Diet-Induced Metabolic Syndromein Rodent Models
A discussion of how diets made from purified ingredients influence
the phenotypes of the MS in commonly used rodent models.
Angela M. Gajda, MS, Michael A. Pellizzon, Ph.D.,
Matthew R. Ricci, Ph.D. and Edward A. Ulman, Ph.D.

A

quick look at a crowd of people showsthat 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 highdensity 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 nonalcoholic fatty liver disease. It is estimated that
individuals with the MS spend over $4000 per
year in treatment and to make matters worse, theprevalence of the MS is growing at an alarming
rate, even in obese children.
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, wemust look to the environment as the main causeof the increase in metabolic disease during thistime frame. To be sure, decreased daily physicalexercise (and fewer calories expended) plays animportant 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 andother ‘diseases of excess’ are in fact the natural
outcome of eating too many calories. During theevolutionary process, because the food supply

was not stable and periods of starvation werecommon, it was advantageous to have genes thatallowed for the efficient storage of excess calories
as fat, given the uncertainty of when the next
meal would come. In our present society, theproblem is that we still have those ‘thrifty genes’
but also have a variety of foods that are high insaturated 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 toname 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 isseeking 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 animalmodels 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 aroundthe 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 gen-Reprinted with permission from animalLABNEWS

March • 2007

erally 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 plantderived phytochemicals that are found in grain-based
chow diets. Some of these compounds, in particular
the phytoestrogens, 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 andspecifically 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 diseaseanimal research uses (and in fact requires) purified
ingredient diets. For an expanded discussion of diets,see our previous article in this publication.3 In thisbrief review, we discuss how diets made from purified
ingredients influence the phenotypes of the MS incommonly used rodent models.

High-Fat Diets for Diet-Induced Obesity
ModelsIn order to gain a greater understanding of humanobesity, rats and mice are commonly used models as
they will readily gain weight when provided with ahigh-fat diet and also develop other risk factors associated with the MS.
Numerous high-fat rodent diets are available fromcommercial vendors. Not all high-fat diets are thesame, 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 othernutrients (protein, vitamins, minerals, and fiber) arediluted. The addition of too much fat can actuallyrender 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 havestrict definitions, low-fat diets (LFD) have about 10% of

Brief Summary of Diet-Induced Metabolic Disease Models
Type of Diet

StrainPhenotype

Comments

References

Purified ingredient diet, 30-60 kcal%
fat with various fat sources

SD rat, Wistar rat

Obesity

BW differences between DR and DIO rats apparent
between 2-10 weeks on diet. Fat type can impact weight gain.

4, 15, 16

Chow with added fat to equal 48 kcal% fat

ZDF ratObesity and diabetes

Males develop diabetes on standard chow, but .
disease is more robust on higher fat diets.
Females require diet with at least 48 kcal% fat to develop diabetes.

18, 19Purified ingredient diet, 45-60 kcal% fat
with various fat sources

C57BL/6 mice

Obesity/hyperglycemia

BW differences between high fat and low fat diets
groups appear as early as 1 week on diet.
Hyperglycemia occurs around 4 weeks.

11, 21

Purified ingredient diet, 10 or 58 kcal%
fat with various fat and CHO sources

A/J mice

Obesity resistanceDo not become obese despite caloric intake similar
to C57BL/6 mice.

21, 22

Purified ingredient diet, 10 or 58 kcal%
fat with various fat and CHO sources

AKR mice

Obesity andinsulin resistance

Become obese on high fat diets. They are more
11, 22glucose tolerant but more insulin resistant, compared to C57BL/6 mice.

Purified ingredient diet, 32 kcal% fat

SD ratHypertension

Hypertension and obesity developed after 10 weeks on high fat diet.

Purified ingredient diet, 8% NaCl

Dahl SS rat

Hypertension

Hypertension developed after 2-4 weeks on diet.

59-62

Purified ingredient diet, 60% fructose

SD rat, Wistar rat

Hypertension

Hypertension developed after 6-8 weeks on diet.

67

Purified ingredient diet, 60 - 70 kcal%
SucroseSD rat, Wistar rat

IR/hypertriglyceridemia

Both IR and hypertriglyceridemia after 2 weeks on diet.

47,48

Purified ingredient diet, 60 - 70 kcal%
Fructose

Golden Syrian Hamster IR/hypertriglyceridemia

Both IR and hypertriglyceridemia after 2 weeks on diet.

54

Purified ingredient diet, high saturated fat,
1% cholesterol, 0.25% cholic acid

C57BL/6 mice

Atherosclerosis/
Hypercholesterolemia

Hypercholesterolemia and mild atherosclerosis after
14-18 weeks on diet.

26, 27

Purified ingredient diet,
0.1 - 1.25% cholesterol

LDL receptor KO,
apolipoprotein E KO

Atherosclerosis/
Hypercholesterolemia

Hypercholesterolemia and atherosclerosis after 12 weeks on diet.

29-31

Purified ingredient diet, high in saturated
fat, 0.05 - 1% cholesterol

Golden Syrian Hamster Atherosclerosis/
Hypercholesterolemia

Hypercholesterolemia and atherosclerotic after 6
weeks on diet.

38, 40Purified ingredient diet, high saturated fat,
~0.3% cholesterol

Hartley Guinea Pigs

Hypercholesterolemia and atherosclerosis after 12
weeks on diet.

43, 44

Atherosclerosis/
Hypercholesterolemia

Reprinted with permission from animalLABNEWS

March • 200766

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 containgreater than 50 kcal% fat. For comparison, most lowfat chow diets contain 10-12% of the calories from fat.
To induce obesity, both HFD and VHFD are used, andthere is a dose-response for body weight as a function of dietary fat.4 When studying the influence of adrug, nutraceutical, or gene mutation on obesity, onemust 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 andwere 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 andgender.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), andother parameters depending on the strain and gender 10,11 and source of dietary fat.6-8 Outbred SpragueDawley 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, thisresearch was done with chow-based diets12 but
purified ingredient diets were developed13 which
now researchers commonly use to separate therats into diet-induced obese (DIO) and diet-resistant (DR) groups.14-16 Furthermore, the outbred
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 ofobesity) for genetic traits that may later predisposethem 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 obeseand diabetic on a LFD, but HFD feeding promotes
more robust disease. The female ZDF rat is uniquein 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 inweight gain on a purified ingredient VHFD (~60% byenergy).20 Some inbred strains such as the C57BL/6
or AKR mouse are quite susceptible to obesity on a
VHFD,11 while mice of the A/J and SWR/J strains
tend to be resistant to obesity.21,22 However, strainsthat may exhibit similar levels of obesity may havevaried 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 totalcholesterol (TC) and low density lipoproteins (LDLC),23,24 increases the risk of ASCVD. As withhumans, a purified ingredient HFD (with much asSF), and cholesterol (~0.2% by weight), commonlyreferred to as a ‘Western diet,’ can elevate TC andLDL-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 thisis seen with the diet-induced development of atherosclerosis in rodents. Normal mice and rats havetraditionally not been ideal models of cardiovascular disease research since they typically have very
low levels of TC and LDL-C but high levels of highdensity lipoprotein cholesterol (HDL-C). This is incontrast 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 sincecholic acid can also promote liver inflammation,
decrease bile acid production, and alter circulating
TG and HDL-C, 26,28,29 it may independently affectthe development of atherosclerosis.
The ability to change the genetic make-up ofmice and produce ‘transgenic’ or ‘knockout’ micehas allowed for the development of many interesting and useful disease models. Genetically modified

Reprinted with permission from animalLABNEWS March • 2007

mice such as those with mutations that slow theremoval 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 turncan develop mature atherosclerotic lesions when fed
purified ingredient high cholesterol diets without theneed 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 Even in 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 beenused 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 likehumans, SF can increase these levels further.34,35
The combination of high dietary SF and cholesterol
is commonly used to promote atherosclerosis inthese 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 highconcentrations of SF (as hydrogenated coconut oil)can promote more aortic cholesterol accumulationcompared to a diet with both cocoa butter and 0.15%
cholesterol.40 This was despite the fact that bothgroups had similar levels of LDL-C, suggesting thatthe 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 possessother 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 forHypertriglyceridemia and Insulin Resistancein 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 inhumans have suggested that carbohydrate intake ison 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 thisincreased availability of nutrients ultimately leads
to IR and hypertriglyceridemia.45,46 Typically, lowfat chow diets contain about 4% sucrose and < 0.5%
free fructose. Low-fat purified diets can containhigher 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 candevelop within two weeks when these animals are
fed a diet containing 65% sucrose (by weight) relative to one with 65% corn starch.47 It seems that thefructose component of sucrose is largely responsible for the hypertriglyceridemia and IR produced byhigh 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 infructose.54,55 Interestingly, hamsters fed highsucrose diets did not have elevated TG levels anddeveloped only mild IR relative to those fed dietshigh in fructose.54 Since sucrose is one-half fructose, it appears that the level of dietary fructose isquite important in the rapid development of IR andelevated TG in hamsters.
In contrast to rats and hamsters, the mouse isused less frequently as a model for sucrose/fructose-induced IR and hypertriglyceridemia. The
response to high fructose/sucrose diets is verystrain-dependent in the mouse56 and commonlyused strains like the C57BL/6 mouse either do notdevelop IR or develop IR slowly.56,57 However, themouse genome is easier to manipulate than that of
the rat and several knockout models (that are prone

Reprinted with permission from animalLABNEWS March • 2007

to develop atherosclerosis) do show TG responses (which is in widespread use for obesity research)
to high dietary fructose.58
can develop hypertension on high NaCl diets, andthis usually occurs over a longer time period (comDiets High In Sodium (and Fructose) For
pared to Dahl SS rats) or concurrent with the develHypertension
opment of obesity.66 Interestingly, diets with norThe causes of hypertension in humans are not fully mal levels of NaCl but high in fructose (around 60%
understood but are correlated with sodium chloride of calories) will also increase blood pressure67,68(NaCl) intake, obesity, insulin resistance and of and produce signs of kidney damage in bothcourse, genetics. The rat is the historically pre- Sprague-Dawley and Wistar rats.67-69 Such highferred small animal model for diet-induced hyper- fructose diets also cause IR69 (see section on hightension, perhaps because of its size, the amount of fructose diets) and this may in fact have a role inphysiological data available, and robust blood pres- causing the hypertension.70
sure response that some strains present.
Even in a spontaneous rat model of hypertenBoth the level of dietary NaCl and the background sion, (such as the spontaneously hypertensive rat
diet are important in generating a hypertensive phe- [SHR] which will develop hypertension on a variety
notype in the rat. Typical purified ingredient diets of diets), diet can be used to modify the onset or
contain about 0.1% Na, while chow diets contain degree of this disease. For example, dietary supabout 0.3-0.4% Na. Both types of diets have been plementation with antioxidants (such as vitamins
modified to contain increased NaCl to study hyper- E and C) can lower blood pressure in stroke-prone,tension. The Dahl salt-sensitive rat shows a signifi- SHR.71
cant rise in blood pressure within 2-4 weeks after
As mentioned earlier, the mouse is not as widebeing fed a purified diet containing 8% NaCl.59-62 ly used for the study of diet-induced hypertension.
Lower levels of NaCl (4%) will still raise blood pres- Inbred mice such as the C57BL/6 can develop elesure63 and this is reported to occur at a slower vated blood pressure on purified diets high in NaClrate.19 This rise in blood pressure can be attenuat- (8%), though the time frame for this appears to be
ed by the addition of extra vitamin E to the diet.64 on the order of several months.72
Similar to findings in humans, hypertension due to
It should be clear that in order to develop andan 8% NaCl diet can be prevented by supplementing study an animal model of the MS, special diets are
the diet with extra potassium,59 suggesting that needed. Purified ingredient diets are ideally suited
diets low in potassium may aid in the promotion of to this task, since they can be intentionally modihypertension. Thus, diet can be used to both fied to meet researcher’s needs, contain little to no
induce and attenuate hypertension in the Dahl SS extraneous compounds, and have very little variarat.
tion from batch to batch. Though it is well-known
The diet to which the NaCl is added also affects to most researchers, it is worth stating that no phethe level of hypertension and concurrent kidney notype is guaranteed and that careful choice of thedamage. When 4% NaCl was added to both a chow species/strain and adequate control over environdiet and a purified ingredient diet, Dahl SS rats fed mental variables will be extremely important in genthe purified diet had higher blood pressure and erating and repeating data. In this article, we havemore renal damage compared to chow-fed rats.65 Of briefly covered only some of the disease models
equal interest is the finding that offspring from par- that can be induced by diet. What should be clear
ents who were fed the 4% NaCl purified diet had is that while some dietary factors promote one
higher blood pressures regardless of the diet they specific phenotype (i.e. sodium induces hypertenwere fed after weaning, suggesting that the diet fed sion), others may promote multiple phenotypes.
to the mother during pregnancy can promote Examples include the use of high-fat diets to
hypertension in the offspring. How does the back- induce obesity, IR, and hyperglycemia and using
ground diet (chow vs. purified) affect the outcome high fructose diets to promote IR, hypertriglycin this case? The reasons are not clear but may be eridemia, and hypertension. This simultaneous
related to fundamental differences between chows development of disease should not be very surand purified diets in their protein sources, pres- prising given the complex interactions and causal
ence or absence of phytochemicals, level and type relationships between these diseases. At present,of fiber, carbohydrate type, and/or the level of min- diet-driven animal models of the MS are still developing and there may not be one single model thaterals such as potassium.
Outbred rat strains such as the Sprague-Dawley will satisfy all metabolic disease research needs.

Reprinted with permission from animalLABNEWS March • 2007

However, the demand for a diet-driven MS animalmodel is relatively new. Ongoing research using different species/strains along with existing and new
purified ingredient diet formulations should lead tothe 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 bereached at Pellizzon@ResearchDiets.com.
Matthew R. Ricci, Ph.D. is Vice-President,
Science Director of Research Diets, Inc. He can bereached at Ricci@ResearchDiets.com
Edward A. Ulman, Ph.D. is President ofResearch 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 andultimate 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 animalmodels. 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 andobesity 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, andAgRP 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 dif-ferent 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 andmetabolism 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 SpragueDawley 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:R412R419, 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 diet-induced obesity in susceptible and resistantrats. 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 -resistantrats. 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: Effectof 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:R1025R1032, 1992
21. Surwit,RS, Feinglos,MN, Rodin,J, Sutherland,A, Petro,AE,
Opara,EC, Kuhn,CM, Rebuffe-Scrive,M: Differential effects offat 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

Reprinted with permission from animalLABNEWS March • 2007

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 plantsources 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 inmice. Proc.Natl.Acad.Sci.U.S.A. 99:7604-7609, 2002
32. Teupser,D, Persky,AD, Breslow,JL: Induction of atherosclerosis by low-fat, semisynthetic diets in LDL receptordeficient C57BL/6J and FVB/NJ mice: comparison oflesions of the aortic root, brachiocephalic artery, andwhole 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, dietarymonounsaturated 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 dietarycholesterol 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 LDLcholesterol 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 andcholestyramine similarly decrease fatty streak formation in the aortic arch of hyperlipidemic 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 highmolecular weight barley beta-glucans decrease plasma total andnon-HDL-cholesterol in hypercholesterolemic Syrian golden hamsters. Journal of Nutrition 134: 1995
39. Pien,CS, Davis,WP, Marone,AJ, Foxall,TL: Characterization ofdiet 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 tostudy lipoprotein metabolism, atherosclerosis and inflammation.
Nutrition and Metabolism 3: 2006
42. Lin,EC, Fernandez,ML, Tosca,MA, McNamara,DJ: Regulation ofhepatic 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 andhormonal status determine lesion extension. Lipids 36:12091216, 2001
44. Zern,TL, West,KL, Fernandez,ML: Grape polyphenols
decrease plasma triglycerides and cholesterol accumulationin 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 andclinical implications. Am J Clin Nutr. 66:1072-1085, 1997
46. Basciano,H, Federico,L, Adeli,K: Fructose, insulin resistance, andmetabolic dyslipidemia. Nutr.Metab (Lond). 2:5, 2005
47. Pagliassotti,MJ, Prach,PA, Koppenhafer,TA, Pan,DA: Changes ininsulin 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- andclosed-formula laboratory animal diets. Lab Anim Sci.
49:530-536, 1999

Reprinted with permission from animalLABNEWS March • 2007

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 resistanceand 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 andinsulin secretion are altered in insulin-resistant rats fed a highsucrose 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 associateswith 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 highfat 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 whichsimilar plasma cholesterol levels are achieved by a fructose-richdiet. 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 40:8389, 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 definedrisk of salt sensitivity in an intercross of Brown Norway andDahl 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 ofeplerenone 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-sensitiverats. 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 andgenetics 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: Developmentof 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 withglomerular hypertension and renal microvascular damage inrats. 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: Fructoseinduced 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: Effectsof 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 dietson cardiac and vascular function in mice.
Cardiovasc.Toxicol. 4:37-46, 2004

Reprinted with permission from animalLABNEWS March • 2007