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A discussion of how diets made from purified ingredients influence the phenotypes of the MS in commonly used rodent models.

A quick look at a crowd of people shows that many of our fellow humans are carrying around too much excess weight. The prevalence of obesity is at epidemic levels in the developed world, and obesity may be the root cause of or precursor to other diseases such as insulin resistance, abnormal blood lipid levels (hypertriglyceridemia and reduced high density lipoprotein cholesterol), and hypertension (high blood pressure). The term ‘metabolic syndrome’ (MS) is used to describe the simultaneous occurrence of these diseases and people with the MS are at increased risk for type 2 diabetes, cardiovascular disease, cancer, and non-alcoholic fatty liver disease. It is estimated that individuals with the MS spend over $4,000 per year in treatment and to make matters worse, the prevalence of the MS is growing at an alarming rate, even in obese children.


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Like many diseases, the risk of developing the MS will depend upon the interaction of one’s genes and their environment. Since the genetic make-up, or genotype of the human population has not changed over the past several decades, we must look to the environment as the main cause of the increase in metabolic disease during this time frame. To be sure, decreased daily physical exercise (and fewer calories expended) plays an important causal role. Research has shown that increased exercise can ameliorate or even reverse the progression of diseases that make up the MS.

On the other side of the energy balance equation is the food that we eat. From an evolutionary point of view, it has been argued that obesity and other ‘diseases of excess’ are in fact the natural outcome of eating too many calories. During the evolutionary process, because the food supply was not stable and periods of starvation were common, it was advantageous to have genes that allowed for the efficient storage of excess calories as fat, given the uncertainty of when the next meal would come. In our present society, the problem is that we still have those ‘thrifty genes’ but also have a variety of foods that are high in saturated fat, simple sugars, and salt. Unfortunately for us, many of these foods are inexpensive and highly accessible (not to mention very tasty), and we find them easy to consume in excess, leading to disease and most likely early death. On the flip side of caloric intake coin is the very interesting finding that long-term restriction of calories prolongs the lifespan.1 This concept that nutrients can change our biology or phenotype, called nutriphenomics, is very important and brings together many disciplines — physiology, endocrinology, and molecular biology to name a few — in the pursuit of how the nutrients we eat can affect biological outcomes.

The costs of treating the MS are clearly growing, and it is no surprise that the research community is seeking animal models that mimic the human phenotype so that potential therapies can be tested. Because of the pivotal role that diet plays in causing the MS in humans, most metabolic disease animal models do (and we believe should) use diet as a way to precipitate this syndrome. Though this was not the case decades ago, today, most diet-driven animal disease models are generated using open source, purified ingredient diets. The open source nature of purified ingredient diets allows researchers around the world to compare data from different studies, since the diet formulas are generally freely available to the public (this is in contrast to chow diets, which are generally ‘closed,’ meaning the formulas are generally kept secret). In addition, purified ingredient diets have very little variability from batch to batch (compared to chows), and so help to minimize data variability. Since the ingredients used are so highly refined, purified diets lack the hundreds of plant-derived phyto-chemicals that are found in grain-based chow diets. Some of these compounds, in particular the phy-toestrogens, are known to affect disease progression2 and so are usually unwanted variables. Finally, purified ingredient diet formulas can be easily modified so that researchers can intentionally and specifically change one ingredient at a time, allowing them to study the effects of large or small changes in the nutritional quantity and quality of the diet. Because of these advantages (being able to report, repeat, and revise the diets), most metabolic disease animal research uses (and in fact requires) purified ingredient diets. For an expanded discussion of diets, see our previous article in this publication.3 In this brief review, we discuss how diets made from purified ingredients influence the phenotypes of the MS in commonly used rodent models.

 

High-Fat Diets for Diet-Induced Obesity Models
In order to gain a greater understanding of human obesity, rats and mice are commonly used models as they will readily gain weight when provided with a high-fat diet and also develop other risk factors associated with the MS.

Numerous high-fat rodent diets are available from commercial vendors. Not all high-fat diets are the same, since both the level and source of fat may differ between diets. While most obesity research is being conducted with purified ingredient diets, some studies use a mixture of chow plus added fat. This can lead to nutritional inadequacies, since as more and more fat is added to a chow, the other nutrients (protein, vitamins, minerals, and fiber) are diluted. The addition of too much fat can actually render the final diet protein deficient, which is clearly not the intention when feeding a high-fat diet.

When choosing a purified ingredient diet with elevated fat, the level of fat in the diet should be taken into consideration. While these terms do not have strict definitions, low-fat diets (LFD) have about 10% of the calories coming from fat, high-fat diets (HFD) have about 30-50% of the calories coming from fat, and very high-fat diets (VHFD) generally contain greater than 50 kcal% fat. For comparison, most low-fat chow diets contain 10-12% of the calories from fat. To induce obesity, both HFD and VHFD are used, and there is a dose-response for body weight as a function of dietary fat.4 When studying the influence of a drug, nutraceutical, or gene mutation on obesity, one must consider that it may be more difficult to reverse the drive to obesity on a VHFD, whereas something like compound efficacy may be more detectable when used in conjunction with a HFD.

The source of dietary fat is also important. As one researcher has said, “Oils ain’t oils,”5 meaning all fats are not equal in terms of the phenotype they produce. For example, when rodents were fed purified ingredient diets with similar amounts of fat, those fed diets with fish oil did not gain as much weight and were more insulin sensitive compared to those fed saturated fats (SF).6-8 However, not all studies support this and it may depend on dietary fat level and gender.6,9 Most rodents tend to become obese on HFD and VHFD, but there can be variable responses in glucose tolerance, insulin resistance (IR), triglycerides (TG), and other parameters depending on the strain and gender10-11 and source of dietary fat.6-8Outbred Sprague-Dawley and Wistar rats have a variable response to a HFD (32 or 45 kcal% fat) such that some animals rapidly gain excess weight while others gain only as much weight as they would on a LFD. At first, this research was done with chow-based diets12 but purified ingredient diets were developed13 which now researchers commonly use to separate the rats into diet-induced obese (DIO) and diet-resistant (DR) groups.14-16 Furthermore, the out-bred Sprague-Dawley DIO and DR rats have been selectively bred over time such that their future body weight response to a HFD is known in utero, allowing the researcher to look early in life (prior to the onset of obesity) for genetic traits that may later predispose them to their DIO or DR phenotypes.10,17 For researchers interested in an obesity and type 2 diabetes rat model, the inbred obese Zucker diabetic fatty (ZDF) rat is available. The males become obese and diabetic on a LFD, but HFD feeding promotes more robust disease. The female ZDF rat is unique in that while they are obese, they do not develop diabetes unless fed a diet (in this case, chow-based) containing 48 kcal% fat.18 The prolonged period of insulin sensitivity prior to the onset of diet-induced diabetes allows the researcher more time to study female ZDF rat in a pre-diabetic state.19

Different strains of mice show variability in weight gain on a purified ingredient VHFD (~60% by energy).20 Some inbred strains such as the C57BL/6 or AKR mouse are quite susceptible to obesity on a VHFD,11while mice of the A/J and SWR/J strains tend to be resistant to obesity.21,22 However, strains that may exhibit similar levels of obesity may have varied metabolic responses. For example, C57BL/6 mice will become obese on a VHFD and are more glucose intolerant while obese AKR mice become more insulin resistant.11

Diets High in SF and Cholesterol for Hypercholesterolemia and Atherosclerosis
Humans with the MS are more prone to developing atherosclerotic cardiovascular disease (ASCVD). It is believed that an increased intake of SF and cholesterol, which raise the levels of circulating total cholesterol (TC) and low density lipoproteins (LDL-C),23,24 increases the risk of ASCVD. As with humans, a purified ingredient HFD (with much as SF), and cholesterol (~0.2% by weight), commonly referred to as a ‘Western diet,’ can elevate TC and LDL-C and in turn cause atherosclerosis in certain rodent models.

Careful choice of the animal model is always crucial for any experiment and a good example of this is seen with the diet-induced development of atherosclerosis in rodents. Normal mice and rats have traditionally not been ideal models of cardiovascular disease research since they typically have very low levels of TC and LDL-C but high levels of high density lipoprotein cholesterol (HDL-C). This is in contrast to humans in whom the reverse is true. The ability of rats and mice to maintain their cholesterol profile (which is thought to be athero-protective) even in the face of high-cholesterol diets25 means that very little actual atherosclerosis develops. In order to ‘force’ the atherosclerosis phenotype on normal rats and mice, it is usually necessary to combine high concentrations of dietary cholesterol with 0.25%-0.5% cholic acid (a bile acid which promotes fat and cholesterol absorption from the intestine).26,27 Researchers should be aware that since cholic acid can also promote liver inflammation, decrease bile acid production, and alter circulating TG and HDL-C, 26,28,29 it may independently affect the development of atherosclerosis.

The ability to change the genetic make-up of mice and produce ‘transgenic’ or ‘knockout’ mice has allowed for the development of many interesting and useful disease models. Genetically modified mice such as those with mutations that slow the removal of LDL-C from the blood have led to more ‘human-like’ models which can show significant elevations in circulating LDL-C. These models in turn can develop mature atherosclerotic lesions when fed purified ingredient high cholesterol diets without the need for dietary cholic acid.29 Some of these knockout mouse models (such as the LDL receptor knockout and the Apolipoprotein E knockout) can be very responsive to elevations in dietary cholesterol (0.15% - 1.25%) and can have significant elevations in both plasma LDL-C and atherosclerotic lesions after being fed for 12 weeks.29-32 Evenin these susceptible knockout mice, the source of fat can be used to further modify the phenotype to the researcher’s advantage. For example, diets high in monounsaturated fats (i.e. olive oil) promoted more atherosclerosis than those high in SF (i.e. coconut oil) and polyunsaturated fats (PF) (i.e. corn oil, safflower oil) in LDL receptor knockout mice.33

Another model of atherosclerosis that has been used frequently is the Golden Syrian hamster. Like rats and mice, these animals normally have high levels of HDL-C, but in contrast, dietary cholesterol (~ 0.1%) can significantly elevate LDL-C and like humans, SF can increase these levels further.34,35The combination of high dietary SF and cholesterol is commonly used to promote atherosclerosis in these animals36-38 and atherosclerotic lesions similar to those found in humans can be found after prolonged feeding periods.39 Actually, cholesterol itself may not always be necessary for this phenotype, since a purified diet with no cholesterol but high concentrations of SF (as hydrogenated coconut oil) can promote more aortic cholesterol accumulation compared to a diet with both cocoa butter and 0.15% cholesterol.40 This was despite the fact that both groups had similar levels of LDL-C, suggesting that the type of fat may play an important role in atherosclerosis formation in the hamster.

Guinea pigs are often used for lipid research, since unlike rats, mice, and hamsters, they begin with a cholesterol profile similar to humans (higher in LDL and lower levels of HDL-C), and also possess other human-like traits of cholesterol metabolism.41 As with hamsters, diets high in SF will elevate TC and LDL-C levels relative to those fed high levels of PF; the addition of cholesterol can promote further elevations.42 Atherosclerotic lesions and aortic cholesterol accumulation can develop when high levels (~0.33%) of dietary cholesterol are fed.43,44

High Fructose/Sucrose Diets for Hypertriglyceridemia and Insulin Resistance in Rodents
Because it is so sweet and inexpensive, high fructose corn syrup (HFCS) is used in many processed foods which humans eat and recent surveys in humans have suggested that carbohydrate intake is on the rise. As we have learned over the past few decades, an increased intake of refined carbohydrates, such as HFCS and the disaccharide sucrose (which is composed of fructose + glucose), is associated with increased weight gain, elevated circulating TG levels, and insulin resistance (IR) in humans and animal models.45,46 In rodent models, purified diets containing high fructose or sucrose elevate TG and glucose production in the liver and this increased availability of nutrients ultimately leads to IR and hypertriglyceridemia.45,46 Typically, low-fat chow diets contain about 4% sucrose and < 0.5% free fructose. Low-fat purified diets can contain higher levels of sucrose and this will depend heavily on the formula being used. The Sprague-Dawley and Wistar rat are established models of sucrose-induced IR and hypertriglyceridemia.47-49 Both of these phenotypes can develop within two weeks when these animals are fed a diet containing 65% sucrose (by weight) relative to one with 65% corn starch.47It seems that the fructose component of sucrose is largely responsible for the hypertriglyc-eridemia and IR produced by high sucrose diets.50-52 Unless fed for a prolonged period of time, these high fructose/sucrose diets do not appear to lead to excessive weight gain.53

Similar to rats, hamsters fed high fructose diets (~60% of energy) may develop IR and elevations in TG after only two weeks compared to diets low in fructose.54,55 Interestingly, hamsters fed high-sucrose diets did not have elevated TG levels and developed only mild IR relative to those fed diets high in fructose.54 Since sucrose is one-half fructose, it appears that the level of dietary fructose is quite important in the rapid development of IR and elevated TG in hamsters.

In contrast to rats and hamsters, the mouse is used less frequently as a model for sucrose/fructose-induced IR and hypertriglyceridemia. The response to high fructose/sucrose diets is very strain-dependent in the mouse56 and commonly used strains like the C57BL/6 mouse either do not develop IR or develop IR slowly.56,57 However, the mouse genome is easier to manipulate than that of the rat and several knockout models (that are prone to develop hypertension) do show responses to high dietary fructose.30,58

Diets High In Sodium (and Fructose) For Hypertension
The causes of hypertension in humans are not fully understood but are correlated with sodium chloride (NaCl) intake, obesity, insulin resistance and of course, genetics. The rat is the historically preferred small animal model for diet-induced hypertension, perhaps because of its size, the amount of physiological data available, and robust blood pressure response that some strains present.

Both the level of dietary NaCl and the background diet are important in generating a hypertensive phenotype in the rat. Typical purified ingredient diets contain about 0.1% NaCl, while chow diets contain about 0.3-0.4% NaCl. Both types of diets have been modified to contain increased NaCl to study hypertension. The Dahl salt-sensitive rat shows a significant rise in blood pressure within 2-4 weeks after being fed a purified diet containing 8% NaCl.59-62 Lower levels of NaCl (4%) will still raise blood pressure63 and this is reported to occur at a slower rate.19 This rise in blood pressure can be attenuated by the addition of extra vitamin E to the diet.64 Similar to findings in humans, hypertension due to an 8% NaCl diet can be prevented by supplementing the diet with extra potassium,59 suggesting that diets low in potassium may aid in the promotion of hypertension. Thus, diet can be used to both induce and attenuate hypertension in the Dahl SS rat.

The diet to which the NaCl is added also affects the level of hypertension and concurrent kidney damage. When 4% NaCl was added to both a chow diet and a purified ingredient diet, Dahl SS rats fed the purified diet had higher blood pressure and more renal damage compared to chow-fed rats.65 Of equal interest is the finding that offspring from parents who were fed the 4% NaCl purified diet had higher blood pressures regardless of the diet they were fed after weaning, suggesting that the diet fed to the mother during pregnancy can promote hypertension in the offspring. How does the background diet (chow vs. purified) affect the outcome in this case? The reasons are not clear but may be related to fundamental differences between chows and purified diets in their protein sources, presence or absence of phyto-chemicals, level and type of fiber, carbohydrate type, and/or the level of minerals such as potassium.

Outbred rat strains such as the Sprague-Dawley (which is in widespread use for obesity research) can develop hypertension on high NaCl diets, and this usually occurs over a longer time period (compared to Dahl SS rats) or concurrent with the development of obesity.66 Interestingly, diets with normal levels of NaCl but high in fructose (around 60% of calories) will also increase blood pressure67,68and produce signs of kidney damage in both Sprague-Dawley and Wistar rats.67-69 Such high fructose diets also cause IR69 (see section on high fructose diets) and this may in fact have a role in causing the hypertension.70

Even in a spontaneous rat model of hypertension, (such as the spontaneously hypertensive rat [SHR] which will develop hypertension on a variety of diets), diet can be used to modify the onset or degree of this disease. For example, dietary supplementation with antioxidants (such as vitamins E and C) can lower blood pressure in stroke-prone, SHR.71

As mentioned earlier, the mouse is not as widely used for the study of diet-induced hypertension. Inbred mice such as the C57BL/6 can develop elevated blood pressure on purified diets high in NaCl (8%), though the time frame for this appears to be on the order of several months.72 It should be clear that in order to develop and study an animal model of the MS, special diets are needed. Purified ingredient diets are ideally suited to this task, since they can be intentionally modified to meet researcher’s needs, contain little to no extraneous compounds, and have very little variation from batch to batch. Though it is well-known to most researchers, it is worth stating that no phenotype is guaranteed and that careful choice of the species/strain and adequate control over environmental variables will be extremely important in generating and repeating data. In this article, we have briefly covered only some of the disease models that can be induced by diet. What should be clear is that while some dietary factors promote one specific phenotype (i.e. sodium induces hypertension), others may promote multiple phenotypes. Examples include the use of high-fat diets to induce obesity, IR, and hyperglycemia and using high fructose diets to promote IR, hyper-triglyceridemia, and hypertension. This simultaneous development of disease should not be very surprising given the complex interactions and causal relationships between these diseases. At present, diet-driven animal models of the MS are still developing and there may not be one single model that will satisfy all metabolic disease research needs. However, the demand for a diet-driven MS animal model is relatively new. Ongoing research using different species/strains along with existing and new purified ingredient diet formulations should lead to the development of more and more useful MS phenotypes.

Angela M. Gajda, M.S. is Project Development and Management Specialist for Research Diets, Inc. She can be reached at Gajda@ResearchDiets.com.

Michael A. Pellizzon, Ph.D. is Project Manager and Scientist for Research Diets, Inc. He can be reached at Pellizzon@ResearchDiets.com.

Matthew R. Ricci, Ph.D. Vice-President, Science Director of Research Diets, Inc. He can be reached at ricci@ResearchDiets.com

Edward A. Ulman, Ph.D. is President of Research Diets, Inc. He can be reached at Ulman@ResearchDiets.com.

Research Diets, Inc. 20 Jules Lane, New Brunswick, NJ 08901 www.ResearchDiets.com

 

 

References

 

  1. McCay, C. M., Crowell, M. F., and Maynard, L. A. The effect of retarded growth upon the length of the life-span and ultimate body size. J.Nutr. 10, 63-79. 1935.
  2. Thigpen,JE, Setchell,KD, Saunders,HE, Haseman,JK, Grant,MG, Forsythe,DB: Selecting the appropriate rodent diet for endocrine disruptor research and testing studies. ILAR.J 45:401-416, 2004
  3. Ricci, M. R. and Ulman, E. A. Laboratory Animal Diets: A Critical Part of Your In Vivo Research. Animal Lab News 4(6). September/October 2005
  4. Ghibaudi,L, Cook,J, Farley,C, van Heek,M, Hwa,JJ: Fat intake affects adiposity, comorbidity factors, and energy metabolism of sprague-dawley rats. Obes.Res 10:956-963, 2002
  5. Storlien,LH, Higgins,JA, Thomas,TC, Brown,MA, Wang,HQ, Huang,XF, Else,PL: Diet composition and insulin action in animal models. Br.J Nutr. 83 Suppl 1:S85-S90, 2000
  6. Ikemoto,S, Takahashi,M, Tsunoda,N, Maruyama,K, Itakura,H, Ezaki,O: High-fat diet-induced hyperglycemia and obesity in mice: differential effects of dietary oils. Metabolism 45:1539-1546, 1996
  7. Wang,H, Storlien,LH, Huang,XF: Effects of dietary fat types on body fatness, leptin, and ARC leptin receptor, NPY, and AgRP mRNA expression. Am J Physiol Endocrinol Metab 282:E1352-E1359, 2002
  8. Buettner,R, Parhofer,KG, Woenckhaus,M, Wrede,CE, Kunz-Schughart,LA, Scholmerich,J, Bollheimer,LC: Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. J Mol.Endocrinol. 36:485-501, 2006
  9. Pellizzon,M, Buison,A, Ordiz,F, Jr., Santa,AL, Jen,KL: Effects of dietary fatty acids and exercise on body-weight regulation and metabolism in rats. Obes.Res. 10:947-955, 2002
  10. Levin,BE, Dunn-Meynell,AA, Balkan,B, Keesey,RE: Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Physiol 273:R725-R730, 1997
  11. Rossmeisl,M, Rim,JS, Koza,RA, Kozak,LP: Variation in type 2 diabetes--related traits in mouse strains susceptible to diet-induced obesity. Diabetes 52:1958-1966, 2003
  12. Levin,BE, Keesey,RE: Defense of differing body weight set points in diet-induced obese and resistant rats. Am J Physiol 274:R412-R419, 1998
  13. Lauterio,TJ, Bond,JP, Ulman,EA: Development and characterization of a purified diet to identify obesity-susceptible and resistant rat populations. J Nutr. 124:2172-2178, 1994
  14. Farley,C, Cook,JA, Spar,BD, Austin,TM, Kowalski,TJ: Meal pattern analysis of dietinduced obesity in susceptible and resistant rats. Obes.Res 11:845-851, 2003
  15. Chang,S, Graham,B, Yakubu,F, Lin,D, Peters,JC, Hill,JO: Metabolic differences between obesity-prone and obesity-resistant rats. Am J Physiol 259:R1103-R1110, 1990
  16. Levin,BE, Dunn-Meynell,AA: Differential effects of exercise on body weight gain and adiposity in obesity-prone and -resistant rats. Int.J Obes.(Lond) 2006
  17. Ricci,MR, Levin,BE: Ontogeny of diet-induced obesity in selectively bred Sprague-Dawley rats. Am J Physiol Regul.Integr.Comp Physiol 285:R610-R618, 2003
  18. Corsetti,JP, Sparks,JD, Peterson,RG, Smith,RL, Sparks,CE: Effect of dietary fat on the development of non-insulin dependent diabetes mellitus in obese Zucker diabetic fatty male and female rats. Atherosclerosis 148:231-241, 2000
  19. Owens D: Spontaneous, Surgically and Chemically Induced Models of Disease In The Laboratory Rat. Suckow MA, Weisbroth SH, Franklin CL, Eds. Elsevier Academic Press, 2006, p. 711-732
  20. West,DB, Boozer,CN, Moody,DL, Atkinson,RL: Dietary obesity in nine inbred mouse strains. Am J Physiol 262:R1025-R1032, 1992
  21. Surwit,RS, Feinglos,MN, Rodin,J, Sutherland,A, Petro,AE, Opara,EC, Kuhn,CM, Rebuffe-Scrive,M: Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism 44:645-651, 1995
  22. Prpic,V, Watson,PM, Frampton,IC, Sabol,MA, Jezek,GE, Gettys,TW: Adaptive changes in adipocyte gene expression differ in AKR/J and SWR/J mice during diet-induced obesity. J Nutr. 132:3325-3332, 2002
  23. Hegsted,DM, Ausman,LM, Johnson,JA, Dallal,GE: Dietary fat and serum lipids: an evaluation of the experimental data. Am J Clin Nutr. 57:875-883, 1993
  24. Mensink,RP, Katan,MB: Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials.
    Arterioscler.Thromb. 12:911-919, 1992
  25. Maxwell,KN, Soccio,RE, Duncan,EM, Sehayek,E, Breslow,JL: Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res. 44:2109-2119, 2003
  26. Nishina,PM, Verstuyft,J, Paigen,B: Synthetic low and high fat diets for the study of atherosclerosis in the mouse. J Lipid Res 31:859-869, 1990
  27. Nishina,PM, Lowe,S, Verstuyft,J, Naggert,JK, Kuypers,FA, Paigen,B: Effects of dietary fats from animal and plant sources on diet-induced fatty streak lesions in C57BL/6J mice. J Lipid Res. 34:1413-1422, 1993
  28. Getz,GS, Reardon,CA: Diet and murine atherosclerosis. Arterioscler. Thromb.Vasc.Biol. 26:242-249, 2006
  29. Lichtman,AH, Clinton,SK, Iiyama,K, Connelly,PW, Libby,P, Cybulsky,MI: Hyperlipidemia and atherosclerotic lesion development in LDL receptor-deficient mice fed defined semipurified diets with and without cholate. Arterioscler.Thromb.Vasc.Biol. 19:1938-1944, 1999
  30. Collins,AR, Meehan,WP, Kintscher,U, Jackson,S, Wakino,S, Noh,G, Palinski,W, Hsueh,WA, Law,RE: Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler. Thromb.Vasc.Biol. 21:365-371, 2001
  31. Joseph,SB, McKilligin,E, Pei,L, Watson,MA, Collins,AR, Laffitte,BA, Chen,M, Noh,G, Goodman,J, Hagger,GN, Tran,J, Tippin,TK, Wang,X, Lusis,AJ, Hsueh,WA, Law,RE, Collins,JL, Willson,TM, Tontonoz,P: Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc.Natl.Acad.Sci.U.S.A. 99:7604-7609, 2002
  32. Teupser,D, Persky,AD, Breslow,JL: Induction of atherosclerosis by low-fat, semisyn-thetic diets in LDL receptor-deficient C57BL/6J and FVB/NJ mice: comparison of lesions of the aortic root, brachiocephalic artery, and whole aorta (en face measurement). Arterioscler.Thromb.Vasc.Biol. 23:1907-1913, 2003
  33. Merkel,M, Velez-Carrasco,W, Hudgins,LC, Breslow,JL: Compared with saturated fatty acids, dietary monounsaturated fatty acids and carbohydrates increase atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice. Proc.Natl.
    Acad.Sci.U.S.A. 98:13294-13299, 2001
  34. Dietschy,JM, Woollett,LA, Spady,DK: The interaction of dietary cholesterol and specific fatty acids in the regulation of LDL receptor activity and plasma LDL-cholesterol concentrations. Ann N.Y.Acad.Sci. 676:11-26, 1993
  35. Spady,DK, Woollett,LA, Dietschy,JM: Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids. Annu.Rev.Nutr. 13:355-381, 1993
  36. Otto,J, Ordovas,JM, Smith,D, van Dongen,D, Nicolosi,RJ, Schaefer,EJ: Lovastatin inhibits diet induced atherosclerosis in F1B golden Syrian hamsters. Atherosclerosis 114:19-28, 1995
  37. Kowala,MC, Nunnari,JJ, Durham,SK, Nicolosi,RJ: Doxazosin and cholestyra-mine similarly decrease fatty streak formation in the aortic arch of hyperlipi-demic hamsters. Atherosclerosis 91:35-49, 1991
  38. Wilson,TA, Nicolosi,RJ, Delaney,B, Chadwell,K, Moolchandani,V, Kotyla,T, Ponduru,S, Zheng,GH, Knutson,N, Curry,L, Kolberg,L, Goulson,M, Ostergren,K: Reduced and high molecular weight barley beta-glucans decrease plasma total and non-HDL-cholesterol in hypercho-lesterolemic Syrian golden hamsters. Journal of Nutrition 134: 1995
  39. Pien,CS, Davis,WP, Marone,AJ, Foxall,TL: Characterization of diet induced aortic atherosclerosis in Syrian F1B Hamsters. Journal of Experimental Animal Science 42:65-83, 2006
  40. Alexaki,A, Wilson,TA, Atallah,MT, Handelman,G, Nicolosi,RJ: Hamsters fed diets high in saturated fat have increased cholesterol accumulation and cytokine production in the aortic arch compared with cholesterol-fed hamsters with moderately elevated plasma non-HDL cholesterol concentrations. J Nutr. 134:410-415, 2004
  41. Fernandez,ML, Volek,JS: Guinea pigs: A suitable animal model to study lipoprotein metabolism, atherosclerosis and inflammation. Nutrition and Metabolism 3: 2006
  42. Lin,EC, Fernandez,ML, Tosca,MA, McNamara,DJ: Regulation of hepatic LDL metabolism in the guinea pig by dietary fat and cholesterol. J Lipid Res 35:446-457, 1994
  43. Cos,E, Ramjiganesh,T, Roy,S, Yoganathan,S, Nicolosi,RJ, Fernandez,ML: Soluble fiber and soybean protein reduce atherosclerotic lesions in guinea pigs. Sex and hormonal status determine lesion extension. Lipids 36:1209-1216, 2001
  44. Zern,TL, West,KL, Fernandez,ML: Grape polyphenols decrease plasma triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs. J Nutr. 133:2268-2272, 2003
  45. Daly,ME, Vale,C, Walker,M, Alberti,KG, Mathers,JC: Dietary carbohydrates and insulin sensitivity: a review of the evidence and clinical implications. Am J Clin Nutr. 66:1072-1085, 1997
  46. Basciano,H, Federico,L, Adeli,K: Fructose, insulin resistance, and metabolic dyslipi-demia. Nutr.Metab (Lond). 2:5, 2005
  47. Pagliassotti,MJ, Prach,PA, Koppenhafer,TA, Pan,DA: Changes in insulin action, triglycerides, and lipid composition during sucrose feeding in rats. Am J Physiol 271:R1319-R1326, 1996
  48. Pagliassotti,MJ, Gayles,EC, Podolin,DA, Wei,Y, Morin,CL: Developmental stage modifies diet-induced peripheral insulin resistance in rats. Am J Physiol Regul.Integr.Comp Physiol 278:R66-R73, 2000
  49. Thigpen,JE, Setchell,KD, Ahlmark,KB, Locklear,J, Spahr,T, Caviness,GF, Goelz,MF, Haseman,JK, Newbold,RR, Forsythe,DB: Phytoestrogen content of purified, open- and closed-formula laboratory animal diets. Lab Anim Sci. 49:530-536, 1999
  50. Sleder,J, Chen,YD, Cully,MD, Reaven,GM: Hyperinsulinemia in fructose-induced hypertriglyceridemia in the rat. Metabolism 29:303-305, 1980
  51. Thresher,JS, Podolin,DA, Wei,Y, Mazzeo,RS, Pagliassotti,MJ: Comparison of the effects of sucrose and fructose on insulin action and glucose tolerance. Am J Physiol Regul.Integr.Comp Physiol 279:R1334-R1340, 2000
  52. Thorburn,AW, Storlien,LH, Jenkins,AB, Khouri,S, Kraegen,EW: Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats. Am J Clin Nutr. 49:1155-1163, 1989
  53. Chicco,A, D'Alessandro,ME, Karabatas,L, Pastorale,C, Basabe,JC, Lombardo,YB: Muscle lipid metabolism and insulin secretion are altered in insulin-resistant rats fed a high sucrose diet. J Nutr. 133:127-133, 2003
  54. Kasim-Karakas,SE, Vriend,H, Almario,R, Chow,LC, Goodman,MN: Effects of dietary carbohydrates on glucose and lipid metabolism in golden Syrian hamsters. J Lab Clin Med 128:208-213, 1996
  55. 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. 275:8416-8425, 2000
  56. Nagata,R, Nishio,Y, Sekine,O, Nagai,Y, Maeno,Y, Ugi,S, Maegawa,H, Kashiwagi,A: Single nucleotide polymorphism (-468 Gly to A) at the promoter region of SREBP-1c associates with genetic defect of fructose-induced hepatic lipogenesis [corrected]. J Biol.Chem. 279:29031-29042, 2004
  57. Sumiyoshi,M, Sakanaka,M, Kimura,Y: Chronic intake of high-fat and high-sucrose diets differentially affects glucose intolerance in mice. J Nutr. 136:582-587, 2006
  58. Merat,S, Casanada,F, Sutphin,M, Palinski,W, Reaven,PD: Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet. Arterioscler.Thromb.Vasc.Biol. 19:1223-1230, 1999
  59. Ogihara,T, Asano,T, Ando,K, Sakoda,H, Anai,M, Shojima,N, Ono,H, Onishi,Y, Fujishiro,M, Abe,M, Fukushima,Y, Kikuchi,M, Fujita,T: High-salt diet enhances insulin signaling and induces insulin resistance in Dahl salt-sensitive rats. Hypertension 40:83-89, 2002
  60. Tian,N, Thrasher,KD, Gundy,PD, Hughson,MD, Manning,RD, Jr.: Antioxidant treatment prevents renal damage and dysfunction and reduces arterial pressure in salt-sensitive hypertension. Hypertension 45:934-939, 2005
  61. Cowley,AW, Jr., Stoll,M, Greene,AS, Kaldunski,ML, Roman,RJ, Tonellato,PJ, Schork,NJ, Dumas,P, Jacob,HJ: Genetically defined risk of salt sensitivity in an intercross of Brown Norway and Dahl S rats. Physiol Genomics 2:107-115, 2000
  62. Kobayashi,N, Yoshida,K, Nakano,S, Ohno,T, Honda,T, Tsubokou,Y, Matsuoka,H: Cardioprotective mechanisms of eplerenone on cardiac performance and remodeling in failing rat hearts. Hypertension 47:671-679, 2006
  63. Konda,T, Enomoto,A, Takahara,A, Yamamoto,H: Effects of L/N-type calcium channel antagonist, cilnidipine on progressive renal injuries in Dahl salt-sensitive rats.
    Biol.Pharm.Bull. 29:933-937, 2006
  64. Vasdev,S, Gill,V, Parai,S, Gadag,V: Dietary vitamin e supplementation attenuates hypertension in Dahl salt-sensitive rats. J Cardiovasc.Pharmacol.Ther. 10:103-111, 2005
  65. Mattson,DL, Kunert,MP, Kaldunski,ML, Greene,AS, Roman,RJ, Jacob,HJ, Cowley,AW, Jr.: Influence of diet and genetics on hypertension and renal disease in Dahl salt-sensitive rats. Physiol Genomics 16:194-203, 2004
  66. Dobrian,AD, Davies,MJ, Prewitt,RL, Lauterio,TJ: Development of hypertension in a rat model of diet-induced obesity. Hypertension 35:1009-1015, 2000
  67. Sanchez-Lozada,LG, Tapia,E, Jimenez,A, Bautista,P, Cristobal,M, Nepomuceno,T, Soto,V, Avila-Casado,C, Nakagawa,T, Johnson,RJ, Herrera-Acosta,J, Franco,M: Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats. Am J Physiol Renal Physiol 2006
  68. Vasudevan,H, Xiang,H, McNeill,JH: Differential regulation of insulin resistance and hypertension by sex hormones in fructose-fed male rats. Am J Physiol Heart Circ Physiol 289:H1335-H1342, 2005
  69. Hwang,IS, Ho,H, Hoffman,BB, Reaven,GM: Fructose-induced insulin resistance and hypertension in rats. Hypertension 10:512-516, 1987
  70. DeFronzo,RA: The effect of insulin on renal sodium metabolism. A review with clinical implications. Diabetologia 21:165-171, 1981
  71. Noguchi,T, Ikeda,K, Sasaki,Y, Yamamoto,J, Yamori,Y: Effects of vitamin e and sesamin on hypertension and cerebral thrombogenesis in stroke-prone spontaneously hypertensive rats. Clin Exp.Pharmacol.Physiol 31 Suppl 2:S24-S26, 2004
  72. Yu,Q, Larson,DF, Slayback,D, Lundeen,TF, Baxter,JH, Watson,RR: Characterization of high-salt and high-fat diets on cardiac and vascular function in mice.
    Cardiovasc.Toxicol. 4:37-46, 2004

 

 

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