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.

  • Original Article
  • Published:

Animal Models

A novel cobiotic-based preventive approach against high-fat diet-induced adiposity, nonalcoholic fatty liver and gut derangement in mice

Abstract

Background:

High-fat diets (HFDs) induce systemic inflammation, gut microbial derangements and disturb metabolic homeostasis, resulting in weight gain, insulin resistance and nonalcoholic fatty liver (NAFL). Numerous antioxidants and prebiotic/probiotics per se may prevent HFD-associated comorbidities, but there are no reports related to their combination.

Objective:

In the present study, we aim to evaluate a cobiotic combination of lycopene (antioxidant) and isomalto-oligosaccharides (IMOs, a prebiotic) for prevention of HFD-induced alterations.

Design:

Male Swiss albino mice were fed either normal pellet diet (NPD) or HFD and lycopene (5 and 10 mg kg−1), IMOs (0.5 and 1 g kg−1) or their combination for 12 weeks. Systemic adiposity, glucose tolerance, insulin sensitivity, feeding regulators in hypothalamus, hepatosteatosis and liver inflammation, cecal short chain fatty acids (SCFAs), serum inflammatory cytokines, gut morphology and alterations in selected gut microbes were studied.

Results:

Lycopene, IMOs and their combination prevented weight gain, adiposity, improved adipose tissue fat mobilization and reduced insulin resistance. Hypothalamic orexigenic and anorectic genes have also been modulated by these treatments. Dietary interventions prevented NAFL-like symptoms and improved glucose homeostasis. Improvement in selected gut microbial abundance and SCFA concentration along with reduced systemic inflammation, metabolic endotoxemia and improved ileal and colonic health were observed in mice supplemented with lycopene, IMOs and their combination. Interestingly, cobiotic combination synergistically improved many of the HFD-induced alterations.

Conclusion:

The present work provide evidence that new approach based on cobiotic combination (antioxidant plus prebiotic) can be employed to develop novel class of functional foods for their application against HFD-associated pathological complications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Frohnert BI, Jacobs DR Jr, Steinberger J, Moran A, Steffen LM, Sinaiko AR . Relation between serum free fatty acids and adiposity, insulin resistance, and cardiovascular risk factors from adolescence to adulthood. Diabetes 2013; 62: 3163–3169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Imamura F, Mukamal KJ, Meigs JB, Luchsinger JA, Ix JH, Siscovick DS et al. Risk factors for type 2 diabetes mellitus preceded by beta-cell dysfunction, insulin resistance, or both in older adults: the Cardiovascular Health Study. Am J Epidemiol 2013; 177: 1418–1429.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gilbert CA, Slingerland JM . Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annu Rev Med 2013; 64: 45–57.

    Article  CAS  PubMed  Google Scholar 

  4. Louie SM, Roberts LS, Nomura DK . Mechanisms linking obesity and cancer. Biochim Biophys Acta 2013; 1831: 1499–1508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Baboota RK, Bishnoi M, Ambalam P, Kondepudi KK, Sarma SM, Boparai RK et al. Functional food ingredients for the management of obesity and associated co-morbidities – a review. J Funct Foods 2013; 5: 997–1012.

    Article  Google Scholar 

  6. Bakker GC, van Erk MJ, Pellis L, Wopereis S, Rubingh CM, Cnubben NH et al. An antiinflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am J Clin Nutr 2010; 91: 1044–1059.

    Article  CAS  PubMed  Google Scholar 

  7. Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun 2014; 5: 3611.

    Article  CAS  PubMed  Google Scholar 

  8. Arora V, Sachdeva AK, Singh P, Baveja A, Chopra K, Kuhad A Resveratrol and lycopene in the diet and cancer prevention. In: Preedy V (ed). Cancer. Academic Press: San Diego, 2014; pp 127–138.

    Book  Google Scholar 

  9. Ferreira AL, Correa CR Lycopene bioavailability and its effects on health. In: Lima GPP, Vianello F (eds). Food Quality, Safety and Technology. Springer-Verlag: Wien, 2013; pp 63–76.

    Book  Google Scholar 

  10. Goffin D, Delzenne N, Blecker C, Hanon E, Deroanne C, Paquot M . Will isomalto-oligosaccharides, a well-established functional food in Asia, break through the European and American market? The status of knowledge on these prebiotics. Crit Rev Food Sci Nutr 2011; 51: 394–409.

    Article  PubMed  Google Scholar 

  11. Kohmoto T, Fukui F, Takaku H, Mitsuoka T . Dose-response test of isomaltooligosaccharides for increasing fecal bifidobacteria. Agric Biol Chem 1991; 55: 2157–2159.

    CAS  Google Scholar 

  12. Oku T, Nakamura S . Comparison of digestibility and breath hydrogen gas excretion of fructo-oligosaccharide, galactosyl-sucrose, and isomalto-oligosaccharide in healthy human subjects. Eur J Clin Nutr. 2003; 57: 1150–1156.

    Article  CAS  PubMed  Google Scholar 

  13. Mizubuchi H, Yajima T, Aoi N, Tomita T, Yoshikai Y . Isomalto-oligosaccharides polarize Th1-like responses in intestinal and systemic immunity in mice. J Nutr 2005; 135: 2857–2861.

    Article  CAS  PubMed  Google Scholar 

  14. Delzenne NM, Williams CM . Prebiotics and lipid metabolism. Curr Opin Lipidol 2002; 13: 61–67.

    Article  CAS  PubMed  Google Scholar 

  15. Lee, do K, Park SY, Jang S, Baek EH, Kim MJ, Huh SM et al. The combination of mixed lactic acid bacteria and dietary fiber lowers serum cholesterol levels and fecal harmful enzyme activities in rats. Arch Pharm Res 2011; 34: 23–29.

    Article  CAS  PubMed  Google Scholar 

  16. Frece J, Kos B, Svetec IK, Zgaga Z, Beganovic J, Lebos A et al. Synbiotic effect of Lactobacillus helveticus M92 and prebiotics on the intestinal microflora and immune system of mice. J Dairy Res 2009; 76: 98–104.

    Article  CAS  PubMed  Google Scholar 

  17. Greenway F, Wang S, Heiman M . A novel cobiotic containing a prebiotic and an antioxidant augments the glucose control and gastrointestinal tolerability of metformin: a case report. Benef Microbes 2014; 5: 29–32.

    Article  CAS  PubMed  Google Scholar 

  18. Delzenne NM, Neyrinck AM, Backhed F, Cani PD . Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nat Rev Endocrinol 2011; 7: 639–646.

    Article  CAS  PubMed  Google Scholar 

  19. Murtaza N, Baboota RK, Jagtap S, Singh DP, Khare P, Sarma SM et al. Finger millet bran supplementation alleviates obesity-induced oxidative stress, inflammation and gut microbial derangements in high-fat diet-fed mice. Br J Nutr 2014; 112: 1447–1458.

    Article  CAS  PubMed  Google Scholar 

  20. Baboota RK, Murtaza N, Jagtap S, Singh DP, Karmase A, Kaur J et al. Capsaicin-induced transcriptional changes in hypothalamus and alterations in gut microbial count in high fat diet fed mice. J Nutr Biochem 2014; 25: 893–902.

    Article  CAS  PubMed  Google Scholar 

  21. Anhe FF, Roy D, Pilon G, Dudonne S, Matamoros S, Varin TV et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 2015; 64: 872–883.

    Article  CAS  PubMed  Google Scholar 

  22. Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009; 58: 1091–1103.

    Article  CAS  PubMed  Google Scholar 

  23. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57: 1470–1481.

    Article  CAS  PubMed  Google Scholar 

  24. Gummesson A, Carlsson LM, Storlien LH, Backhed F, Lundin P, Lofgren L et al. Intestinal permeability is associated with visceral adiposity in healthy women. Obesity (Silver Spring) 2011; 19: 2280–2282.

    Article  Google Scholar 

  25. Rapin JR, Wiernsperger N . Possible links between intestinal permeablity and food processing: a potential therapeutic niche for glutamine. Clinics 2010; 65: 635–643.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Caesar R, Fåk F, Bäckhed F . Effects of gut microbiota on obesity and atherosclerosis via modulation of inflammation and lipid metabolism. J Intern Med 2010; 268: 320–328.

    Article  CAS  PubMed  Google Scholar 

  27. Sahin H, Trautwein C, Wasmuth HE . TLR4 stresses the liver. Gut 2012; 61: 1241–1242.

    Article  CAS  PubMed  Google Scholar 

  28. Hu Y, Ketabi A, Buchko A, Gänzle MG . Metabolism of isomalto-oligosaccharides by Lactobacillus reuteri and bifidobacteria. Lett Appl Microbiol 2013; 57: 108–114.

    Article  CAS  PubMed  Google Scholar 

  29. Ganzle MG, Follador R . Metabolism of oligosaccharides and starch in lactobacilli: a review. Front Microbiol 2012; 3: 340.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Koleva P, Ketabi A, Valcheva R, Gänzle MG, Dieleman LA . Chemically defined diet alters the protective properties of fructo-oligosaccharides and isomalto-oligosaccharides in HLA-B27 transgenic rats. PLoS One 2014; 9: e111717.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ghavipour M, Sotoudeh G, Ghorbani M . Tomato juice consumption improves blood antioxidative biomarkers in overweight and obese females. Clin Nutr 2015; 34: 805–809.

    Article  CAS  PubMed  Google Scholar 

  32. Luvizotto Rde A, Nascimento AF, Imaizumi E, Pierine DT, Conde SJ, Correa CR et al. Lycopene supplementation modulates plasma concentrations and epididymal adipose tissue mRNA of leptin, resistin and IL-6 in diet-induced obese rats. Br J Nutr 2013; 110: 1803–1809.

    Article  PubMed  Google Scholar 

  33. Riso P, Pinder A, Santangelo A, Porrini M . Does tomato consumption effectively increase the resistance of lymphocyte DNA to oxidative damage? Am J Clin Nutr 1999; 69: 712–718.

    Article  CAS  PubMed  Google Scholar 

  34. Kim AY, Jeong Y-J, Park YB, Lee M-K, Jeon S-M, McGregor RA et al. Dose dependent effects of lycopene enriched tomato-wine on liver and adipose tissue in high-fat diet fed rats. Food Chem 2012; 130: 42–48.

    Article  CAS  Google Scholar 

  35. Gouranton E, Thabuis C, Riollet C, Malezet-Desmoulins C, El Yazidi C, Amiot MJ et al. Lycopene inhibits proinflammatory cytokine and chemokine expression in adipose tissue. J Nutr Biochem 2011; 22: 642–648.

    Article  CAS  PubMed  Google Scholar 

  36. Sesso HD, Buring JE, Norkus EP, Gaziano JM . Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in men. Am J Clin Nutr 2005; 81: 990–997.

    Article  CAS  PubMed  Google Scholar 

  37. Rissanen TH, Voutilainen S, Nyyssonen K, Lakka TA, Sivenius J, Salonen R et al. Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr 2001; 85: 749–754.

    Article  CAS  PubMed  Google Scholar 

  38. Ip BC, Liu C, Ausman LM, von Lintig J, Wang XD . Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice. Cancer Prev Res (Phila) 2014; 7: 1219–1227.

    Article  CAS  Google Scholar 

  39. Bernal C, Martin-Pozuelo G, Lozano AB, Sevilla A, Garcia-Alonso J, Canovas M et al. Lipid biomarkers and metabolic effects of lycopene from tomato juice on liver of rats with induced hepatic steatosis. J Nutr Biochem 2013; 24: 1870–1881.

    Article  CAS  PubMed  Google Scholar 

  40. Reid BN, Ables GP, Otlivanchik OA, Schoiswohl G, Zechner R, Blaner WS et al. Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. J Biol Chem 2008; 283: 13087–13099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tsukita S, Yamada T, Uno K, Takahashi K, Kaneko K, Ishigaki Y et al. Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals. Cell Metab 2012; 16: 825–832.

    Article  CAS  PubMed  Google Scholar 

  42. Shulman GI . Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 2014; 371: 2237–2238.

    Article  PubMed  Google Scholar 

  43. Samuel VT, Beddow SA, Iwasaki T, Zhang XM, Chu X, Still CD et al. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with type 2 diabetes. Proc Natl Acad Sci USA 2009; 106: 12121–12126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Charbonneau A, Couturier K, Gauthier MS, Lavoie JM . Evidence of hepatic glucagon resistance associated with hepatic steatosis: reversal effect of training. Int J Sports Med 2005; 26: 432–441.

    Article  CAS  PubMed  Google Scholar 

  45. Eaton RP, Schade DS . Glucagon resistance as a hormonal basis for endogenous hyperlipemia. Lancet 1973; 301: 973–974.

    Article  Google Scholar 

  46. Mighiu PI, Yue JT, Filippi BM, Abraham MA, Chari M, Lam CK et al. Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat Med 2013; 19: 766–772.

    Article  CAS  PubMed  Google Scholar 

  47. Dalamaga M, Chou SH, Shields K, Papageorgiou P, Polyzos SA, Mantzoros CS . Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab 2013; 18: 29–42.

    Article  CAS  PubMed  Google Scholar 

  48. Friedman JM, Halaas JL . Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763–770.

    Article  CAS  PubMed  Google Scholar 

  49. Schwartz MW, Woods SC, Porte D Jr., Seeley RJ, Baskin DG . Central nervous system control of food intake. Nature 2000; 404: 661–671.

    Article  CAS  PubMed  Google Scholar 

  50. Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 2014; 15: 423–430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 2002; 8: 75–79.

    Article  CAS  PubMed  Google Scholar 

  52. Covarrubias AJ, Horng T . IL-6 strikes a balance in metabolic inflammation. Cell Metab 2014; 19: 898–899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ip BC, Hu KQ, Liu C, Smith DE, Obin MS, Ausman LM et al. Lycopene metabolite, apo-10'-lycopenoic acid, inhibits diethylnitrosamine-initiated, high fat diet-promoted hepatic inflammation and tumorigenesis in mice. Cancer Prev Res (Phila) 2013; 6: 1304–1316.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Department of Biotechnology, Government of India, for research grants given to National Agri-food Biotechnology Institute, Dr Mahendra Bishnoi and Dr Kanthi Kiran Kondepudi. The Lycovit gift samples provided by BASF-the chemical company and the efforts of Ms Sangeetha Srinivasan (Manager, New Business Development, Human Nutrition) for the same is highly acknowledged. IMO gift sample was provided by BioNeutra North America Inc. We also acknowledge the help of Ms Vandana Bijalwan for taking care of the mice during the study.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to K K Kondepudi, K Chopra or M Bishnoi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, D., Khare, P., Zhu, J. et al. A novel cobiotic-based preventive approach against high-fat diet-induced adiposity, nonalcoholic fatty liver and gut derangement in mice. Int J Obes 40, 487–496 (2016). https://doi.org/10.1038/ijo.2015.197

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2015.197

This article is cited by

Search

Quick links