherosclerosis 2012; 224: 492–499.

  46. 46.

    , , , , , . Determination of inflammatory and prominent proteomic changes in plasma and adipose tissue after high-intensity intermittent training in overweight and obese males. J Appl Physiol (1985) 2012; 112: 1353–1360.

  47. 47.

    , , , , , et al. Proteomic analysis of rosiglitazone and guggulsterone treated 3T3-L1 preadipocytes. Mol Cell Biochem 2013; 376: 81–93.

  48. 48.

    , , , . Proteomic profiling of lipid droplet-associated proteins in primary adipocytes of normal and obese mouse. Acta Biochim Biophys Sin (Shanghai) 2012; 44: 394–406.

  49. 49.

    , , , , , et al. On the formation of lipid droplets in human adipocytes: the organization of the perilipin-vimentin cortex. PLoS One 2014; 9: e90386.

  50. 50.

    , , , , , et al. Adipose-selective overexpression of ABHD5/CGI-58 does not increase lipolysis or protect against diet-induced obesity. J Lipid Res 2011; 52: 2032–2042.

  51. 51.

    , , , , , . Bacterial endotoxin stimulates adipose lipolysis via toll-like receptor 4 and extracellular signal-regulated kinase pathway. J Biol Chem 2009; 284: 5915–5926.

  52. 52.

    , , , , , et al. Effect of dietary fat modification on subcutaneous white adipose tissue insulin sensitivity in patients with metabolic syndrome. Mol Nutr Food Res 2014; 58: 2177–2188.

  53. 53.

    , . Disruption of the vimentin intermediate filament system during adipose conversion of 3T3-L1 cells inhibits lipid droplet accumulation. J Cell Sci 1996; 109: 3047–3058.

  54. 54.

    , , , , , et al. OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis. Eur J Cancer 2014; 50: 2463–2477.

  55. 55.

    , , , . Inhibition of cell-free splicing by saccharides that bind galectins and SR proteins. J Carbohydr Chem 2012; 31: 519–534.

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Acknowledgements

This work was supported by the Mid-career Researcher Program (2013R1A2A2A05004195) and by the SRC Program (Center for Food & Nutritional Genomics, grant number 2015R1A5A6001906) through an NRF grant funded by the Ministry of Science, ICT and Future Planning, Korea.

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Affiliations

  1. Department of Biotechnology, Daegu University, Kyungsan, Republic of Korea

    • R Mukherjee
    • , S W Kim
    •  & J W Yun
  2. Department of Food and Nutrition, Yonsei University, Seoul, Republic of Korea

    • T Park
  3. Department of Food Science and Nutrition, Center for Food and Nutritional Genomics Research, Kyungpook National University, Daegu, Republic of Korea

    • M S Choi

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The authors declare no conflict of interest.

Corresponding author

Correspondence to J W Yun.

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DOI

https://doi.org/10.1038/ijo.2015.74

Supplementary Information accompanies this paper on International Journal of Obesity website (http://www.nature.com/ijo)

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