Liraglutide induces beige fat development and promotes mitochondrial function in diet induced obesity mice partially through AMPK-SIRT-1-PGC1-α cell signaling pathway

Abstract

Purpose

Glucagon like peptide-1 (GLP-1) is produced to induce postprandial insulin secretion. Liraglutide, a full agonist of the GLP-1 receptor, has a protective effect on weight gain in obese subjects. Brown adipose tissue plays a major role in the control of energy balance and is known to be involved in the weight loss regulated by liraglutide. The putative anti-obesity properties of liraglutide and the cell signaling pathways involved were examined.

Methods

Four groups of C57/BL6 mice fed with chow or HFHS diet were injected with either liraglutide or vehicle for four weeks. Western blotting was used to analyze protein expression.

Results

Liraglutide significantly attenuated the weight gain in mice fed with HFHS diet and was associated with significant reductions of epididymal fat and inguinal fat mass. Furthermore, liraglutide significantly upregulated the expression of brown adipose-specific markers in perigonadal fat in association with upregulation of AMPK-SIRT-1-PGC1-α cell signaling. However, elevation of brown fat markers in skeletal muscle was only observed in HFHS diet fed mice after liraglutide treatment, and AMPK-SIRT-1 cell signaling is not involved in this process.

Conclusions

the anti-obesity effect of liraglutide occurs through adaptive thermogenesis and may act through different cell signaling pathways in fat and skeletal muscle tissue. Liraglutide induces beige fat development partially through the AMPK-SIRT-1-PGC1-α cell signaling pathway. Therefore, liraglutide is a potential medication for obesity prevention and in targeting pre-diabetics.

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References

  1. 1.

    C.L. Ogden, M.D. Carroll, B.K. Kit, K.M. Flegal, Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief 82, 1–8 (2012)

    Google Scholar 

  2. 2.

    C.S. Elangbam, Review paper: current strategies in the development of anti-obesity drugs and their safety concerns. Vet. Pathol. 46, 10–24 (2009)

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    W.C. Knowler, E. Barrett-Connor, S.E. Fowler, R.F. Hamman, J.M. Lachin, E.A. Walker et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002)

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    D.H. Ryan, G.A. Bray, Pharmacologic treatment options for obesity: what is old is new again. Curr. Hypertens. Rep. 15, 182–189 (2013)

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    D.J. Drucker, Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 122, 531–544 (2002)

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    E. Tomas, J.A. Wood, V. Stanojevic, J.F. Habener, Glucagon-like peptide-1(9-36)amide metabolite inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice. Diabetes Obes. Metab. 13, 26–33 (2011)

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    L.B. Knudsen, Liraglutide: the therapeutic promise from animal models. Int. J. Clin. Pract. 167, 4–11 (2010)

    Article  CAS  Google Scholar 

  8. 8.

    J.J. Meier, GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728–742 (2012)

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    S.C. Tang, J.J. Hendrikx, J.H. Beijnen, A.H. Schinkel, Genetically modified mouse models for oral drug absorption and disposition. Curr. Opin. Pharmacol. 13, 853–858 (2013)

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    M. Namba, T. Katsuno, Y. Kusunoki, T. Matsuo, M. Miuchi, J. Miyagawa, New strategy for the treatment of type 2 diabetes mellitus with incretin-based therapy. Clin. Exp. Nephrol. 17, 10–15 (2013)

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    M. Zander, S. Madsbad, J.L. Madsen, J.J. Holst, Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359, 824–830 (2002)

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    S. Madsbad, The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes Obes. Metab. 16, 9–21 (2014)

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    S. Kalra, B. Kalra, S. Kumar, A. Sharma, Managing insulin resistance: role of liraglutide. Clin. Pharmacol. 2, 131–134 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    S.H. Kim, F. Abbasi, C. Lamendola, A. Liu, D. Ariel, P. Schaaf et al. Benefits of liraglutide treatment in overweight and obese older individuals with prediabetes. Diabetes Care 36, 3276–3282 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    K.M. Heppner, S. Marks, J. Holland, N. Ottaway, D. Smiley, R. Dimarchi et al. Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice. Diabetologia 58, 2124–2132 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    M. Giralt, F. Villarroya, White, brown, beige/brite: different adipose cells for different functions? Endocrinology 154, 2992–3000 (2013)

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    A.M. Cypess, C.R. Kahn, The role and importance of brown adipose tissue in energy homeostasis. Curr. Opin. Pediatr. 22, 478–484 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    D. Beiroa, M. Imbernon, R. Gallego, A. Senra, D. Herranz, F. Villarroya et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63, 3346–3358 (2014)

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    L.X. Li, P.E. MacDonald, D.S. Ahn, G.Y. Oudit, P.H. Backx, P.L. Brubaker, Role of phosphatidylinositol 3-kinasegamma in the beta-cell: interactions with glucagon-like peptide-1. Endocrinology 147, 3318–3325 (2006)

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    A. Park, W.K. Kim, K.H. Bae, Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. World J. Stem Cells 6, 33–42 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    E.E. Ladenheim, Liraglutide and obesity: a review of the data so far. Drug Des. Devel Ther. 9, 1867–1875 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    M.A. Zuriaga, J.J. Fuster, N. Gokce, K. Walsh, Humans and mice display opposing patterns of “browning” gene expression in visceral and subcutaneous white adipose tissue depots. Front. Cardiovasc. Med. 4, 27 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    E.D. Rosen, C.H. Hsu, X. Wang, S. Sakai, M.W. Freeman, F.J. Gonzalez et al. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev. 16, 22–26 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    M. Rosell, M. Kaforou, A. Frontini, A. Okolo, Y.W. Chan, E. Nikolopoulou et al. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am. J. Physiol. Endocrinol. Metab. 306, E945–964 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    M. Harms, P. Seale, Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013)

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    J.I. Kim, J.Y. Huh, J.H. Sohn, S.S. Choe, Y.S. Lee, C.Y. Lim et al. Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation. Mol. Cell. Biol. 35, 1686–1699 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    W. Wang, P. Seale, Control of brown and beige fat development. Nat. Rev. Mol. Cell Biol. 17, 691–702 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    R.C. Scarpulla, Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 1813, 1269–1278 (2011)

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    K.L. Townsend, D. An, M.D. Lynes, T.L. Huang, H. Zhang, L.J. Goodyear et al. Increased mitochondrial activity in BMP7-treated brown adipocytes, due to increased CPT1- and CD36-mediated fatty acid uptake. Antioxid. Redox Signal. 19, 243–257 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    W. Lea, A.S. Abbas, H. Sprecher, J. Vockley, H. Schulz, Long-chain acyl-CoA dehydrogenase is a key enzyme in the mitochondrial beta-oxidation of unsaturated fatty acids. Biochim. Biophys. Acta 1485, 121–128 (2000)

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    B. Cannon, J. Nedergaard, Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004)

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    E. García-Ruiz, B. Reynés, R. Díaz-Rúa, E. Ceresi, P. Oliver, A. Palou, The intake of high-fat diets induces the acquisition of brown adipocyte gene expression features in white adipose tissue. Int. J. Obes. 39, 1619–1629 (2015)

    Article  CAS  Google Scholar 

  33. 33.

    P. Seale, B. Bjork, W. Yang, S. Kajimura, S. Chin, S. Kuang et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    X. Pi-Sunyer, A. Astrup, K. Fujioka, F. Greenway, A. Halpern, M. Krempf et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Engl. J. Med. 373, 11–22 (2015)

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    J. van Can, B. Sloth, C.B. Jensen, A. Flint, E.E. Blaak, W.H. Saris, Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int. J. Obes. 38, 784–793 (2014)

    Article  CAS  Google Scholar 

  36. 36.

    K. Raun, P. von Voss, C.F. Gotfredsen, V. Golozoubova, B. Rolin, L.B. Knudsen, Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 56, 8–15 (2007)

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    M.J. Davies, R. Bergenstal, B. Bode, R.F. Kushner, A. Lewin, T.V. Skjøth et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA 314, 687–699 (2015)

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    M. Nauck, A. Frid, K. Hermansen, N.S. Shah, T. Tankova, I.H. Mitha et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 32, 84–90 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    M. Ahmadian, J.M. Suh, N. Hah, C. Liddle, A.R. Atkins, M. Downes et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat. Med. 19, 557–566 (2013)

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    M.S. Choi, Y.J. Kim, E.Y. Kwon, J.Y. Ryoo, S.R. Kim, U.J. Jung, High-fat diet decreases energy expenditure and expression of genes controlling lipid metabolism, mitochondrial function and skeletal system development in the adipose tissue, along with increased expression of extracellular matrix remodelling- and inflammation-related genes. Br. J. Nutr. 113, 867–877 (2015)

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Y.H. Lee, A.P. Petkova, E.P. Mottillo, J.G. Granneman, In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell. Metab. 15, 480–491 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    K. Ban, M.H. Noyan-Ashraf, J. Hoefer, S.S. Bolz, D.J. Drucker, M. Husain, Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117, 2340–2350 (2008)

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    F.R. Jornayvaz, G.I. Shulman, Regulation of mitochondrial biogenesis. Essays Biochem. 47, 69–84 (2010)

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    P. Puigserver, B.M. Spiegelman, Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24, 78–90 (2003)

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    K.A. Virtanen, M.E. Lidell, J. Orava, M. Heglind, R. Westergren, T. Niemi et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009)

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    W.D. van Marken Lichtenbelt, J.W. Vanhommerig, N.M. Smulders, J.M. Drossaerts, G.J. Kemerink, N.D. Bouvy et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009)

    Article  PubMed  Google Scholar 

  47. 47.

    S.R. Farmer, Regulation of PPARgamma activity during adipogenesis. Int. J. Obes. 29(Suppl 1), S13–16 (2005)

    Article  CAS  Google Scholar 

  48. 48.

    J.R. Jones, C. Barrick, K.A. Kim, J. Lindner, B. Blondeau, Y. Fujimoto et al. Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proc. Natl Acad. Sci. USA 102, 6207–6212 (2005)

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    J. Decara, S. Arrabal, D. Beiroa, P. Rivera, A. Vargas, A. Serrano et al. Antiobesity efficacy of GLP-1 receptor agonist liraglutide is associated with peripheral tissue-specific modulation of lipid metabolic regulators. Biofactors 42, 600–611 (2016)

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Y. Shao, G. Yuan, J. Zhang, X. Guo, Liraglutide reduces lipogenetic signals in visceral adipose of db/db mice with AMPK activation and Akt suppression. Drug Des. Devel Ther. 9, 1177–1184 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    G. Svegliati-Baroni, S. Saccomanno, C. Rychlicki, L. Agostinelli, S. De Minicis, C. Candelaresi et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver. Int. 31, 1285–1297 (2011)

    Article  CAS  PubMed  Google Scholar 

  52. 52.

    B.B. Zhang, G. Zhou, C. Li, AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell. Metab. 9, 407–416 (2009)

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    R. Siersbaek, R. Nielsen, S. Mandrup, PPARgamma in adipocyte differentiation and metabolism--novel insights from genome-wide studies. FEBS Lett. 584, 3242–3249 (2010)

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    A. Astrup, S. Rössner, L. Van Gaal, A. Rissanen, L. Niskanen, M. Al Hakim et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 374, 1606–1616 (2009)

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    J. Rosenstock, L.J. Klaff, S. Schwartz, J. Northrup, J.H. Holcombe, K. Wilhelm et al. Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care 33, 1173–1175 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    C.W. le Roux, A. Astrup, K. Fujioka, F. Greenway, D.C.W. Lau, L. Van Gaal et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 389, 1399–1409 (2017)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

L.L. is supported by the new faculty start-up fund from Central Michigan University. The authors thank Jamsheed Bahaee, and Mellissa Andrew for their technical support and Darren Story for the editing of English grammar.

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Correspondence to Lixin Li.

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Zhou, J., Poudel, A., Chandramani-Shivalingappa, P. et al. Liraglutide induces beige fat development and promotes mitochondrial function in diet induced obesity mice partially through AMPK-SIRT-1-PGC1-α cell signaling pathway. Endocrine 64, 271–283 (2019). https://doi.org/10.1007/s12020-018-1826-7

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Keywords

  • Liraglutide
  • Insulin resistance
  • Beige fat
  • Diet induced obesity