Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Physiology and Biochemistry

Effects of a novel polyphenol-rich plant extract on body composition, inflammation, insulin sensitivity, and glucose homeostasis in obese mice

Abstract

Background/objectives

The worldwide prevalence of obesity, metabolic syndrome and type 2 diabetes (T2D) is reaching epidemic proportions that urge the development of new management strategies. Totum-63 is a novel, plant-based polyphenol-rich active principle that has been shown to reduce body weight, fasting glycemia, glucose intolerance, and fatty liver index in obese subjects with prediabetes. Here, we investigated the effects and underlying mechanism(s) of Totum-63 on metabolic homeostasis in insulin-resistant obese mice.

Methods

Male C57Bl6/J mice were fed a high-fat diet for 12 weeks followed by supplementation with Totum-63 for 4 weeks. The effects on whole-body energy and metabolic homeostasis, as well as on tissue-specific inflammation and insulin sensitivity were assessed using a variety of immunometabolic phenotyping tools.

Results

Totum-63 decreased body weight and fat mass in obese mice, without affecting lean mass, food intake and locomotor activity, and increased fecal energy excretion and whole-body fatty acid oxidation. Totum-63 reduced fasting plasma glucose, insulin and leptin levels, and improved whole-body insulin sensitivity and peripheral glucose uptake. The expression of insulin receptor β and the insulin-induced phosphorylation of Akt/PKB were increased in liver, skeletal muscle, white adipose tissue (WAT) and brown adipose tissue (BAT). Hepatic steatosis was also decreased by Totum-63 and associated with a lower expression of genes involved in fatty acid uptake, de novo lipogenesis, inflammation, and fibrosis. Furthermore, a significant reduction in pro-inflammatory macrophages was also observed in epidydimal WAT. Finally, a potent decrease in BAT mass associated with enhanced tissue expression of thermogenic genes was found, suggesting BAT activation by Totum-63.

Conclusions

Our results show that Totum-63 reduces inflammation and improves insulin sensitivity and glucose homeostasis in obese mice through pleiotropic effects on various metabolic organs. Altogether, plant-derived Totum-63 might constitute a promising novel nutritional supplement for alleviating metabolic dysfunctions in obese people with or without T2D.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Totum-63 decreases body weight, fat mass and energy assimilation efficiency in HFD-fed mice.
Fig. 2: Totum-63 improves whole-body metabolic homeostasis in obese mice.
Fig. 3: Totum-63 improves systemic and tissue-specific insulin sensitivity in obese mice.
Fig. 4: Totum-63 reduces hepatic steatosis, inflammation and fibrosis in obese mice.
Fig. 5: Totum-63 reduces inflammation in white adipose tissues from obese mice.
Fig. 6: Totum-63 promotes thermogenic program and reduces inflammation in brown adipose tissue from obese mice.

References

  1. 1.

    WHO. Obesity and overweight. Key facts. 2020. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.

  2. 2.

    IDF. IDF Diabetes Atlas. 9th ed. 2019. http://www.diabetesatlas.org/.

  3. 3.

    Williams R, Karuranga S, Malanda B, Saeedi P, Basit A, Besancon S, et al. Global and regional estimates and projections of diabetes-related health expenditure: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2020;162:108072.

    Article  Google Scholar 

  4. 4.

    DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1:15019.

    Article  Google Scholar 

  5. 5.

    Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature. 2019;576:51–60.

    CAS  Article  Google Scholar 

  6. 6.

    Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542:177–85.

    CAS  Article  Google Scholar 

  7. 7.

    Jais A, Bruning JC. Hypothalamic inflammation in obesity and metabolic disease. J Clin Investig. 2017;127:24–32.

    Article  Google Scholar 

  8. 8.

    Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16:145–59.

    CAS  Article  Google Scholar 

  9. 9.

    Lackey DE, Olefsky JM. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol. 2016;12:15–28.

    CAS  Article  Google Scholar 

  10. 10.

    Lee YS, Wollam J, Olefsky JM. An integrated view of immunometabolism. Cell. 2018;172:22–40.

    CAS  Article  Google Scholar 

  11. 11.

    Castejon-Vega B, Giampieri F, Alvarez-Suarez JM. Nutraceutical compounds targeting inflammasomes in human diseases. Int J Mol Sci. 2020;21:4829.

    Article  Google Scholar 

  12. 12.

    Granato D, Barba FJ, Bursac Kovacevic D, Lorenzo JM, Cruz AG, Putnik P. Functional foods: product development, technological trends, efficacy testing, and safety. Annu Rev Food Sci Technol. 2020;11:93–118.

    CAS  Article  Google Scholar 

  13. 13.

    Martel J, Ojcius DM, Chang CJ, Lin CS, Lu CC, Ko YF, et al. Anti-obesogenic and antidiabetic effects of plants and mushrooms. Nat Rev Endocrinol. 2017;13:149–60.

    CAS  Article  Google Scholar 

  14. 14.

    Alkhatib A, Tsang C, Tiss A, Bahorun T, Arefanian H, Barake R. et al. Functional foods and lifestyle approaches for diabetes prevention and management. Nutrients. 2017;9:1310.

    Article  Google Scholar 

  15. 15.

    Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal. 2013;2013:162750.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Hussain T, Tan B, Murtaza G, Liu G, Rahu N, Saleem Kalhoro M, et al. Flavonoids and type 2 diabetes: Evidence of efficacy in clinical and animal studies and delivery strategies to enhance their therapeutic efficacy. Pharmacol Res. 2020;152:104629.

    CAS  Article  Google Scholar 

  17. 17.

    Cory H, Passarelli S, Szeto J, Tamez M, Mattei J. The role of polyphenols in human health and food systems: a mini-review. Front Nutr. 2018;5:87.

    Article  Google Scholar 

  18. 18.

    Peltier S, Chavanelle V, Otero YF, Bargetto M, Cazaubiel M, Sirvent P, et al. Totum-63 lowers fasting glycemia in subjects with prediabetes: a phase 2A clinical trial. Diabetes. 2020;69:848-P.

    Article  Google Scholar 

  19. 19.

    Hussaarts L, Garcia-Tardon N, van Beek L, Heemskerk MM, Haeberlein S, van der Zon GC, et al. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J. 2015;29:3027–39.

    CAS  Article  Google Scholar 

  20. 20.

    van der Zande HJP, Gonzalez MA, de Ruiter K, Wilbers RHP, Garcia-Tardon N, van Huizen M, et al. The helminth glycoprotein omega-1 improves metabolic homeostasis in obese mice through type 2 immunity-independent inhibition of food intake. FASEB J. 2021;35:e21331.

    Article  Google Scholar 

  21. 21.

    Lantier L, Williams AS, Williams IM, Guerin A, Bracy DP, Goelzer M, et al. Reciprocity between skeletal muscle AMPK deletion and insulin action in diet-induced obese mice. Diabetes. 2020;69:1636–49.

    Article  Google Scholar 

  22. 22.

    Lee S, Muniyappa R, Yan X, Chen H, Yue LQ, Hong EG, et al. Comparison between surrogate indexes of insulin sensitivity and resistance and hyperinsulinemic euglycemic clamp estimates in mice. Am J Physiol Endocrinol Metab. 2008;294:E261–70.

    CAS  Article  Google Scholar 

  23. 23.

    Thomas A, Belaidi E, Aron-Wisnewsky J, van der Zon GC, Levy P, Clement K, et al. Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice. Sci Rep. 2016;6:24618.

    Article  Google Scholar 

  24. 24.

    Zinsou JF, Janse JJ, Honpkehedji YY, Dejon-Agobe JC, Garcia-Tardon N, Hoekstra PT, et al. Schistosoma haematobium infection is associated with lower serum cholesterol levels and improved lipid profile in overweight/obese individuals. PLoS Negl Trop Dis. 2020;14:e0008464.

    CAS  Article  Google Scholar 

  25. 25.

    Thomas A, Belaidi E, Moulin S, Horman S, van der Zon GC, Viollet B, et al. Chronic intermittent hypoxia impairs insulin sensitivity but improves whole-body glucose tolerance by activating skeletal muscle AMPK. Diabetes. 2017;66:2942–51.

    CAS  Article  Google Scholar 

  26. 26.

    Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2:217–25.

    CAS  Article  Google Scholar 

  27. 27.

    Tadera K, Minami Y, Takamatsu K, Matsuoka T. Inhibition of alpha-glucosidase and alpha-amylase by flavonoids. J Nutr Sci Vitaminol. 2006;52:149–53.

    CAS  Article  Google Scholar 

  28. 28.

    McDougall GJ, Kulkarni NN, Stewart D. Current developments on the inhibitory effects of berry polyphenols on digestive enzymes. Biofactors. 2008;34:73–80.

    Article  Google Scholar 

  29. 29.

    Tan Y, Chang SKC. Digestive enzyme inhibition activity of the phenolic substances in selected fruits, vegetables and tea as compared to black legumes. J Funct Foods. 2017;38:644–55.

    CAS  Article  Google Scholar 

  30. 30.

    Ko CW, Qu J, Black DD, Tso P. Regulation of intestinal lipid metabolism: current concepts and relevance to disease. Nat Rev Gastroenterol Hepatol. 2020;17:169–83.

    CAS  Article  Google Scholar 

  31. 31.

    Khoshbin K, Camilleri M. Effects of dietary components on intestinal permeability in health and disease. Am J Physiol Gastrointest Liver Physiol. 2020;319:G589–608.

    CAS  Article  Google Scholar 

  32. 32.

    Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 2008;8:301–9.

    CAS  Article  Google Scholar 

  33. 33.

    Han X, Zhang Y, Guo J, You Y, Zhan J, Huang W. Chlorogenic acid stimulates the thermogenesis of brown adipocytes by promoting the uptake of glucose and the function of mitochondria. J Food Sci. 2019;84:3815–24.

    CAS  Article  Google Scholar 

  34. 34.

    Oi-Kano Y, Kawada T, Watanabe T, Koyama F, Watanabe K, Senbongi R, et al. Oleuropein, a phenolic compound in extra virgin olive oil, increases uncoupling protein 1 content in brown adipose tissue and enhances noradrenaline and adrenaline secretions in rats. J Nutr Sci Vitaminol. 2008;54:363–70.

    CAS  Article  Google Scholar 

  35. 35.

    Ahmad TR, Haeusler RA. Bile acids in glucose metabolism and insulin signalling—mechanisms and research needs. Nat Rev Endocrinol. 2019;15:701–12.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Bruno Guigas.

Ethics declarations

Conflict of interest

VC, YO, FLJ, SLP, and PS are all employees of Valbiotis. SLP and PS are listed as co-inventors on Totum-63 patent and possess company stock. None of the other authors have any potential competing interests. This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases grants DK059637 and S10RR028101 (LL, OMcG), the NWO project 184.034.019 (MG), and Valbiotis (BG). Study design, collection of the data, analysis and interpretation of the results, writing and decision to submit the article for publication was performed by Guigas’ group at the Leiden University Medical Center, in agreement with Valbiotis.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

van der Zande, H.J.P., Lambooij, J.M., Chavanelle, V. et al. Effects of a novel polyphenol-rich plant extract on body composition, inflammation, insulin sensitivity, and glucose homeostasis in obese mice. Int J Obes 45, 2016–2027 (2021). https://doi.org/10.1038/s41366-021-00870-x

Download citation

Search

Quick links