Cinchonine (C19H22N2O) is a natural compound of Cinchona bark. Although cinchonine's antiplatelet effect has been reported in the previous study, antiobesity effect of cinchonine has never been studied. The main objective of this study was to investigate whether cinchonine reduces high-fat-diet- (HFD-) induced adipogenesis and inflammation in the epididymal fat tissues of mice and to explore the underlying mechanisms involved in these reductions. HFD-fed mice treated with 0.05% dietary cinchonine for 10 weeks had reduced body weight gain (？38%), visceral fat-pad weights (？26%), and plasma levels of triglyceride, free fatty acids, total cholesterol, and glucose compared with mice fed with the HFD. Moreover, cinchonine significantly reversed HFD-induced downregulations of WNT10b and galanin-mediated signaling molecules and key adipogenic genes in the epididymal adipose tissues of mice. Cinchonine also attenuated the HFD-induced upregulation of proinflammatory cytokines by inhibiting toll-like-receptor-2- (TLR2-) and TLR4-mediated signaling cascades in the adipose tissue of mice. Our findings suggest that dietary cinchonine with its effects on adipogenesis and inflammation may have a potential benefit in preventing obesity. 1. Introduction Obesity is defined as a phenotypic manifestation of abnormal or excessive fat accumulation that alters health and increases mortality [1]. In obesity phenotypes, the adipose tissue is influenced by diet and genes, as well as by their interactions [2, 3]. Adipocytes are the main cellular component of adipose tissues [4, 5] which is the largest endocrine organ in the body which secretes numerous cytokines and adipokines into the circulation altering body physiology in significant ways [6]. In obese people’s adipocytes, both hyperplasia and hypertrophy [7] are observed. The WNT family of autocrine and paracrine growth factors regulates adult tissue maintenance and remodeling and, consequently, is well suited to mediate adipose cell communication [8]. The studies on animals have reported that WNT10b and galanin play important roles in regulating adipogenesis [8]. WNT signaling repressed adipogenesis by blocking induction of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) [8]. In high-fat-diet- (HFD-) induced obesity, the expression of WNT10b is decreased, which further reduces the level of β-catenin transported to nucleus. β-Catenin serves as a cofactor of forkhead transcription factor 1 (FOXO 1) and binds directly to FOXO 1 and enhances FOXO 1 transcriptional activity.
References
[1]
M. Gonzalez-Castejon and A. Rodriguez-Casado, “Dietary phytochemicals and their potential effects on obesity: a review,” Pharmacological Research, vol. 64, no. 5, pp. 438–455, 2011.
[2]
J. M. Ordovas and J. Shen, “Gene-environment interactions and susceptibility to metabolic syndrome and other chronic diseases,” Journal of Periodontology, vol. 79, no. 8, pp. 1508–1513, 2008.
[3]
A. Marti, M. A. Martinez-Gonzalez, and J. A. Martinez, “Interaction between genes and lifestyle factors on obesity,” Proceedings of the Nutrition Society, vol. 67, no. 1, pp. 1–8, 2008.
[4]
S. P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R. L. Leibel, and A. W. Ferrante, “Obesity is associated with macrophage accumulation in adipose tissue,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1796–1808, 2003.
[5]
H. Xu, G. T. Barnes, Q. Yang, et al., “Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 2094–2101, 2011.
[6]
N. Ouchi, J. L. Parker, J. J. Lugus, and K. Walsh, “Adipokines in inflammation and metabolic disease,” Nature Reviews Immunology, vol. 11, no. 2, pp. 85–97, 2011.
[7]
J. Jo, O. Gavrilova, S. Pack et al., “Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth,” PLoS Computational Biology, vol. 5, no. 3, Article ID e1000324, 2009.
[8]
C. Christodoulides, C. Lagathu, J. K. Sethi, and A. Vidal-Puig, “Adipogenesis and WNT signalling,” Trends in Endocrinology and Metabolism, vol. 20, no. 1, pp. 16–24, 2009.
[9]
S. C. Manolagas and M. Almeida, “Gone with the Wnts: β-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism,” Molecular Endocrinology, vol. 21, no. 11, pp. 2605–2614, 2007.
[10]
M. A. G. Essers, L. M. M. de Vries-Smits, N. Barker, P. E. Polderman, B. M. T. Burgering, and H. C. Korswagen, “Functional interaction between β-catenin and FOXO in oxidative stress signaling,” Science, vol. 308, no. 5725, pp. 1181–1184, 2005.
[11]
D. Hoogeboom, M. A. G. Essers, P. E. Polderman, E. Voets, L. M. M. Smits, and B. M. T. Burgering, “Interaction of FOXO with β-catenin inhibits β-catenin/T cell factor activity,” The Journal of Biological Chemistry, vol. 283, no. 14, pp. E9224–E9230, 2008.
[12]
K. Munekata and K. Sakamoto, “Forkhead transcription factor Foxo1 is essential for adipocyte differentiation,” In Vitro Cellular and Developmental Biology—Animal, vol. 45, no. 10, pp. 642–651, 2009.
[13]
A. Kim and T. Park, “Diet-induced obesity regulates the galanin-mediated signaling cascade in the adipose tissue of mice,” Molecular Nutrition and Food Research, vol. 54, no. 9, pp. 1361–1370, 2010.
[14]
T. Kawai and S. Akira, “The role of pattern-recognition receptors in innate immunity: update on toll-like receptors,” Nature Immunology, vol. 11, no. 5, pp. 373–384, 2010.
[15]
M. Fresno, R. Alvarez, and N. Cuesta, “Toll-like receptors, inflammation, metabolism and obesity,” Archives of Physiology and Biochemistry, vol. 117, no. 3, pp. 151–164, 2011.
[16]
S. Schenk, M. Saberi, and J. M. Olefsky, “Insulin sensitivity: modulation by nutrients and inflammation,” Journal of Clinical Investigation, vol. 118, no. 9, pp. 2992–3002, 2008.
[17]
G. S. Hotamisligil, “Inflammation and metabolic disorders,” Nature, vol. 444, no. 7121, pp. 860–867, 2006.
[18]
A. H. Berg and P. E. Scherer, “Adipose tissue, inflammation, and cardiovascular disease,” Circulation Research, vol. 96, no. 9, pp. 939–949, 2005.
[19]
V. Z. Rocha and P. Libby, “Obesity, inflammation, and atherosclerosis,” Nature reviews. Cardiology, vol. 6, no. 6, pp. 399–409, 2009.
[20]
Y. Matsuzawa, T. Funahashi, and T. Nakamura, “Molecular mechanism of Metabolic Syndrome X: contribution of adipocytokines-adipocyte-derived bioactive substances,” Annals of the New York Academy of Sciences, vol. 892, pp. 146–154, 1999.
[21]
S. Cho, Y. Choi, S. Park, and T. Park, “Carvacrol prevents diet-induced obesity by modulating gene expressions involved in adipogenesis and inflammation in mice fed with high-fat diet,” Journal of Nutritional Biochemistry, vol. 23, no. 2, pp. 192–201, 2011.
[22]
J. W. Tracy and L. T. Webster, “Drugs used in the chemotherapy of protozoal infections,” The Pharmacological Basis of Therapeutics, vol. 9, pp. 80–808, 1996.
[23]
P. Genne, O. Duchamp, E. Solary et al., “Comparative effects of quinine and cinchonine in reversing multidrug resistance on human leukemic cell line K562/ADM,” Leukemia, vol. 8, no. 1, pp. 160–164, 1994.
[24]
P. Genne, O. Duchamp, E. Solary, J. Magnette, J. P. Belon, and B. Chauffert, “Cinchonine per os: efficient circumvention of P-glycoprotein-mediated multidrug resistance,” Anti-Cancer Drug Design, vol. 10, no. 2, pp. 103–118, 1995.
[25]
B. H. Shah, B. Safdar, S. S. Virani, Z. Nawaz, S. A. Saeed, and A. H. Gilani, “The antiplatelet aggregatory activity of Acacia nilotica is due to blockade of calcium influx through membrane calcium channels,” General Pharmacology, vol. 29, no. 2, pp. 251–255, 1997.
[26]
A. H. Gilani and F. Shaheen, “Studies on dual antihypertensive activity of cinchonine: an alkaloid from cinchona bark,” in Proceedings of the International Symposium on Bioassay Methods in Natural Product Research and Drug Development, p. 62, 1997.
[27]
A. Kablan, R. A. Saunders, M. Szkudlarek-Mikho, et al., “Prieurianin causes weight loss in diet-induced obese mice and inhibits adipogenesis in cultured preadipocytes,” Journal of Diabetes & Metabolism, vol. 1, no. 1, pp. 101–105, 2010.
[28]
P. Genne, M. T. Dimanche-Boitrel, R. Y. Mauvernay et al., “Cinchonine, a potent efflux inhibitor to circumvent anthracycline resistance in vivo,” Cancer Research, vol. 52, no. 10, pp. 2797–2801, 1992.
[29]
M. Nassiri-Asl, F. Zamansoltani, and B. Torabinejad, “Antiepileptic effects of quinine in the pentylenetetrazole model of seizure,” Seizure, vol. 18, no. 2, pp. E129–E132, 2009.
[30]
S. Sae-Tan, K. A. Grove, M. J. Kennett, and J. D. Lambert, “(？)-Epigallocatechin-3-gallate increases the expression of genes related to fat oxidation in the skeletal muscle of high fat-fed mice,” Food and Function, vol. 2, no. 2, pp. 111–116, 2011.
[31]
A. Ejaz, D. Wu, P. Kwan, and M. Meydani, “Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice,” Journal of Nutrition, vol. 139, no. 5, pp. 919–925, 2009.
[32]
B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999.
[33]
J. J. Hawes, R. Narasimhaiah, and M. R. Picciotto, “Galanin and galanin-like peptide modulate neurite outgrowth via protein kinase C-mediated activation of extracellular signal-related kinase,” European Journal of Neuroscience, vol. 23, no. 11, pp. 2937–2946, 2006.
[34]
T. J. Little, M. Horowitz, and C. Feinle-Bisset, “Modulation by high-fat diets of gastrointestinal function and hormones associated with the regulation of energy intake: implications for the pathophysiology of obesity,” American Journal of Clinical Nutrition, vol. 86, no. 3, pp. 531–541, 2007.
[35]
S. Obici and L. Rossetti, “Minireview: nutrient sensing and the regulation of insulin action and energy balance,” Endocrinology, vol. 144, no. 12, pp. 5172–5178, 2003.
[36]
M. B. Fessler, L. L. Rudel, and J. M. Brown, “Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome,” Current Opinion in Lipidology, vol. 20, no. 5, pp. 379–385, 2009.
[37]
H. Shi, M. V. Kokoeva, K. Inouye, I. Tzameli, H. Yin, and J. S. Flier, “TLR4 links innate immunity and fatty acid-induced insulin resistance,” Journal of Clinical Investigation, vol. 116, no. 11, pp. 3015–3025, 2006.
[38]
M. J. Song, K. H. Kim, J. M. Yoon, and J. B. Kim, “Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes,” Biochemical and Biophysical Research Communications, vol. 346, no. 3, pp. 739–745, 2006.
[39]
T. Suganami, K. Tanimoto-Koyama, J. Nishida et al., “Role of the Toll-like receptor 4/NF-κB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 1, pp. 84–91, 2007.
