D-allulose ameliorates adiposity through the AMPK-SIRT1-PGC-1α pathway in HFD-induced SD rats

  • Geum Hwa Lee Non-Clinical Evaluation Center, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju
  • Cheng Peng Non-Clinical Evaluation Center, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju
  • Hwa-Young Lee Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju
  • Seon-Ah Park Non-Clinical Evaluation Center, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju
  • The-Hiep Hoang Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju
  • Jung Hyun Kim Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju
  • Soonok Sa Samyang Corp., 295 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do
  • Go-Eun Kim Samyang Corp., 295 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do
  • Jung-Sook Han Samyang Corp., 295 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do
  • Han Jung Chae Non-Clinical Evaluation Center, Biomedical Research Institute, Jeonbuk National University Hospital
Keywords: D-allulose; obesity; adipose tissue; AMPK; SIRT1.


Background: Adiposity is a major health-risk factor, and D-allulose has beneficial effects on adiposity-related metabolic disturbances. However, the modes of action underlying anti-hyperglycemic and hypolipidemic activity are partly understood.

Objective: This study investigated the in vivo and in vitro effects of D-allulose involved in adipogenesis and activation of the AMPK/SIRT1/PGC-1α pathway in high-fat diet (HFD)-fed rats.

Design: In this study, 8-week-old male SD (Sprague Dawley) rats were divided into five groups (n = 8/group), (1) Control (chow diet, 3.5%); (2) 60% HFD; (3) 60% HFD supplemented with allulose powder (AP) at 0.4 g/kg; (4) 60% HFD supplemented with allulose liquid (AL) at 0.4 g/kg; (5) 60% HFD supplemented with glucose (AL) at 0.4 g/kg. All the group received the product through oral gavage for 6 weeks. Control and HFD groups were gavaged with double-distilled water.

Results: Rats receiving AP and AL showed reduced body weight gain and fat accumulation in HFD-fed rats. Also, supplementation of AL/AP regulated the cytokine secretion and recovered biochemical parameters to alleviate metabolic dysfunction and hepatic injury. Additionally, AL/AP administration improved adipocyte differentiation via regulation of the PPARγ and C/EBPα signaling pathway and adipogenesis-related genes owing to the combined effect of the AMPK/SIRT1 pathway. Furthermore, AL/AP treatment mediated PGC-1α expression triggering mitochondrial genesis via activating the AMPK phosphorylation and SIRT1 deacetylation activity in adipose tissue.

Conclusion: The anti-adiposity activity of D-allulose is observed on a marked alleviation in adipogenesis and AMPK/SIRT1/PGC-1α deacetylation in the adipose tissue of HFD-fed rat.


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  1. de Melo KM, de Oliveira FTB, Costa Silva RA, Gomes Quindere AL, Marinho Filho JDB, Araujo AJ, et al. α, β-Amyrin, a pentacyclic triterpenoid from Protium heptaphyllum suppresses adipocyte differentiation accompanied by down regulation of PPARγ and C/EBPα in 3T3-L1 cells. Biomed Pharmacother 2019; 109: 1860–6. doi: 10.1016/j.biopha.2018.11.027

  2. Liu P, Hsieh P, Lin H, Liu T, Wu H, Chen C, et al. Grail is involved in adipocyte differentiation and diet-induced obesity. Cell Death Dis 2018; 9(5): 525. doi: 10.1038/s41419-018-0596-8

  3. Salmenniemi U, Ruotsalainen E, Pihlajamaki J, Vauhkonen I, Kainulainen S, Punnonen K, et al. Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines, and adhesion molecules in subjects with metabolic syndrome. Circulation 2004; 110(25): 3842–8. doi: 10.1161/01.CIR.0000150391.38660.9B

  4. Li J, Papadopoulos V. Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis. Biochem Pharmacol 2015; 97(1): 99–110. doi: 10.1016/j.bcp.2015.06.020

  5. Xiao P, Yang Z, Sun J, Tian J, Chang Z, Li X, et al. Silymarin inhibits adipogenesis in the adipocytes in grass carp Ctenopharyngodon idellus in vitro and in vivo. Fish Physiol Biochem 2017; 43(6): 1487–500. doi: 10.1007/s10695-017-0387-7

  6. Oshima H, Kimura I, Izumori K. Psicose contents in various food products and its origin. Food Sci Technol Res 2006; 12: 137–43. doi: 10.3136/fstr.12.137

  7. Zhang W, Yu S, Zhang T, Jiang B, Mu W. Recent advances in d-allulose: physiological functionalities, applications, and biological production. Trends Food Sci Technol 2016; 54: 127–37. doi: 10.1016/j.tifs.2016.06.004

  8. Kishida K, Martinez G, Iida T, Yamada T, Ferraris RP, Toyoda Y. D-allulose is a substrate of glucose transporter type 5 (GLUT5) in the small intestine. Food Chem 2019; 277: 604–8. doi: 10.1016/j.foodchem.2018.11.003

  9. Van Opstal AM, Hafkemeijer A, van den Berg-Huysmans AA, Hoeksma M, Mulder TPJ, Pijl H, et al. Brain activity and connectivity changes in response to nutritive natural sugars, non-nutritive natural sugar replacements and artificial sweeteners. Nutr Neurosci 2021; 24(5): 395–405. doi: 10.1080/1028415X.2019.1639306

  10. Han Y, Park H, Choi BR, Ji Y, Kwon EY, Choi MS. Alteration of microbiome profile by d-allulose in amelioration of high-fat-diet-induced obesity in mice. Nutrients 2020; 12(2): 352.

  11. Pratchayasakul W, Jinawong K, Pongkan W, Jaiwongkam T, Arunsak B, Chunchai T, et al. Not only metformin, but also D-allulose, alleviates metabolic disturbance and cognitive decline in prediabetic rats. Nutr Neurosci 2020; 5: 1–13.

  12. Maeng HJ, Yoon JH, Chun KH, Kim ST, Jang DJ, Park JE, et al. Metabolic stability of d-allulose in biorelevant media and hepatocytes: comparison with fructose and erythritol. Foods 2019; 8(10): 448. doi: 10.3390/foods8100448

  13. Kimura T, Kanasaki A, Hayashi N, Yamada T, Iida T, Nagata Y, et al. D-allulose enhances postprandial fat oxidation in healthy humans. Nutrition 2017; 43–44: 16–20. doi: 10.1016/j.nut.2017.06.007

  14. Shintani T, Yamada T, Hayashi N, Iida T, Nagata Y, Ozaki N, et al. Rare sugar syrup containing d-allulose but not high-fructose corn syrup maintains glucose tolerance and insulin sensitivity partly via hepatic glucokinase translocation in wistar rats. J Agric Food Chem 2017; 65(13): 2888–94. doi: 10.1021/acs.jafc.6b05627

  15. Kanasaki A, Niibo M, Iida T. Effect of d-allulose feeding on the hepatic metabolomics profile in male Wistar rats. Food Funct 2021; 12: 3931–3938. doi: 10.1039/D0FO03024D

  16. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009; 458(7241): 1056–60. doi: 10.1038/nature07813

  17. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007; 8(10): 774–85. doi: 10.1038/nrm2249

  18. Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α. EMBO J 2007; 26(7): 1913–23. doi: 10.1038/sj.emboj.7601633

  19. Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 2019; 20(4): 242–58. doi: 10.1038/s41580-018-0093-z

  20. Farmer SR. Transcriptional control of adipocyte formation. Cell Metab 2006; 4(4): 263–73. doi: 10.1016/j.cmet.2006.07.001

  21. Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 2006; 7(12): 885–96. doi: 10.1038/nrm2066

  22. Ali AT, Hochfeld WE, Myburgh R, Pepper MS. Adipocyte and adipogenesis. Eur J Cell Biol 2013; 92(6–7): 229–36. doi: 10.1016/j.ejcb.2013.06.001

  23. Khalilpourfarshbafi M, Gholami K, Murugan DD, Abdul Sattar MZ, Abdullah NA. Differential effects of dietary flavonoids on adipogenesis. Eur J Nutr 2019; 58(1): 5–25. doi: 10.1007/s00394-018-1663-8

  24. Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med 2004; 10(4): 355–61. doi: 10.1038/nm1025

  25. Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 2017; 66(6): 789–800. doi: 10.1016/j.molcel.2017.05.032

  26. Jones JR, Barrick C, Kim KA, Lindner J, Blondeau B, Fujimoto Y, et al. Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A 2005; 102(17): 6207–12. doi: 10.1073/pnas.0306743102

  27. Madsen MS, Siersbaek R, Boergesen M, Nielsen R, Mandrup S. Peroxisome proliferator-activated receptor gamma and C/EBPalpha synergistically activate key metabolic adipocyte genes by assisted loading. Mol Cell Biol 2014; 34(6): 939–54. doi: 10.1128/MCB.01344-13

  28. Macdougall CE, Wood EG, Loschko J, Scagliotti V, Cassidy FC, Robinson ME, et al. Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab 2018; 27(3): 588–601.e4. doi: 10.1016/j.cmet.2018.02.007

  29. Vitale SG, Lagana AS, Nigro A, La Rosa VL, Rossetti P, Rapisarda AM, et al. Peroxisome proliferator-activated receptor modulation during metabolic diseases and cancers: master and minions. PPAR Res 2016; 2016: 6517313. doi: 10.1155/2016/6517313

  30. Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 2014; 25(3): 138–45. doi: 10.1016/j.tem.2013.12.001

  31. Wang YM, Huang TL, Meng C, Zhang J, Fang NY. SIRT1 deacetylates mitochondrial trifunctional enzyme alpha subunit to inhibit ubiquitylation and decrease insulin resistance. Cell Death Dis 2020; 11(10): 821. doi: 10.1038/s41419-020-03012-9

  32. Lee MS, Han HJ, Han SY, Kim IY, Chae S, Lee CS, et al. Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation. Nat Commun 2018; 9(1): 3404. doi: 10.1038/s41467-018-05721-4

  33. Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 2006; 116(7): 1776–83. doi: 10.1172/JCI29044

  34. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, et al. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 2003; 299(5608): 896–9. doi: 10.1126/science.1079368

  35. den Besten G, Bleeker A, Gerding A, van Eunen K, Havinga R, van Dijk TH, et al. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation. Diabetes 2015; 64(7): 2398–408. doi: 10.2337/db14-1213

  36. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 2001; 108(12): 1875–81. doi: 10.1172/JCI14120

  37. Huynh MK, Kinyua AW, Yang DJ, Kim KW. Hypothalamic AMPK as a regulator of energy homeostasis. Neural Plast 2016; 2016: 2754078. doi: 10.1155/2016/2754078

  38. Cho YR, Lee JA, Kim YY, Kang JS, Lee JH, Ahn EK. Anti-obesity effects of Clausena excavata in high-fat diet-induced obese mice. Biomed Pharmacother 2018; 99: 253–60. doi: 10.1016/j.biopha.2018.01.069

  39. Iwasaki Y, Sendo M, Dezaki K, Hira T, Sato T, Nakata M, et al. GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose. Nat Commun 2018; 9(1): 113. doi: 10.1038/s41467-017-02488-y

  40. Xu F, Lin B, Zheng X, Chen Z, Cao H, Xu H, et al. GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia 2016; 59(5): 1059–69. doi: 10.1007/s00125-016-3896-5

  41. van Bloemendaal L, RG IJ, Ten Kulve JS, Barkhof F, Konrad RJ, Drent ML, et al. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 2014; 63(12): 4186–96. doi: 10.2337/db14-0849

How to Cite
Lee G. H., Cheng Peng, Lee H.-Y., Park S.-A., Hoang T.-H., Kim J. H., Sa S., Kim G.-E., Han J.-S., & Chae H. J. (2021). D-allulose ameliorates adiposity through the AMPK-SIRT1-PGC-1α pathway in HFD-induced SD rats. Food & Nutrition Research, 65. https://doi.org/10.29219/fnr.v65.7803
Original Articles