Skip to main content
SpringerLink
Log in

A combination of rebaudioside A and neohesperidin dihydrochalcone suppressed weight gain by regulating visceral fat and hepatic lipid metabolism in ob/ob mice

  • Research Article
  • Published:
Food Science and Biotechnology Aims and scope Submit manuscript

Abstract

Rebaudioside A (Reb A) and neohesperidin dihydrochalcone (NHDC) are known as intense sweeteners. This study aimed to examine the anti-obesity effects of Reb A and NHDC. C57BL/6 J-ob/ob mice were supplemented with Reb A (50 mg/kg body weight [b.w.]), NHDC (100 mg/kg b.w.), or their combination (COMB) for 4 weeks. COMB-supplemented mice showed significant reduction in b.w. gain, food efficiency ratio, and fat mass. Additionally, mice in the COMB group showed suppressed levels of genes related to adipogenesis, lipogenesis, and lipolysis in the perirenal fat and the levels of hepatic triglyceride, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. The lipogenesis and pro-inflammatory gene expressions were also downregulated in the liver, whereas β-oxidation related genes were upregulated in the COMB group. In addition, mice that received COMB showed distinct gut microbiota structure, enriched in Blautia and Parabacteroides, and depleted in Faecalibaculum and Mucispirillum, in relation to the control group. These results suggest that supplementation with Reb A and NHDC may be an effective treatment for obesity-related metabolic disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. Molecular pathways in non-alcoholic fatty liver disease. Clinical and Experimental Gastroenterology. 7: 221–239 (2014)

    PubMed  PubMed Central  Google Scholar 

  • Berry D, Kuzyk O, Rauch I, Heider S, Schwab C, Hainzl E, Decker T, Müller M, Strobl B, Schleper C, Urich T, Wagner M, Kenner L, Loy A. Intestinal Microbiota Signatures Associated with Inflammation History in Mice Experiencing Recurring Colitis. Front Microbiol. 6: 1408 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  • Berry D, Schwab C, Milinovich G, Reichert J, Ben Mahfoudh K, Decker T, Engel M, Hai B, Hainzl E, Heider S, Kenner L, Müller M, Rauch I, Strobl B, Wagner M, Schleper C, Urich T, Loy A. Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis. The ISME Journal. 6: 2091-2106 (2012)

    CAS  Google Scholar 

  • Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, Alexander H, Alm EJ, Arumugam M, Asnicar F. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nature Biotechnology. 37: 852–857 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cai W, Xu J, Li G, Liu T, Guo X, Wang H, Luo L. Ethanol extract of propolis prevents high-fat diet-induced insulin resistance and obesity in association with modulation of gut microbiota in mice. Food Research International. 130: 108939 (2020)

    Article  CAS  PubMed  Google Scholar 

  • Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJA, Holmes SP. DADA2: High-resolution sample inference from Illumina amplicon data. Nature Methods. 13: 581–583 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chait A, Den Hartigh LJ. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Frontiers in Cardiovascular Medicine. 7: 22 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Zhou J, Wang L. Role and mechanism of gut microbiota in human disease. Frontiers in Cellular and Infection Microbiology. 11: 625913 (2021)

    Article  CAS  Google Scholar 

  • Choi J-Y, McGregor RA, Kwon E-Y, Kim YJ, Han Y, Park JHY, Lee KW, Kim S-J, Kim J, Yun JW. The metabolic response to a high-fat diet reveals obesity-prone and-resistant phenotypes in mice with distinct mRNA-seq transcriptome profiles. International Journal of Obesity. 40: 1452-1460 (2016)

    Article  CAS  Google Scholar 

  • Curry LL, Roberts A. Subchronic toxicity of rebaudioside A. Food and Chemical Toxicology. 46: S11-S20 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Farzanegi P, Dana A, Ebrahimpoor Z, Asadi M, Azarbayjani MA. Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD): Roles of oxidative stress and inflammation. European Journal of Sport Science. 19: 994–1003 (2019)

    Article  PubMed  Google Scholar 

  • Frydman A, Weisshaus O, Huhman DV, Sumner LW, Bar-Peled M, Lewinsohn E, Fluhr R, Gressel J, Eyal Y. Metabolic engineering of plant cells for biotransformation of hesperedin into neohesperidin, a substrate for production of the low-calorie sweetener and flavor enhancer NHDC. Journal of Agricultural and Food Chemistry. 53: 9708–9712 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Jakab J, Miškić B, Mikšić Š, Juranić B, Ćosić V, Schwarz D, Včev A. Adipogenesis as a potential anti-obesity target: A review of pharmacological treatment and natural products. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 14: 67-83 (2021)

    Article  Google Scholar 

  • Kakleas K, Christodouli F, Karavanaki K. Nonalcoholic fatty liver disease, insulin resistance, and sweeteners: a literature review. Expert Review of Endocrinology & Metabolism. 15: 83-93 (2020)

    Article  CAS  Google Scholar 

  • Katoh K, Misawa K, Kuma Ki, Miyata T. MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Research. 30: 3059-3066 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim WR, Flamm SL, Di Bisceglie AM, Bodenheimer HC. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology. 47: 1363-1370 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Kroeze JH. Neohesperidin dihydrochalcone is not a taste enhancer in aqueous sucrose solutions. Chemical Senses 25: 555–559 (2000)

    Article  CAS  PubMed  Google Scholar 

  • Kwok KH, Lam KS, Xu A. Heterogeneity of white adipose tissue: molecular basis and clinical implications. Experimental & Molecular Medicine. 48: e215–e215 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon M, Kim Y, Lee J, Manthey JA, Kim Y, Kim Y. Neohesperidin dihydrochalcone and neohesperidin dihydrochalcone-O-glycoside attenuate subcutaneous fat and lipid accumulation by regulating PI3K/AKT/mTOR pathway in vivo and in vitro. Nutrients. 14: 1087 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HW, Kim KJ, Jung KS, Chon YE, Huh JH, Park KH, Chung JB, Kim CO, Han K-H, Park JY. The relationship between visceral obesity and hepatic steatosis measured by controlled attenuation parameter. PLoS One. 12: e0187066 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  • Lina B, Dreef-van der Meulen H, Leegwater D. Subchronic (13-week) oral toxicity of neohesperidin dihydrochalcone in rats. Food and Chemical Toxicology. 28: 507-513 (1990)

    Article  CAS  PubMed  Google Scholar 

  • Lujan PV, Esmel EV, Meseguer SE. Overview of non-alcoholic fatty liver disease (NAFLD) and the role of sugary food consumption and other dietary components in its development. Nutrients. 13: 1442 (2021)

    Article  CAS  Google Scholar 

  • Mn M, Smvk P, Battula KK, Kalashikam RR. Differential response of rat strains to obesogenic diets underlines the importance of genetic makeup of an individual towards obesity. Scientific Reports. 7: 9162 (2017)

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  • Ozato N, Saito S, Yamaguchi T, Katashima M, Tokuda I, Sawada K, Katsuragi Y, Kakuta M, Imoto S, Ihara K. Blautia genus associated with visceral fat accumulation in adults 20–76 years of age. NPJ Biofilms and Microbiomes. 5: 28 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  • Park HJ, DiNatale DA, Chung M-Y, Park Y-K, Lee J-Y, Koo SI, O'Connor M, Manautou JE, Bruno RS. Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice. The Journal of Nutritional Biochemistry. 22: 393–400 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Price MN, Dehal PS, Arkin AP. FastTree 2–approximately maximum-likelihood trees for large alignments. PLoS One. 5: e9490 (2010)

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  • Qian M, Hu H, Yao Y, Zhao D, Wang S, Pan C, Duan X, Gao Y, Liu J, Zhang Y, Yang S, Qi L-W, Wang L. Coordinated changes of gut microbiome and lipidome differentiates nonalcoholic steatohepatitis (NASH) from isolated steatosis. Liver International. 40: 622-637 (2020)

    Article  CAS  PubMed  Google Scholar 

  • Romieu I, Dossus L, Barquera S, Blottière HM, Franks PW, Gunter M, Hwalla N, Hursting S D, Leitzmann M, Margetts B. Energy balance and obesity: what are the main drivers? Cancer Causes & Control. 28: 247–258 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  • Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C. Metagenomic biomarker discovery and explanation. Genome Biology. 12: 1–18 (2011)

    Article  Google Scholar 

  • Skat‐Rørdam J, Højland Ipsen D, Lykkesfeldt J, Tveden-Nyborg P. A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease. Basic & Clinical Pharmacology & Toxicology. 124:528–537 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  • Suez J, Korem T, Zilberman-Schapira G, Segal E, Elinav E. Non-caloric artificial sweeteners and the microbiome: findings and challenges. Gut Microbes. 6: 149–155 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suriano F, Vieira-Silva S, Falony G, Roumain M, Paquot A, Pelicaen R, Régnier M, Delzenne NM, Raes J, Muccioli GG. Novel insights into the genetically obese (ob/ob) and diabetic (db/db) mice: Two sides of the same coin. Microbiome. 9: 1-20 (2021)

    Article  Google Scholar 

  • Thompson LR, Sanders JG, McDonald D, Amir A, Ladau J, Locey KJ, Prill RJ, Tripathi A, Gibbons SM, Ackermann G. A communal catalogue reveals Earth’s multiscale microbial diversity. Nature. 551: 457-463 (2017)

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Wang Y, Chen L, Li Y, Li Y, Yan M, Chen K, Hao N, Xu L. Efficient enzymatic production of rebaudioside A from stevioside. Bioscience, Biotechnology, and Biochemistry. 80: 67-73 (2016)

    Article  CAS  PubMed  Google Scholar 

  • WHO. Obesity and overweight. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Oct. 20 (2022)

  • Wu TR, Lin CS, Chang CJ, Lin TL, Martel J, Ko YF, Ojcius DM, Lu CC, Young JD, Lai HC. Gut commensal Parabacteroides goldsteinii plays a predominant role in the anti-obesity effects of polysaccharides isolated from Hirsutella sinensis. Gut. 68: 248-262 (2019)

    Article  CAS  PubMed  Google Scholar 

  • Wutthi-In M, Cheevadhanarak S, Yasom S, Kerdphoo S, Thiennimitr P, Phrommintikul A, Chattipakorn N, Kittichotirat W, Chattipakorn S. Gut microbiota profiles of treated metabolic syndrome patients and their relationship with metabolic health. Scientific Reports. 10: 10085 (2020)

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Xi D, Bhattacharjee J, Salazar-Gonzalez R-M, Park S, Jang A, Warren M, Merritt R, Michail S, Bouret S, Kohli R. Rebaudioside affords hepatoprotection ameliorating sugar sweetened beverage-induced nonalcoholic steatohepatitis. Scientific Reports. 10: 6689 (2020)

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Yilmaz P, Parfrey LW, Yarza P, Gerken J, Pruesse E, Quast C, Schweer T, Peplies J, Ludwig W, Glöckner FO. The SILVA and “all-species living tree project (LTP)” taxonomic frameworks. Nucleic Acids Research. 42: D643–D648 (2014)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, and Forestry (IPET) through the Innovative Food Product and Natural Food Materials Development Program, funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA) (119020-03-2-HD040).

Author information

Authors and Affiliations

  1. Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, 03760, Republic of Korea

    Yeri Kim & Yuri Kim

  2. Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul, Republic of Korea

    Hyejin Han, Yeonsoo Oh & Yuri Kim

  3. Department of Food Science & Biotechnology, and Carbohydrate Bioproduct Research Center, Sejong University, Seoul, 05006, Republic of Korea

    Hakdong Shin & Gwoncheol Park

  4. CJ CheilJedang Blossom Park, Suwon, 16495, Republic of Korea

    Sunghee Park

  5. U.S. Horticultural Research Lab., U. S. Department of Agriculture, Agricultural Research Service, 2001 South Rock Road, Fort Pierce, FL, 34945, USA

    John A. Manthey

  6. Center for Food & Bioconvergence, Seoul National University, Seoul, 08826, Republic of Korea

    Yang Kim

Authors
  1. Yeri Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyejin Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeonsoo Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hakdong Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gwoncheol Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sunghee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John A. Manthey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yang Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuri Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuri Kim.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest to declare.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, Y., Han, H., Oh, Y. et al. A combination of rebaudioside A and neohesperidin dihydrochalcone suppressed weight gain by regulating visceral fat and hepatic lipid metabolism in ob/ob mice. Food Sci Biotechnol 33, 913–923 (2024). https://doi.org/10.1007/s10068-023-01391-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10068-023-01391-1

Keywords

Search

Navigation