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Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist



The weight loss following Semaglutide treatment, a GLP-1 receptor agonist, might be responsible for some effects observed on the nonalcoholic fatty liver disease of obese mice.


Two groups of C57BL/6 male mice (n = 30/group) were fed the diets Control (C) or high-fat (HF) for 16 weeks. Then, separated into six new groups for an additional four weeks (n = 10/group) and treated with Semaglutide (S, 40 µg/kg) or paired feeding (PF) with S groups (C; C-S; C-PF; HF; HF-S; HF-PF).


Semaglutide reduced energy consumption leading to weight loss. Simultaneously it improved glucose intolerance, glycated hemoglobin, insulin resistance/sensitivity, plasma lipids, and gastric inhibitory polypeptide. Semaglutide and paired feeding mitigated liver steatosis and adipose differentiation-related protein (Plin2) expression. Semaglutide also improved hormones and adipokines, reduced lipogenesis and inflammation, and increased beta-oxidation. Semaglutide lessened liver glucose uptake and endoplasmic reticulum (ER) stress. Among the 14 genes analyzed, 13 were modified by Semaglutide (93 %, six genes were changed exclusively by Semaglutide, and seven other genes were affected by the combination of Semaglutide and paired feeding). In seven genes, the paired diet showed no effect (50% of the genes tested). No marker was affected exclusively by paired feeding.


Semaglutide and the consequent weight loss reduced obese mice liver inflammation, insulin resistance, and ER stress. However, weight loss alone did show few or no action on some significant study findings, like liver steatosis, leptin, insulin, resistin, and amylin. Furthermore, hepatic inflammation mediated by MCP-1 and partially by TNF-alpha and IL6 were also not reduced by weight loss. Furthermore, weight loss alone did not lessen hepatic lipogenesis as determined by the findings of SREBP-1c, CHREBP, PPAR-alpha, and SIRT1. Semaglutide was implicated in improving glucose uptake and lessening ER stress by reducing GADD45, independent of weight loss.

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Fig. 1: Body mass evolution (mean ± SD, 16th week, n = 30/group; 20th week, n = 10/group).
Fig. 2: Liver steatosis (mean ± SD, n = 5/group; the left upper corner identifies the group).
Fig. 3: Plasma concentrations of hormones and adipokines (mean ± SD, n = 5/group).
Fig. 4: Liver gene expressions (mRNA relative expressions, mean ± SD, n = 5/group).
Fig. 5: Liver gene expressions (continuation, mRNA relative expressions, mean ± SD, n = 5/group).


  1. 1.

    Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide as a promising antiobesity drug. Obes Rev. 2019;20:805–15.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Kushner RF, Calanna S, Davies M, Dicker D, Garvey WT, Goldman B, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity. 2020;28:1050–61.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384:1113–24.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med. 2008;132:1761–6.

    Article  PubMed  Google Scholar 

  5. 5.

    Lebeaupin C, Vallee D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of nonalcoholic fatty liver disease. J Hepatol. 2018;69:927–47.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Wei J, Fang D. Endoplasmic reticulum stress signaling and the pathogenesis of hepatocarcinoma. Int J Mol Sci. 2021;22,

  7. 7.

    Buratta S, Shimanaka Y, Costanzi E, Ni S, Urbanelli L, Kono N, et al. Lipotoxic stress alters the membrane lipid profile of extracellular vesicles released by Huh-7 hepatocarcinoma cells. Sci Rep. 2021;11:4613

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Vianna AB, Aguila MB, Mandarim-de-Lacerda CA. Effects of liraglutide in hypothalamic arcuate nucleus of obese mice. Obesity. 2016;24:626–33.

    CAS  Article  Google Scholar 

  9. 9.

    Vianna AB, Aguila MB, Mandarim-de-Lacerda CA. Beneficial effects of liraglutide (GLP1 analog) in the hippocampal inflammation. Metab Brain Dis. 2017;32:1735–45.

    CAS  Article  Google Scholar 

  10. 10.

    Schulte EM, Tuerk PW, Wadden TA, Garvey WT, Weiss D, Hermayer KL, et al. Changes in weight control behaviors and hedonic hunger in a commercial weight management program adapted for individuals with type 2 diabetes. Int J Obes. 2020;44:990–8.

    Article  Google Scholar 

  11. 11.

    Fraulob JC, Ogg-Diamantino R, Santos CF, Aguila MB, Mandarim-de-Lacerda CA. A mouse model of metabolic syndrome: insulin resistance, fatty liver and nonalcoholic fatty pancreas disease (NAFPD) in C57BL/6 mice fed a high fat diet. J Clin Biochem Nutr. 2010;46:212–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Aguila MB, Ornellas F, Mandarim-de-Lacerda CA. Nutritional research and fetal programming: parental nutrition influences the structure and function of the organs. Int J Morphol. 2021;39:327–34.

    Article  Google Scholar 

  13. 13.

    Peterson RG, Jackson CV, Zimmerman KM, Alsina-Fernandez J, Michael MD, Emmerson PJ, et al. Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse. PLoS One. 2017;12:e0179856

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Pang J, Xi C, Huang X, Cui J, Gong H, Zhang T. Effects of excess energy intake on glucose and lipid metabolism in C57BL/6 mice. PLoS One. 2016;11:e0146675

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402–10.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Mandarim-de-Lacerda CA. Stereological tools in biomedical research. An Acad Bras Cienc. 2003;75:469–86.

    Article  PubMed  Google Scholar 

  17. 17.

    Catta-Preta M, Mendonca LS, Fraulob-Aquino J, Aguila MB, Mandarim-de-Lacerda CA. A critical analysis of three quantitative methods of assessment of hepatic steatosis in liver biopsies. Virchows Arch. 2011;459:477–85.

    Article  PubMed  Google Scholar 

  18. 18.

    Mandarim-de-Lacerda CA, Del-Sol M. Tips for studies with quantitative morphology (morphometry and stereology). Int J Morphol. 2017;35:1482–94.

    Article  Google Scholar 

  19. 19.

    Rao X, Lai D, Huang X. A new method for quantitative real-time polymerase chain reaction data analysis. J Comput Biol. 2013;20:703–11.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    De Minicis S, Day C, Svegliati-Baroni G. From NAFLD to NASH and HCC: pathogenetic mechanisms and therapeutic insights. Curr Pharm Des. 2013;19:5239–49.

    Article  PubMed Central  Google Scholar 

  21. 21.

    Zhong F, Zhou X, Xu J, Gao L. Rodent models of nonalcoholic fatty liver disease. Digestion. 2020;101:522–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Negrin KA, Roth Flach RJ, DiStefano MT, Matevossian A, Friedline RH, Jung D, et al. IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS One. 2014;9:e107265

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Williamson DA, Bray GA, Ryan DH. Is 5% weight loss a satisfactory criterion to define clinically significant weight loss? Obesity. 2015;23:2319–20.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Magkos F, Fraterrigo G, Yoshino J, Luecking C, Kirbach K, Kelly SC, et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab. 2016;23:591–601.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325:1414–25.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Rakipovski G, Rolin B, Nohr J, Klewe I, Frederiksen KS, Augustin R, et al. The GLP-1 Analogs Liraglutide and Semaglutide reduce atherosclerosis in ApoE(−/−) and LDLr(−/−) mice by a mechanism that includes inflammatory pathways. JACC Basic Transl Sci. 2018;3:844–57.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Zhang L, Zhang L, Li L, Holscher C. Semaglutide is neuroprotective and reduces alpha-synuclein levels in the chronic MPTP mouse model of Parkinson’s disease. J Parkinsons Dis. 2019;9:157–71.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Chubb B, Gupta P, Gupta J, Nuhoho S, Kallenbach K, Orme M. Once-daily oral Semaglutide versus injectable GLP-1 RAs in people with type 2 diabetes inadequately controlled on basal insulin: systematic review and network meta-analysis. Diabetes Ther. 2021;12:1325–39.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Li J, He K, Ge J, Li C, Jing Z. Efficacy and safety of the glucagon-like peptide-1 receptor agonist oral semaglutide in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2021;172:108656

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394:39–50.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Barbosa-da-Silva S, Fraulob-Aquino JC, Lopes JR, Mandarim-de-Lacerda CA, Aguila MB. Weight cycling enhances adipose tissue inflammatory responses in male mice. PLoS One. 2012;7:e39837

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Barbosa-da-Silva S, Silva NC, Aguila MB, Mandarim-de-Lacerda CA. Liver damage is not reversed during the lean period in diet-induced weight cycling in mice. Hepatol Res. 2014;44:450–9.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Spezani R, Silva RR, Martins FF, Marinho TS, Aguila MB, Mandarim-de-Lacerda CA. Intermittent fasting, adipokines, insulin sensitivity, and hypothalamic neuropeptides in a dietary overload with high-fat or high-fructose diet in mice. J Nutr Biochem. 2020;83:108419

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Gonnissen HK, Hulshof T, Westerterp-Plantenga MS. Chronobiology, endocrinology, and energy- and food-reward homeostasis. Obes Rev. 2013;14:405–16.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Gabery S, Salinas CG, Paulsen SJ, Ahnfelt-Ronne J, Alanentalo T, Baquero AF, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020;5,

  38. 38.

    Adolph TE, Grander C, Grabherr F, Tilg H. Adipokines and nonalcoholic fatty liver disease: multiple interactions. Int J Mol Sci. 2017;18:

  39. 39.

    D’Souza AM, Neumann UH, Glavas MM, Kieffer TJ. The glucoregulatory actions of leptin. Mol Metab. 2017;6:1052–65.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Pretz D, Le Foll C, Rizwan MZ, Lutz TA, Tups A. Hyperleptinemia as a contributing factor for the impairment of glucose intolerance in obesity. FASEB J. 2021;35:e21216

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Moonishaa TM, Nanda SK, Shamraj M, Sivaa R, Sivakumar P, Ravichandran K. Evaluation of leptin as a marker of insulin resistance in type 2 diabetes mellitus. Int J Appl Basic Med Res. 2017;7:176–80.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Schultz A, Da Silva SB, Aguila MB, Mandarim-de-Lacerda CA. Differences and similarities in hepatic lipogenesis, gluconeogenesis and oxidative imbalance in mice fed diets rich in fructose or sucrose. Food Funct. 2015;6:1684–91.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Hodson L, Gunn PJ. The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state. Nat Rev Endocrinol. 2019;15:689–700.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Libby AE, Bales ES, Monks J, Orlicky DJ, McManaman JL. Perilipin-2 deletion promotes carbohydrate-mediated browning of white adipose tissue at ambient temperature. J Lipid Res. 2018;59:1482–500.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Marinho TS, Ornellas F, Barbosa-da-Silva S, Mandarim-de-Lacerda CA, Aguila MB. Beneficial effects of intermittent fasting on steatosis and inflammation of the liver in mice fed a high-fat or a high-fructose diet. Nutrition. 2019;65:103–12.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Zhou R, Lin C, Cheng Y, Zhuo X, Li Q, Xu W, et al. liraglutide alleviates hepatic steatosis and liver injury in T2MD rats via a GLP-1R dependent AMPK pathway. Front Pharmacol. 2020;11:600175

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Iizuka K, Takao K, Yabe D. ChREBP-Mediated regulation of lipid metabolism: involvement of the gut microbiota, liver, and adipose tissue. Front Endocrinol. 2020;11:587189

    Article  Google Scholar 

  48. 48.

    Chen J, Zhao H, Ma X, Zhang Y, Lu S, Wang Y, et al. GLP-1/GLP-1R Signaling in regulation of adipocyte differentiation and lipogenesis. Cell Physiol Biochem. 2017;42:1165–76.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Scerif M, Goldstone AP, Korbonits M. Ghrelin in obesity and endocrine diseases. Mol Cell Endocrinol. 2011;340:15–25.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Nauck MA, Meier JJ. Incretin hormones: their role in health and disease. Diabetes Obes Metab. 2018;20:5–21.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29:313–26.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Tzanavari T, Giannogonas P, Karalis KP. TNF-alpha and obesity. Curr Dir Autoimmun. 2010;11:145–56.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Akash MSH, Rehman K, Liaqat A. Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J Cell Biochem. 2018;119:105–10.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Zhou JY, Poudel A, Welchko R, Mekala N, Chandramani-Shivalingappa P, Rosca MG, et al. liraglutide improves insulin sensitivity in high fat diet induced diabetic mice through multiple pathways. Eur J Pharmacol. 2019;861:172594

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Luo Y, Yang P, Li Z, Luo Y, Shen J, Li R, et al. liraglutide improves nonalcoholic fatty liver disease in diabetic mice by modulating inflammatory signaling pathways. Drug Des Devel Ther. 2019;13:4065–74.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Thorens B. GLUT2, glucose sensing and glucose homeostasis. Diabetologia. 2015;58:221–32.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Deng XQ, Chen LL, Li NX. The expression of SIRT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats. Liver Int. 2007;27:708–15.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529:326–35.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Shore GC, Papa FR, Oakes SA. Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol. 2011;23:143–9.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Li X, Wang Y, Wang H, Huang C, Huang Y, Li J. Endoplasmic reticulum stress is the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in liver fibrosis. Inflamm Res. 2015;64:1–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Cao J, Dai DL, Yao L, Yu HH, Ning B, Zhang Q, et al. Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol Cell Biochem. 2012;364:115–29.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Guo X, Tang R, Yang S, Lu Y, Luo J, Liu Z. Rutin and its combination with inulin attenuate gut dysbiosis, the inflammatory status and endoplasmic reticulum stress in Paneth cells of obese mice induced by high-fat diet. Front Microbiol. 2018;9:2651

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Santos FO, Correia BRO, Marinho TS, Barbosa-da-Silva S, Mandarim-de-Lacerda CA, Souza-Mello V. Anti-steatotic linagliptin pleiotropic effects encompasses suppression of de novo lipogenesis and ER stress in high-fat-fed mice. Mol Cell Endocrinol. 2020;509:110804

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Vanweert F, Boone SC, Brouwers B, Mook-Kanamori DO, de Mutsert R, Rosendaal FR, et al. The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity. Int J Obes. 2021;45:1510–20.

    CAS  Article  Google Scholar 

  66. 66.

    Motta VF, Aguila MB, Mandarim-de-Lacerda CA. High-intensity interval training (swimming) significantly improves the adverse metabolism and comorbidities in diet-induced obese mice. J Sports Med Phys Fitness. 2016;56:655–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Schultz A, Mendonca LS, Aguila MB, Mandarim-de-Lacerda CA. Swimming training beneficial effects in a mice model of nonalcoholic fatty liver disease. Exp Toxicol Pathol. 2012;64:273–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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The authors are grateful for the technical assistance of Mrs. Aline Penna. The study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil) (CNPq, Grant nos. 302.920/2016-1 and 40.60.81/2018-2 to CML and 305.865/2017-0 to MBA), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (Faperj, Grant nos. E-26/202.935/2017 and E-26/010.100947/2018 to CML and E-26/202.795/2017 to MBA). RPS received a bursary from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001. These foundations had no interference in the accomplishment and submission of the study.

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Conception and design of the study (MBA, CML); acquisition of data, analysis, and interpretation of data (RPS, TSM); drafting the article or revising it critically for valuable intellectual content (RPS, TSM, LMC); final approval of the version to be submitted (MBA, CML).

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Correspondence to Carlos Alberto Mandarim-de-Lacerda.

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Pontes-da-Silva, R.M., de Souza Marinho, T., de Macedo Cardoso, L.E. et al. Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist. Int J Obes (2021).

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