Cinnamon Extract Regulates Plasma Levels of Adipose-derived Factors and Expression of Multiple Genes Related to Carbohydrate Metabolism and Lipogenesis in Adipose Tissue of Fructose-fed Rats

Abstract

We reported earlier that dietary cinnamon extract (CE) improves systemic insulin sensitivity and dyslipidemia by enhancing insulin signaling. In the present study, we have examined the effects of CE on several biomarkers including plasma levels of adipose-derived adipokines, and the potential molecular mechanisms of CE in epididymal adipose tissue (EAT). In Wistar rats fed a high-fructose diet (HFD) to induce insulin resistance, supplementation with a CE (Cinnulin PF^®, 50 mg/kg daily) for 8 weeks reduced blood glucose, plasma insulin, triglycerides, total cholesterol, chylomicron-apoB48, VLDL-apoB100, and soluble CD36. CE also inhibited plasma retinol binding protein 4 (RBP4) and fatty acid binding protein 4 (FABP4) levels. CE-induced increases in plasma adiponectin were not significant. CE did not affect food intake, bodyweight, and EAT weight. In EAT, there were increases in the insulin receptor (Ir) and Ir substrate 2 (Irs2) mRNA, but CE-induced increases in mRNA expression of Irs1, phosphoinositide-3-kinase, Akt1, glucose transporters 1 and 4, and glycogen synthase 1 expression and decreased trends in mRNA expression of glycogen synthase kinase 3β were not statistically significant. CE also enhanced the mRNA levels of adipoQ, and inhibited sterol regulatory element binding protein-1c mRNA levels. mRNA and protein levels of fatty acid synthase and FABP4 were inhibited by CE and RBP4, and CD36 protein levels were also decreased by CE. These results suggest that CE effectively ameliorates circulating levels of adipokines partially mediated via regulation of the expression of multiple genes involved in insulin sensitivity and lipogenesis in the EAT.

Key words

cinnamon extract - adiponectin - FABP4 - RBP4 - adipose tissue

References

• 1 Alberti KG, Zimmet P, Shaw J. Metabolic syndrome – a new world-wide definition. A Consensus Statement from the International Diabetes Federation.  Diabet Med. 2006;  23 469-480
• 2 Ahima RS, Flier JS. Adipose tissue as an endocrine organ.  Trends Endocrinol Metab. 2000;  11 327-332
• 3 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.  Nat Med. 2001;  7 941-946
• 4 Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.  J Clin Endocrinol Metab. 2001;  86 1930-1935
• 5 Iacobellis G, di Gioia CR, Cotesta D, Petramala L, Travaglini C, De SV, Vitale D, Tritapepe L, Letizia C. Epicardial adipose tissue adiponectin expression is related to intracoronary adiponectin levels.  Horm Metab Res. 2009;  41 227-231
• 6 Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM. Adipocyte P2 gene: developmental expression and homology of 5-flanking sequences among fat cell-specific genes.  Proc Natl Acad Sci USA. 1986;  83 3786-3790
• 7 Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, Linton MF, Hotamisligil GS. Combined adipocyte-macrophage fatty acid-binding protein deficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice.  Circulation. 2004;  110 1492-1498
• 8 Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis.  Nat Med. 2001;  7 699-705
• 9 Yeung DC, Xu A, Cheung CW, Wat NM, Yau MH, Fong CH, Chau MT, Lam KS. Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis.  Arterioscler Thromb Vasc Biol. 2007;  27 1796-1802
• 10 Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J, Wat NM, Wong WK, Lam KS. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome.  Clin Chem. 2006;  52 405-413
• 11 Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.  Nature. 2005;  436 356-362
• 12 Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.  N Engl J Med. 2006;  354 2552-2563
• 13 Polonsky KS. Retinol-binding protein 4, insulin resistance, and type 2 diabetes.  N Engl J Med. 2006;  354 2596-2598
• 14 Sirtori CR, Galli C, Anderson JW, Arnoldi A. Nutritional and nutraceutical approaches to dyslipidemia and atherosclerosis prevention: Focus on dietary proteins.  Atherosclerosis. 2009;  203 8-17
• 15 Anderson RA, Broadhurst CL, Polansky MM, Schmidt WF, Khan A, Flanagan VP, Schoene NW, Graves DJ. Isolation and characterization of polyphenol type-A polymers from cinnamon with insulin-like biological activity.  J Agric Food Chem. 2004;  52 65-70
• 16 Broadhurst CL, Polansky MM, Anderson RA. Insulin-like biological activity of culinary and medicinal plant aqueous extracts in vitro.  J Agric Food Chem. 2000;  48 849-852
• 17 Imparl-Radosevich J, Deas S, Polansky MM, Baedke DA, Ingebritsen TS, Anderson RA, Graves DJ. Regulation of PTP-1 and insulin receptor kinase by fractions from cinnamon: implications for cinnamon regulation of insulin signalling.  Horm Res. 1998;  50 177-182
• 18 Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Cinnamon extract (traditional herb) potentiates in vivo insulin-regulated glucose utilization via enhancing insulin signaling in rats.  Diabetes Res Clin Pract. 2003;  62 139-148
• 19 Ziegenfuss TN, Hofheins JE, Mendel RW, Landis J, Anderson RA. Effects of a water-soluble cinnamon extract on body composition and features of the metabolic syndrome in pre-diabetic men and women.  J Int Soc Sports Nutr. 2006;  3 45-53
• 20 Roussel AM, Hininger I, Benaraba R, Ziegenfuss TN, Anderson RA. Antioxidant effects of a cinnamon extract in people with impaired fasting glucose that are overweight or obese.  J Am Coll Nutr. 2009;  28 16-21
• 21 Wang JG, Anderson RA, Graham GM, III, Chu MC, Sauer MV, Guarnaccia MM, Lobo RA. The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome: a pilot study.  Fertil Steril. 2007;  88 240-243
• 22 Qin B, Polansky MM, Sato Y, Adeli K, Anderson RA. Cinnamon extract inhibits the postprandial overproduction of apolipoprotein B48-containing lipoproteins in fructose-fed animals.  J Nutr Biochem. 2009;  20 901-908
• 23 Qin B, Dawson H, Polansky MM, Anderson RA. Cinnamon extract attenuates TNF-alpha-induced intestinal lipoprotein ApoB48 overproduction by regulating inflammatory, insulin, and lipoprotein pathways in enterocytes.  Horm Metab Res. 2009;  41 516-522
• 24 Federico LM, Naples M, Taylor D, Adeli K. Intestinal insulin resistance and aberrant production of apolipoprotein B48 lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia: evidence for activation of protein tyrosine phosphatase-1B, extracellular signal-related kinase, and sterol regulatory element-binding protein-1c in the fructose-fed hamster intestine.  Diabetes. 2006;  55 1316-1326
• 25 Qin B, Qiu W, Avramoglu RK, Adeli K. Tumor necrosis factor-alpha induces intestinal insulin resistance and stimulates the overproduction of intestinal apolipoprotein B48-containing lipoproteins.  Diabetes. 2007;  56 450-461
• 26 Qin B, Anderson RA, Adeli K. Tumor necrosis factor-alpha directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling.  Am J Physiol Gastrointest Liver Physiol. 2008;  294 G1120-G1129
• 27 Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Cinnamon extract prevents the insulin resistance induced by a high-fructose diet.  Horm Metab Res. 2004;  36 119-125
• 28 Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, Lewis GF, Adeli K. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model.  J Biol Chem. 2000;  275 8416-8425
• 29 Taghibiglou C, Rashid-Kolvear F, Van Iderstine SC, Le Tien H, Fantus IG, Lewis GF, Adeli K. Hepatic very low density lipoprotein-ApoB overproduction is associated with attenuated hepatic insulin signaling and overexpression of protein-tyrosine phosphatase 1B in a fructose-fed hamster model of insulin resistance.  J Biol Chem. 2002;  277 793-803
• 30 Ukkola O, Santaniemi M. Adiponectin: a link between excess adiposity and associated comorbidities?.  J Mol Med. 2002;  80 696-702
• 31 Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity.  J Biol Chem. 1996;  271 10697-10703
• 32 Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, Nawrocki AR, Rajala MW, Parlow AF, Cheeseboro L, Ding YY, Russell RG, Lindemann D, Hartley A, Baker GR, Obici S, Deshaies Y, Ludgate M, Rossetti L, Scherer PE. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity.  Endocrinology. 2004;  145 367-383
• 33 Roffey B, Atwal A, Kubow S. Cinnamon water extracts increase glucose uptake but inhibit adiponectin secretion in 3T3-L1 adipose cells.  Mol Nutr Food Res. 2006;  50 739-745
• 34 Seale AP, de Jesus LA, Park MC, Kim YS. Vanadium and insulin increase adiponectin production in 3T3-L1 adipocytes.  Pharmacol Res. 2006;  54 30-38
• 35 Kamari Y, Peleg E, Herman MO, Bursztyn M, Grossman E, Sharabi Y. The effect of chronic hyperinsulinemia on plasma adiponectin levels in Sprague-Dawley rats.  Horm Metab Res. 2009;  41 46-49
• 36 Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2002;  290 1084-1089
• 37 Kim JB, Spiegelman BM. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism.  Genes Dev. 1996;  10 1096-1107
• 38 Yang Y, Zhou L, Gu Y, Zhang Y, Tang J, Li F, Shang W, Jiang B, Yue X, Chen M. Dietary chickpeas reverse visceral adiposity, dyslipidaemia and insulin resistance in rats induced by a chronic high-fat diet.  Br J Nutr. 2007;  98 720-726
• 39 Lee MS, Kim CT, Kim Y. Green Tea (–)-Epigallocatechin-3-Gallate Reduces Body Weight with Regulation of Multiple Genes Expression in Adipose Tissue of Diet-Induced Obese Mice.  Ann Nutr Metab. 2009;  54 151-157
• 40 Hiremagalur BK, Vadlamudi S, Johanning GL, Patel MS. Long-term effects of feeding high carbohydrate diet in pre-weaning period by gastrostomy: a new rat model for obesity.  Int J Obes Relat Metab Disord. 1993;  17 495-502
• 41 Guichard C, Dugail I, Le L, X, Lavau M. Genetic regulation of fatty acid synthetase expression in adipose tissue: overtranscription of the gene in genetically obese rats.  J Lipid Res. 1992;  33 679-687
• 42 Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, Cheung BM, Janus ED, Lam KS. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort.  Diabetes Care. 2007;  30 2667-2672
• 43 Xu A, Tso AW, Cheung BM, Wang Y, Wat NM, Fong CH, Yeung DC, Janus ED, Sham PC, Lam KS. Circulating adipocyte-fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study.  Circulation. 2007;  115 1537-1543
• 44 Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA, Parker RA, Hotamisligil GS. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2.  Nature. 2007;  447 959-965
• 45 Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, Linton MF, Hotamisligil GS. Combined adipocyte-macrophage fatty acid-binding protein deficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice.  Circulation. 2004;  110 1492-1498
• 46 Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis.  Nat Med. 2001;  7 699-705
• 47 Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, Uysal KT, Cao Q, Atsumi G, Malone H, Krishnan B, Minokoshi Y, Kahn BB, Parker RA, Hotamisligil GS. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes.  Cell Metab. 2005;  1 107-119
• 48 Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.  N Engl J Med. 2006;  354 2552-2563
• 49 Polonsky KS. Retinol-binding protein 4, insulin resistance, and type 2 diabetes.  N Engl J Med. 2006;  354 2596-2598
• 50 Handberg A, Levin K, Hojlund K, Beck-Nielsen H. Identification of the oxidized low-density lipoprotein scavenger receptor CD36 in plasma: a novel marker of insulin resistance.  Circulation. 2006;  114 1169-1176
• 51 Koonen DP, Febbraio M, Bonnet S, Nagendran J, Young ME, Michelakis ED, Dyck JR. CD36 expression contributes to age-induced cardiomyopathy in mice.  Circulation. 2007;  116 2139-2147
• 52 Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue - an update.  Horm Metab Res. 2007;  39 314-321

Correspondence