Download PDF
Exp Clin Endocrinol Diabetes 2017; 125(09): 610-617
DOI: 10.1055/s-0043-101919
Article
© Georg Thieme Verlag KG Stuttgart · New York

Lycopene Improves Insulin Sensitivity through Inhibition of STAT3/Srebp-1c-Mediated Lipid Accumulation and Inflammation in Mice fed a High-Fat Diet

Zhaohui Zeng   *
1   Nutritional Department, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China
,
Wang He   *
2   Department of Endocrinology, Xi’an NO.1 Hospital, Xi’an, Shaanxi, China
,
Zhen Jia
2   Department of Endocrinology, Xi’an NO.1 Hospital, Xi’an, Shaanxi, China
,
Shu Hao
2   Department of Endocrinology, Xi’an NO.1 Hospital, Xi’an, Shaanxi, China
› Author Affiliations
Further Information

Publication History

received 02 August 2016
revised 18 January 2017

accepted 23 January 2017

Publication Date:
04 May 2017 (online)

Also available at
    Permissions and Reprints

Abstract

In the past few years, metabolic disorders, such as type 2 diabetes and metabolic syndrome, have reached global prevalence. Lycopene is one of the major carotenoids in tomatoes, watermelons, red grapefruits, and guava. In the current study, using high fat diet (HFD)-fed mice, we investigated the effect of Lycopene on insulin resistance. We showed that diet containing Lycopene significantly prevented HFD-induced increase of fasting blood glucose and insulin level, glucose and insulin intolerance, and decrease of hepatic glycogen content. We found that Lycopene notably prevented the increase of IL-1β, TNFα and CRP levels in mice fed HFD. We showed that Lycopene improved the lipid profiles in HFD-fed mice, as evidenced by decrease of systemic and hepatic TC, TG and LDL, and increase of HDL. Lycopene suppressed the increase of the expression of Srebp-1c, FAS and ACC-1 in mice fed HFD. The administration of Lycopene notably prevented the expression and phosphorylation of STAT3 in livers of mice induced by HFD. The treatment of adenovirus carrying STAT3 significantly suppressed the decrease of Srebp-1c expression induced by Lycopene. Furthermore, enhancement of STAT3 signaling by adenovirus markedly blocked the reduction of fasting blood glucose and insulin level. In conclusion, in the current study, we found that Lycopene prevented STAT3 signaling and inhibited Srebp-1c and downstream gene expression, resulting in inhibition of lipid accumulation, inflammation, insulin resistance and metabolic dysfunction. Overall, the data in the study provide better understanding of the beneficial effects of Lycopene against insulin resistance and metabolic disorder.

Key words

Lycopene - insulin resistance - metabolic disorder - Srebp-1c - STAT3

* These authors contributed equally to this article.


 

  • References

  • 1 Rathmann W, Giani G. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes care 2004; 27: 2568-2569 author reply 9
    CrossrefPubMedGoogle Scholar
  • 2 Wild S, Roglic G, Green A. et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes care 2004; 27: 1047-1053
    CrossrefPubMedGoogle Scholar
  • 3 Chen G, Shi L, Cai L et al. Comparison of insulin resistance and beta-cell dysfunction between the young and the elderly in normal glucose tolerance and prediabetes population: a prospective study. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 2016
    PubMed
  • 4 Hesselink MK, Schrauwen-Hinderling V, Schrauwen P. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nature reviews Endocrinology 2016; 12: 633-645
    CrossrefPubMedGoogle Scholar
  • 5 Hu FB, van Dam RM, Liu S. Diet and risk of Type II diabetes: The role of types of fat and carbohydrate. Diabetologia 2001; 44: 805-817
    CrossrefPubMedGoogle Scholar
  • 6 Chen L, Li Y, Zhang F. et al. Association of serum ferritin levels with metabolic syndrome and insulin resistance in a Chinese population. Journal of diabetes and its complications 2016; 31: 364-368
    PubMedGoogle Scholar
  • 7 Szalat A, Durst R, Leitersdorf E. Managing dyslipidaemia in type 2 diabetes mellitus. Best practice & research Clinical endocrinology & metabolism 2016; 30: 431-444
    CrossrefPubMedGoogle Scholar
  • 8 Vlassara H, Cai W, Tripp E. et al. Oral AGE restriction ameliorates insulin resistance in obese individuals with the metabolic syndrome: A randomised controlled trial. Diabetologia 2016; 59: 2181-2192
    CrossrefPubMedGoogle Scholar
  • 9 Zhao W, Ge H, Liu K. et al. Nandinine, a Derivative of Berberine, Inhibits Inflammation and Reduces Insulin Resistance in Adipocytes via Regulation of AMP-Kinase Activity. Planta medica 2016; 83: 203-209
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Zhuge F, Ni Y, Nagashimada M. et al. DPP-4 inhibition by linagliptin attenuates obesity-related inflammation and insulin resistance by regulating M1/M2 macrophage polarization. Diabetes 2016; 65: 2966-2979
    CrossrefPubMedGoogle Scholar
  • 11 Frances DE, Motino O, Agra N. et al. Hepatic cyclooxygenase-2 expression protects against diet-induced steatosis, obesity, and insulin resistance. Diabetes 2015; 64: 1522-1531
    CrossrefPubMedGoogle Scholar
  • 12 Bharati AJ, Bansal YK. Phytochemical investigation of natural and in vitro raised Vrddhadaruka plants. Ancient science of life 2014; 34: 80-84
    CrossrefPubMedGoogle Scholar
  • 13 Garcia-Lafuente A, Guillamon E, Villares A. et al. Flavonoids as anti-inflammatory agents: Implications in cancer and cardiovascular disease. Inflammation research: Official journal of the European Histamine Research Society [et al.] 2009; 58: 537-552
    CrossrefPubMedGoogle Scholar
  • 14 Seo MJ, Seo YJ, Pan CH et al. Fucoxanthin Suppresses Lipid Accumulation and ROS Production During Differentiation in 3T3-L1 Adipocytes. Phytotherapy research: PTR 2016
    PubMed
  • 15 Xu Z, Wang S, Ji H. et al. Broccoli sprout extract prevents diabetic cardiomyopathy via Nrf2 activation in db/db T2DM mice. Scientific reports 2016; 6: 30252
    CrossrefPubMedGoogle Scholar
  • 16 Ip BC, Liu C, Lichtenstein AH. et al. Lycopene and apo-10'-lycopenoic acid have differential mechanisms of protection against hepatic steatosis in beta-carotene-9',10'-oxygenase knockout male mice. The Journal of nutrition 2015; 145: 268-276
    CrossrefPubMedGoogle Scholar
  • 17 Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Archives of biochemistry and biophysics 1989; 274: 532-538
    CrossrefPubMedGoogle Scholar
  • 18 Wang XD. Lycopene metabolism and its biological significance. The American journal of clinical nutrition 2012; 96: 1214s-1222s
    CrossrefPubMedGoogle Scholar
  • 19 Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. Journal of the National Cancer Institute. 1999; 91: 317-331
    CrossrefPubMedGoogle Scholar
  • 20 Clinton SK. Lycopene: Chemistry, biology, and implications for human health and disease. Nutrition reviews 1998; 56 2 Pt 1 35-51
    PubMedGoogle Scholar
  • 21 Wertz K, Siler U, Goralczyk R. Lycopene: Modes of action to promote prostate health. Archives of biochemistry and biophysics 2004; 430: 127-134
    CrossrefPubMedGoogle Scholar
  • 22 Yang T, Yang X, Wang X. et al. The role of tomato products and lycopene in the prevention of gastric cancer: A meta-analysis of epidemiologic studies. Medical hypotheses 2013; 80: 383-388
    CrossrefPubMedGoogle Scholar
  • 23 Huang CS, Liao JW, Hu ML. Lycopene inhibits experimental metastasis of human hepatoma SK-Hep-1 cells in athymic nude mice. The Journal of nutrition 2008; 138: 538-543
    CrossrefPubMedGoogle Scholar
  • 24 Hu MY, Li YL, Jiang CH. et al. Comparison of lycopene and fluvastatin effects on atherosclerosis induced by a high-fat diet in rabbits. Nutrition (Burbank, Los Angeles County, Calif) 2008; 24: 1030-1038
    CrossrefPubMedGoogle Scholar
  • 25 Vioque J, Weinbrenner T, Asensio L. et al. Plasma concentrations of carotenoids and vitamin C are better correlated with dietary intake in normal weight than overweight and obese elderly subjects. The British journal of nutrition 2007; 97: 977-986
    CrossrefPubMedGoogle Scholar
  • 26 Wang Y, Ausman LM, Greenberg AS. et al. Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis-promoted hepatocarcinogenesis in rats. International journal of cancer 2010; 126: 1788-1796
    CrossrefPubMedGoogle Scholar
  • 27 Ozmen O, Topsakal S, Haligur M. et al. Effects of Caffeine and Lycopene in Experimentally Induced Diabetes Mellitus. Pancreas 2016; 45: 579-583
    CrossrefPubMedGoogle Scholar
  • 28 Bayramoglu A, Bayramoglu G, Senturk H. Lycopene partially reverses symptoms of diabetes in rats with streptozotocin-induced diabetes. Journal of medicinal food 2013; 16: 128-132
    CrossrefPubMedGoogle Scholar
  • 29 Yin Q, Ma Y, Hong Y. et al. Lycopene attenuates insulin signaling deficits, oxidative stress, neuroinflammation, and cognitive impairment in fructose-drinking insulin resistant rats. Neuropharmacology 2014; 86: 389-396
    CrossrefPubMedGoogle Scholar
  • 30 Bahcecioglu IH, Kuzu N, Metin K. et al. Lycopene prevents development of steatohepatitis in experimental nonalcoholic steatohepatitis model induced by high-fat diet. Veterinary medicine international 2010; 2010 DOI: 10.4061/2010/262179.
    PubMedGoogle Scholar
  • 31 Ahn J, Lee H, Jung CH. et al. Lycopene inhibits hepatic steatosis via microRNA-21-induced downregulation of fatty acid-binding protein 7 in mice fed a high-fat diet. Molecular nutrition & food research 2012; 56: 1665-1674
    CrossrefPubMedGoogle Scholar
  • 32 Li W, Wang G, Lu X. et al. Lycopene ameliorates renal function in rats with streptozotocin-induced diabetes. International journal of clinical and experimental pathology 2014; 7: 5008-5015
    PubMedGoogle Scholar
  • 33 Vida M, Gavito AL, Pavon FJ. et al. Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice. Disease models & mechanisms 2015; 8: 721-731
    CrossrefPubMedGoogle Scholar
  • 34 Simone RE, Russo M, Catalano A. et al. Lycopene inhibits NF-kB-mediated IL-8 expression and changes redox and PPARgamma signalling in cigarette smoke-stimulated macrophages. PloS one 2011; 6: e19652
    CrossrefPubMedGoogle Scholar
  • 35 Gupta SC, Kim JH, Kannappan R. et al. Role of nuclear factor kappaB-mediated inflammatory pathways in cancer-related symptoms and their regulation by nutritional agents. Experimental biology and medicine (Maywood, NJ) 2011; 236: 658-671
    CrossrefPubMedGoogle Scholar
  • 36 Dhindsa S, Ghanim H, Batra M. et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes care 2016; 39: 82-91
    CrossrefPubMedGoogle Scholar
  • 37 Ruscitti P, Cipriani P, Cantarini L. et al. Efficacy of inhibition of IL-1 in patients with rheumatoid arthritis and type 2 diabetes mellitus: Two case reports and review of the literature. Journal of medical case reports 2015; 9: 123
    CrossrefPubMedGoogle Scholar
  • 38 Lin X, Zhang Z, Chen JM. et al. Role of APN and TNF-alpha in type 2 diabetes mellitus complicated by nonalcoholic fatty liver disease. Genetics and molecular research: GMR 2015; 14: 2940-2946
    CrossrefPubMedGoogle Scholar
  • 39 Akram Kooshki A, Tofighiyan T, Rakhshani MH. Effects of synbiotics on inflammatory markers in patients with type 2 diabetes mellitus. Global journal of health science 2015; 7 7 Spec No 1-5
    PubMedGoogle Scholar
  • 40 Liu ZM, Ho SC. The association of serum C-reactive protein, uric acid and magnesium with insulin resistance in Chinese postmenopausal women with prediabetes or early untreated diabetes. Maturitas 2011; 70: 176-181
    CrossrefPubMedGoogle Scholar
  • 41 Tangvarasittichai S, Pongthaisong S, Tangvarasittichai O. Tumor necrosis factor-alpha, interleukin-6, c-reactive protein levels and insulin resistance associated with type 2 diabetes in abdominal obesity women. Indian journal of clinical biochemistry: IJCB 2016; 31: 68-74
    CrossrefPubMedGoogle Scholar
  • 42 Toonen EJ, Mirea AM, Tack CJ. et al. Activation of proteinase 3 contributes to Non-alcoholic Fatty Liver Disease (NAFLD) and insulin resistance. Molecular medicine (Cambridge, Mass) 2016; 22 DOI: 10.2119/molmed.2016.00033.
    PubMedGoogle Scholar
  • 43 Sung KC, Ryu S, Lee JY. et al. Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. Journal of hepatology 2016; 65: 791-797
    CrossrefPubMedGoogle Scholar
  • 44 Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell 2006; 124: 35-46
    CrossrefPubMedGoogle Scholar
  • 45 Guillet-Deniau I, Pichard AL, Kone A. et al. Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-binding-protein-1c-dependent pathway. Journal of cell science 2004; 117 Pt 10 1937-1944
    CrossrefPubMedGoogle Scholar
  • 46 Li J, Ding L, Song B. et al. Emodin improves lipid and glucose metabolism in high fat diet-induced obese mice through regulating SREBP pathway. European journal of pharmacology 2016; 770: 99-109
    CrossrefPubMedGoogle Scholar
  • 47 Taskinen MR. Diabetic dyslipidaemia: From basic research to clinical practice. Diabetologia 2003; 46: 733-749
    CrossrefPubMedGoogle Scholar
  • 48 Melendez-Martinez AJ, Nascimento AF, Wang Y. et al. Effect of tomato extract supplementation against high-fat diet-induced hepatic lesions. Hepatobiliary surgery and nutrition 2013; 2: 198-208
    PubMedGoogle Scholar
  • 49 Kiu H, Nicholson SE. Biology and significance of the JAK/STAT signalling pathways. Growth factors (Chur, Switzerland) 2012; 30: 88-106
    CrossrefPubMedGoogle Scholar
  • 50 Heinrich PC, Behrmann I, Muller-Newen G. et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. The Biochemical journal 1998; 334 Pt 2 297-314
    CrossrefPubMedGoogle Scholar
  • 51 Shen L, Qi Z, Zhu Y. et al. Phosphorylated heat shock protein 27 promotes lipid clearance in hepatic cells through interacting with STAT3 and activating autophagy. Cellular signalling 2016; 28: 1086-1098
    CrossrefPubMedGoogle Scholar
  • 52 Cai X, Fang C, Hayashi S. et al. Pu-erh tea extract ameliorates high-fat diet-induced nonalcoholic steatohepatitis and insulin resistance by modulating hepatic IL-6/STAT3 signaling in mice. Journal of gastroenterology 2016; 51: 819-829
    CrossrefPubMedGoogle Scholar
  • 53 Hu KQ, Liu C, Ernst H. et al. The biochemical characterization of ferret carotene-9',10'-monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. The Journal of biological chemistry 2006; 281: 19327-19338
    CrossrefPubMedGoogle Scholar
  • 54 Kiefer C, Hessel S, Lampert JM. et al. Identification and characterization of a mammalian enzyme catalyzing the asymmetric oxidative cleavage of provitamin A. The Journal of biological chemistry 2001; 276: 14110-14116
    CrossrefPubMedGoogle Scholar