Soy Protein Influences the Development of the Metabolic Syndrome in Male Obese ZDFxSHHF Rats

Abstract

Previous investigations have demonstrated a marked effect of soy protein on the metabolic syndrome (MS). The purpose of this preliminary study was to identify the effects of soy-based diets on male obese ZDFxSHHF (fa/fa-cp/?) rats. Animals were randomly assigned to one of four diets: control, casein (C); low-isoflavone (LIS) soy protein; high-isoflavone (HIS) soy protein; or casein + rosiglitazone (CR). Physiological, biochemical, and molecular parameters were determined at sacrifice. Body weight (p < 0.01) and food intake (p < 0.05) were lower in LIS-fed rodents. Rosiglitazone-treated animals had higher body weight and adiposity (p < 0.05). LIS and CR groups exhibited better glycemic control (p < 0.05), but with a limited effect in rosiglitazone-treated animals. HIS fed rats had higher glucose and triacylglyceride levels (p < 0.01), and lower plasma insulin (p < 0.01). Renal function parameters with the exception of an increase in systolic blood pressure (p < 0.05) were all suppressed in the LIS group (p < 0.01). The CR group had twofold PPARα and PPARγ mRNA abundance (p < 0.01). LIS-fed animals also exhibited greater abundance of PPARγ mRNA (p < 0.001), and nearly threefold FAS and CPT-1 mRNA levels (p < 0.05). HIS-fed rats also had higher abundance of CPT-1 mRNA, as well as a lower abundance of ACC mRNA (p < 0.05). Soy-based diets, influenced by isoflavone content and distinct from rosiglitazone, improved several metabolic parameters in obese ZDFxSHHF rats.

Soy protein - Isoflavone content - Metabolic syndrome - Gene expression - ZDFxSHHF

References

• 1 Cefalu W T. Insulin resistance: cellular and clinical concepts.  Experimental Biology and Metabolism. 2001;  226 13-26
• 2 Reaven G M. Pathophysiology of insulin resistance in human disease.  Physiological Reviews. 1995;  75 473-485
• 3 Kaplan N M. The deadly quartet.  Arch Intern Med. 1989;  149 1514-1520
• 4 Reaven G M. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1595-1607
• 5 Berger J, Moller D E. The mechanisms of action of PPARs.  Annu Rev Med. 2002;  53 409-435
• 6 Ricote M, Huang J T, Welch J S, Glass C K. The peroxisome proliferators-activated receptor-γ (PPARγ) as a regulator of monocyte/macrophage function.  J Leukoc Biol. 1999;  66 733-739
• 7 Keller J M, Collet P, Bianchi A, Huin C, Bouillaud-Kremarik P, Becuwe P, Schohn H, Domenjoud L, Dauca M. Implications of peroxisome proliferators-activatedreceptors (PPARS) in development, cell life status, and disease.  Int J Dev Biol. 2000;  44 429-442
• 8 Willson T M, Lambert M H, Kilewer S A. Peroxisome proliferator-activated receptor-γ and metabolic disease.  Annu Rev Biochem. 2001;  70 341-367
• 9 Emilsson V, O'Dowd J, Wang S, Liu Y L, Sennitt M, Heyman R, Cawthorne M A. The effects of rexinoids and rosiglitazone on body weight and uncoupling protein isoform expression in the Zucker fa/fa rat.  Metabolism. 2000;  49 1610-1615
• 10 Rieusset J, Auwerx J, Vidal H. Regulation of gene expression by activation of the peroxisome proliferator-activated receptor γ with rosiglitazone (BRL 49 653) in human adipocytes.  Biochemical and Biophysical Research Communications. 1999;  265 265-271
• 11 Smith S A, Lister C A, Toseland C DN, Buckingham R E. Rosiglitazone prevents the onset of hyperglycemia and proteinuria in the Zucker Diabetic Fatty rat.  Diabetes, Obesity and Metabolism. 2000;  2 363-372
• 12 Ishizuka T, Itaya S, Wada H, Ishizawa M, Kimura M, Kajita K, Kanoh Y, Miura A, Muto N, Yasuda K. Differential effect of the antidiabetic thiazolidinediones troglitazone and pioglitazone on human platelet aggregation mechanism.  Diabetes. 1998;  47 1494-1500
• 13 Brown K K, Henke B R, Blanchard S G, Cobb J E, Mook R, Kaldor I, Kliewer S A, Lehmann J M, Lenhard J M, Harrington W W, Novak P J, Faison W, Binz J G, Hashim M A, Oliver W O, Brown H R, Parks D J, Plunket K D, Tong W Q, Menius J A, Adkison K, Noble S A, Willson T M. A novel n-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker Diabetic Fatty rat.  Diabetes. 1999;  48 1415-1424
• 14 Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats.  J Clin Invest. 1998;  101 1354-1351
• 15 Kausch C, Krutzfeldt J, Witke A, Rettig A, Bachmann O, Rett K, Matthaei S, Machicao F, Haring H U, Stumvoll M. Effects of troglitazone on cellular differentiation, insulin signaling, and glucose metabolism in cultured human skeletal muscle cells.  Biochemical and Biophysical Research Communications. 2001;  280 664-674
• 16 Yonemitsu S, Nishimura H, Shintani M, Inoue R, Yamamoto Y, Masuzaki H, Ogawa Y, Hosoda K, Inoue G, Hayashi T, Nakao K. Troglitazone induces GLUT4 translocation in L6 myotubes.  Diabetes. 2001;  50 1093-1101
• 17 Vidal-Puig A, Jimenez-Linan M, Lowell B B, Hamann A, Hu E, Spiegelman B, Flier J S, Moller D E. Regulation of PPARγ gene expression by nutrition and obesity in rodents.  J Clin Invest. 1996;  97 2553-2561
• 18 Yakubu-Madus F E, Stephens T W, Johnson W T. Lipid lowering explains the insulin sensitivity enhancing effects of a thizolidinedione, 5-(4-(2-(2-phenyl-4-oxazolyl)ethoxy)benzyl)-2,4 thiazolidinedione.  Diabetes, Obesity and Metabolism. 2000;  2 155-163
• 19 Smith U, Cogg S. Johansson A, Olausson T, Rotter V, Svalstedt B. Thiazolidinediones (PPARγ agonists) but not PPARα agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes.  FASEB. 2001;  15 215-220
• 20 Zierath J R, Ryder J W, Doebber T, Woods J, Wu M, Ventre J, Li Z, McCrary C, Berger J, Zhang B, Moller D E. Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARγ agonist) action.  Endocrinology. 1998;  139 5034-5041
• 21 Scheen A J. Thiazolidinediones and liver toxicity.  Diabetes Metab. 2001;  27 305-313
• 22 Cheng A Y, Fantus I G. Thiazolidinedione-Induced Congestive Heart Failure.  Ann Pharmacother. 2004;  38 817-820
• 23 Setchell K DR. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones.  Am J Clin Nutr.. 1998;  68 (Suppl) 1333S-1346S
• 24 Erdman J W, Fordyce E J. Soy products and the human diet.  Am J Clin Nutr. 1989;  49 724-37
• 25 Potter S M, Baum J A, Teng H, Stillman R J, Shay N F, Erdman J W Jr. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal woman.  Am J Clin Nutr. 1998;  68 1375S-1379S
• 26 Anderson J W, Johnstone B M. Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids.  N Eng J Med. 1995;  333 276-282
• 27 Baum J A, Teng H, Erdman J W Jr, Weigel R M, Klein B P, Persky V W, Freels S, Surya P, Bakhit R M, Ramos E, Shay N F, Potter S M. Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women.  Am J Clin Nutr. 1998;  68 545-551
• 28 Vahouny G V, Adamson I, Chalcarz W, Satchithanandam S, Muesing R, Klurfeld D M, Tepper S A, Sanghvi A, Kritchevsky D. Effects of casein and soy protein on hepatic and serum lipids and lipoprotein lipid distribution in the rat.  Atherosclerosis. 1985;  56 127-137
• 29 Anthony M S, Clarkson T B, Williams K J. Effects of soy isoflavones on atherosclerosis: potential mechanisms.  Am J Clin Nutr.. 1998;  68 1390S-1393S
• 30 Anthony M S, Clarkson T B, Bullock B C, Wagner J D. Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus mokeys.  Atherosclerosis, Thrombosis, and Vascular Biology. 1997;  17 2524-2531
• 31 Maddox D A, Alavi F K, Silbernick E M, Zawada E T. Protective effects of a soy diet in preventing obesity-linked renal disease.  Kidney International. 2002;  61 96-104
• 32 Peluso M R, Winters T A, Shanahan M F, Banz W J. A cooperative interaction between soy protein and its isoflavone-enriched fraction lowers hepatic lipids in male obese Zucker rats and reduces blood platelet sensitivity in male Sprague-Dawley rats.  J Nutr. 2000;  130 2333-2342
• 33 Lavigne C, Marette A, Jacques H. Cod and soy proteins compared with casein improve glucose tolerance and insulin sensitivity in rats.  Endocrinology and Metabolism. 2000;  278 E491-E500
• 34 Iritani N, Sugimoto T, Fukuda H, Komiya M, Ikeda H. Dietary soybean protein increases insulin receptor gene expression in Wistar Fatty rats when dietary polyunsaturated fatty acid level is low.  J Nutr. 1997;  127 1077-1083
• 35 Tovar-Palacio C, Potter S M, Hafermann J C, Shay N F. Intake of soy protein and soy protein extracts influencelipid metabolism and hepatic gene expression in gerbils.  J Nutr. 1998;  128 839-842
• 36 Dixon R A, Ferreira D. Genistein.  Phytochemistry.. 2002;  60 205-211
• 37 Crouse J R 3rd, Morgan T, Terry J G, Ellis J, Vitolins M, Burke G L. A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins.  Arch Intern Med. 1999;  159 2070-2076
• 38 Sanders T A, Dean T S, Grainger D, Miller G J, Wiseman H. Moderate intakes of intact soy protein rich in isoflavones compared with ethanol-extracted soy protein increase HDL but do not influence transforming growth factor β 1 concentrations and hemostatic risk factors for coronary heart disease in healthy subjects.  Am J Clin Nutr. 2002;  76 373-377
• 39 Fukui K, Tachibana N, Wanezaki S, Tsuzaki S, Takamatsu K, Yamamoto T, Hashimoto Y, Shimoda T. Isoflavone-free soy protein prepared by column chromatography reduces plasma cholesterol in rats.  J Agric Food Chem. 2002;  50 5717-5721
• 40 Jenkins D J, Kendall C W, Jackson C J, Connelly P W, Parker T, Faulkner D, Vidgen E, Cunnane S C, Leiter L A, Josse R G. Effects of high- and low-isoflavone soyfoods on blood lipids, oxidized LDL, homocysteine, and blood pressure in hyperlipidemic men and women.  Am J Clin Nutr. 2002;  76 365-372
• 41 Dang Z C, Audinot V, Papapoulos S E, Boutin J A, Lowik C W. PPARγ as a molecular target for the soy phytoestrogen genistein.  J Biol Chem. 2003;  278 962-967
• 42 Harmon A W, Harp J B. Differential effects of flavonoids on 3T3-L1 adipogenesis and lipolysis.  Am J Physio. 2001;  280 C807-C813
• 43 Mezei O, Banz W J, Steger R W, Peluso M R, Winters T A, Shay N. Soy isoflavones exert antidiabetic and hypolipidemic effects through the PPAR pathways in obese Zucker rats and murine RAW 264. 7 cells.  J Nutr. 2003;  133 1238-1243
• 44 Tofovic S P, Kusaka H, Kost C K Jr, Bastacky S. Renal function and structure in diabetic, hypertensive, obese ZDFxSHHF-hybrid rats.  Ren Fail. 2000;  22 387-406
• 45 Reeves P G, Nielsen F H, Fahey G C Jr. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet.  J Nutr. 1993;  123 1939-1951
• 46 Folch J, Lees M, Sloane-Stanley G H. A simple method for the isolation and purification of total lipids from animal tissues.  J Biol Chem. 1957;  226 497-509
• 47 Fletcher M J. A colorimetric method for estimating serum triglycerides.  Clin Chem. 1968;  22 393-397
• 48 Harris R B, Martin R J. Specific depletion of body fat in parabiotic partners of tube-fed obese rats.  Am J Physiol. 1984;  247 R380-R386
• 49 Livak K J, Schmittgen T D. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2-ΔΔCT Method.  Methods. 2001;  25 402-408
• 50 Tomanek R J, Palmer P J, Peiffer G L, Schreiber K L, Eastham C L, Marcus M L. Morphometry of canine coronary arteries, arterioles, and capillaries during hypertension and left ventricular hypertrophy. Circ.  Res. 1986;  58 38-46
• 51 Cimini C M, Weiss H R. Microvascular morphometry and perfusion in renal hypertension-induced cardiac hypertrophy. Am.  J Physiol. 1988;  255 H1384-H1390
• 52 Nevala R, Vaskonen T, Vehniainen J, Korpela R, Vapaatalo H. Soy based diet attenuates the development of hypertension when compared to casein based diet in spontaneously hypertensive rat.  Life Sci. 2000;  66 115-124
• 53 Iqbal M J, Yaegashi S, Ahsan R, Lightfoot D A, Banz W J. Differentially abundant mRNAs in rat liver in response to diets containing soy protein isolate.  Physiol Genomics. 2002;  11 219-226
• 54 Davis J, Higginbotham A, Iqbal J, Peterson R, Shay N, Banz W. Soy protein diets attenuate abnormalities observed in male ZDF rats. 2003 Experimental Biology meeting abstracts [accessed at http://select. biosis. org/faseb].  The FASEB Journal. 18;  Abstract #197. 2
• 55 Nagasawa A, Fukui K, Funahashi T, Maeda N, Shimomura I, Kihara S, Waki M, Takamatsu K, Matsuzawa Y. Effects of soy protein diet on the expression of adipose genes and plasma adiponectin.  Horm Metab Res. 2002;  34 635-639
• 56 Bartke A, Peluso M R, Moretz N, Wright C, Bonkowski M, Winters T A, Shanahan M F, Kopchick J J, Banz W J. Effects of Soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice.  Horm Metab Res. 2004;  36 550-558
• 57 Banz W J, Davis J, Peterson R, Iqbal M J. Gene expression and adiposity are modified by soy protein in male Zucker diabetic fatty rats.  Obes Res. 2004;  12 1907-1913
• 58 Chakrabarti R, Misra P, Vikramadithyan R K, Premkumar M, Hiriyan J, Datla S R, Damarla R K, Suresh J, Rajagopalan R. Antidiabetic and hypolipidemic potential of DRF 2519-a dual activator of PPAR-alpha and PPAR-gamma.  Eur J Pharmacol. 2004;  3 195-206
• 59 Brand C L, Sturis J, Gotfredsen C F, Fleckner J, Fledelius C, Hansen B F, Andersen B, Ye J M, Sauerberg P, Wassermann K. Dual PPAR alpha/ gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats.  Am J Physiol Endocrinol Metab. 2003;  284 E841-E854