Animal models of metabolic syndrome: a review
Wong et al. Nutrition & Metabolism
Animal models of metabolic syndrome: a review
Sok Kuan Wong 0
Kok-Yong Chin 0
Farihah Hj Suhaimi 1
Ahmad Fairus 1
Soelaiman Ima-Nirwana 0
0 Department of Pharmacology, Faculty of Medicine , Universiti Kebangsaan Malaysia, Jalan Yaakob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur , Malaysia
1 Department of Anatomy, Faculty of Medicine , Universiti Kebangsaan Malaysia, Jalan Yaakob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur , Malaysia
Metabolic syndrome (MetS) consists of several medical conditions that collectively predict the risk for cardiovascular disease better than the sum of individual conditions. The risk of developing MetS in human depends on synergy of both genetic and environmental factors. Being a multifactorial condition with alarming rate of prevalence nowadays, establishment of appropriate experimental animal models mimicking the disease state in humans is crucial in order to solve the difficulties in evaluating the pathophysiology of MetS in human. This review aims to summarize the underlying mechanisms involved in the pathophysiology of dietary, genetic, and pharmacological models of MetS. Furthermore, we will discuss the usefulness, suitability, pros and cons of these animal models. Even though numerous animal models of MetS have been established, further investigations on the invention of new animal model and clarification of plausible mechanisms are still necessary to confer a better understanding to researchers on the selection of animal models for their studies.
Antipsychotic drugs; Carbohydrate; Fat; Fructose; Glucocorticoid; Leptin; Sucrose
Metabolic Syndrome (MetS) is characterized by the
simultaneous occurrence of at least three of the following
medical conditions, obesity, hyperglycemia, hypertension
or dyslipidemia . Metabolic syndrome poses a public
healthcare problem worldwide owing to its increasing
prevalence. Worldwide prevalence of MetS ranges from
10 to 84 % depending on age, gender, race, ethnicity and
definition of MetS . Approximately 20–25 % of world’s
adult population is estimated to have MetS . The
prevalence of MetS in Malaysia was 22.9, 16.5 and 6.4 % based
on the definitions by International Diabetes Federation
(IDF), National Cholesterol Education Programme Adult
Treatment Panel III (NCEP ATP III) and modified World
Health Organization (WHO) respectively; whereby men
have a higher prevalence compared to women .
Metabolic syndrome is a collection of various
conditions, thus it does not have a single cause. Contributing
factors for the features of MetS can be hereditary or
environmental. Family history of type II diabetes,
hypertension and insulin resistance and ethnic background are
inevitable genetic factors that greatly increase the risk for
developing MetS [5–8]. Furthermore, senescence is
another important unalterable risk factor for MetS [9–11].
On the other hand, environmental risk factors for MetS
are controllable. These include sedentary lifestyle, physical
inactivity and eating habits . Metabolic syndrome
ultimately predisposes an individual to other medical
complications. For instance, MetS causes increased risk of
cardiovascular disease (CVD) , type II diabetes ,
non-alcoholic fatty liver disease , cancer (liver,
pancreas, breast and bladder) [16–19], kidney and pancreatic
The deleterious effects of MetS draw research efforts
in developing new interventions to reduce its burden on
the healthcare system. Due to its multifactorial nature,
selecting an adequate experimental model that best
represents the pathophysiology of MetS in humans can be
rather challenging. Rats and mice are the most common
animal models used in investigating MetS. Some of the
various approaches used to induce MetS in rodents
include dietary manipulation, genetic modification and
drugs. Previously, a review was produced by Panchal and
Brown, which primarily suggested the rat model that
displayed closest criteria to human MetS was induced by
high-carbohydrate high-fat diet . In this review, we
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collate and discuss the various animal models of MetS.
The caveats and suitability of MetS animal models for
research will also be discussed to provide the readers a
comprehensive overview on the selection of the best
animal models to meet their research purpose.
Diet-induced models of MetS
Numerous dietary approaches capable to induce MetS in
animals have been reported. They included the use of a
single type of diet or a combination of diets, such as
highfructose, high-sucrose (Table 1), high-fat (Table 2),
highfructose/high-fat, or high-sucrose/high-fat diets (Table 3).
A number of dietary studies have become the cornerstone
for the investigation of MetS because diet affects
wholebody metabolism and regulation through effects on
hormones, glucose metabolism, and lipid metabolism
pathways. The most commonly used rodent strains in
diet-induced models of MetS include Sprague-Dawley rats,
Wistar rats, C57BL/6 J mice and Golden Syrian Hamster
[21–24]. Here, we look into how these different diets give
rise to various illnesses of MetS.
Carbohydrates can be divided into simple (e.g.
monosaccharides and disaccharides) and complex (e.g.
oligosaccharides and polysaccharides) forms. Carbohydrates are one of
the essential nutrients acting as the main source of energy
(short-term fuel) in the body because they are simpler to
metabolize compared to fats. Adopting a sedentary lifestyle
puts an individual into the conditions of high energy intake
but low physical activity, thus increasing the tendency
towards energy storage, overweight and finally obesity.
Carbohydrate metabolism begins from digestion in the
small intestine to form glucose molecules, followed by
absorption into the bloodstream and transportation into liver
via the portal vein. When carbohydrate intake greatly
exceeds daily energy requirements, blood glucose
concentration will remain high and insulin is secreted by the
pancreas to allow cells to uptake glucose. At this moment, the
mechanisms involved in utilizing glucose are: (a)
breakdown of glucose in the process of glycolysis, (b) glucose is
converted to glycogen in the liver and muscles, and (c)
insulin acts on adipose tissue to promote fatty acids synthesis
and inhibit release of available fatty acids . Prolonged
Table 1 Effects of fructose- and sucrose-enriched diets on the development of MetS
Treatment length Strains of animal
Shahraki et al. 
Mansour et al. 
Mamikutty et al.  Fructose drinking
Di Luccia et al. 
Jurgens et al. 
Sucrose soft drink (10 %)
Non-caloric soft drink
Aguilera et al. 
Vasanji et al. 
Male Sprague-Dawley rats
Male Wistar albino rats
Male Sprague-Dawley rats ✓
Male Sprague-Dawley rats ✗
Male Sprague-Dawley rats
Male Sprague-Dawley rats
Table represents the effects of fructose- and sucrose-enriched diets on each component of MetS. The symbol ‘✓’ and ‘✗’ indicate the presence and absence of
significant effect of the sign of MetS respectively, while ‘-’ indicates the effects on the component not being evaluated in the study
Table 2 Effects of fat-enriched diet on the development of MetS
Researchers (Year) Types of diet Treatment length Strains of animal
excessive carbohydrate consumption causes sustained high
glucose levels in the blood. Insulin is thus produced in
proportion to lower the blood glucose. Therefore, high
dietary carbohydrates are converted into fats for
storage. Insulin sensitivity is also decreased. Substantial
evidence has demonstrated a strong association between
high carbohydrate intake and insulin resistance [26–28].
Information on the metabolic impact of carbohydrate on
animal models of MetS is absent. Most of the diet regimens
were designed with the combination of high-carbohydrate
Dissard et al.  High-fat high-fructose diet
Barrios-Ramos et al.  Hypercholesterolemic diet &
fructose drinking water
High-fat high-fructose diet
High-fat high sucrose diet
Table 3 Effects of different diet combinations on the development of MetS
Researchers (Year) Types of diet Treatment Strains of animal
High-carbohydrate high-fat diet 16 weeks
High-carbohydrate high-fat diet 16 weeks
High-carbohydrate high-fat diet 14 weeks
High-carbohydrate high-fat diet 16 weeks
and high-fat. Two studies tracing metabolic changes in rats
fed with high-carbohydrate high-fat diet are available. These
studies adopted a high-carbohydrate high-fat diet (consist
of 39.5 % sweetened condensed milk, 20 % beef tallow,
17.5 % fructose, 15.5 % powdered rat food, 2.5 % salt
mixture, 5 % water) to induce MetS in an animal model. The
researchers claimed it mimics more closely the human
disease state compared to other methods of inducing MetS
[29–31]. Test animals developed hypertension, impaired
glucose tolerance, increased abdominal fat deposition,
increased abdominal circumference, and altered lipid profile
after 16 weeks on this diet. Another study by Senaphan and
co-workers reported that high-carbohydrate high-fat diet
with some modifications (35 % sweetened condensed milk,
20 % pork tallow, 17.5 % fructose, 20 % powdered rat food,
2.5 % salt mixture, 5 % water) provided similar outcomes as
the previous study .
Ironically, the combination of high-carbohydrate with
high-fiber was reported to confer hypolipidemic and
hypoglycemic effects as evidenced in human studies. In
a clinical study, high-carbohydrate high-fiber diet was
suggested as dietary therapy in diabetic patients because this
diet was capable of reducing postprandial plasma glucose,
insulin response, cholesterol, and triglycerides levels
. Hence, the composition and combination of
highcarbohydrate diet are important factors that must be taken
into consideration for the induction of MetS.
Fructose, commonly known as the fruit sugar, is one of
the monosaccharides along with glucose and galactose.
Nowadays, fructose is often used as a taste enhancer to
make food more appetizing and tempting. There is no
biological need for dietary fructose; it is only an intermediary
molecule during glucose metabolism. The circulating
concentration of fructose (~0.01 mmol/L) in peripheral blood
is very low compared to glucose (~5.5 mmol/L) .
Interestingly, a small quantity of fructose produces a lower
glycemic response to substitute sucrose and starch in the
diet in diabetic patients . Unfortunately, intake of
fructose is excessive nowadays due to the consumption of
artificially sweetened beverages and food.
Theoretically, a large influx of fructose into the liver
causes accumulation of triglycerides and cholesterol
because of its lipogenic (fat-producing) properties,
subsequently leading to reduced insulin sensitivity, insulin
resistance and glucose intolerance [35, 36]. Fructose
consumption resulted in massive fructose uptake by the liver.
Fructose is converted to fructose-1-phosphate, a reaction
catalyzed by the enzyme phosphofructokinase in the
presence of ATP. It is followed by the cleavage of
fructose1-phosphate into glyceraldehyde and dihydroxyacetone
phosphate without the conversion of glucose to
fructose1,6-bisphosphate, an initial regulatory step of glycolysis
. Phosphofructokinase is a negative regulator for
glucose metabolism, allowing fructose to enter into the
glycolysis pathway continuously. Fructose-1,6-bisphosphate
is then converted to pyruvate through the process of
glycolysis. At this juncture, fructose is involved in several
simultaneous processes: (a) a portion of the fructose is
converted into lactate from pyruvate, (b) another portion
produces triose-phosphate which readily converts to
glucose or glycogen via gluconeogenesis, (c) carbons derived
from the fructose can be converted into fatty acids, and (d)
inhibition of hepatic lipid oxidation by fructose favours
very low density lipoproteins (VLDL)-triglyceride synthesis
and fatty acid re-esterification . As a result, this refined
carbohydrate is rapidly absorbed and readily metabolized
by liver to produce glucose, glycogen, pyruvate, lactate,
glycerol, and acyl-glycerol molecules.
Knowledge on fructose metabolism revealed the
superiority of fructose-feeding for the induction of MetS in
animal models in comparison with glucose or starch. Previous
research indicated that glucose or starch-feeding is not as
effective as fructose-feeding in inducing MetS . In
addition, mice fed with fructose gained more weight
compared to mice fed with the same calories using starch .
The correlation between chronic high intake of dietary
fructose with increased energy intake, body weight,
adiposity, hypertriglyceridemia, hyperlipidemia, hypertension,
glucose intolerance and decreased insulin sensitivity
in laboratory animal, all leading to MetS, is indisputable
[39, 40]. An animal study conducted by Thirunavukkarasu
et al.  showed that increased blood pressure, glucose
intolerance, and decreased insulin sensitivity were
detected in rats fed with a fructose-enriched diet
containing >60 % of total calories. Another study performed
by Sanchez-Lozada et al.  reported that 10 % of
fructose in drinking water resulted in the same effects
as high dose of fructose (60 % in diet) in inducing
hypertension and hyperlipidemia in male
SpragueDawley rats, but they were less severe compared to
high dose of fructose.
To sum up, fructose behaves more like a fat instead of
a carbohydrate in both humans and animals. A low dose
of fructose in drinking water (10 %) is sufficient to
induce MetS in animals.
Sucrose, or table sugar, is a disaccharide found in cane
or beet sugar. It consists of one fructose molecule and
one glucose molecule. Sucrose has the same role as
fructose to make food more palatable. When sucrose is
consumed, it is cleaved into its constituents, i.e. glucose and
fructose by the enzyme sucrase . Both molecules are
then taken up by their specific transport mechanisms.
As outlined earlier, glucose uptake in glucose metabolism
is negatively regulated by phosphofructokinase, leading to
the continuous entry of fructose into the glycolytic
pathway. Excess fructose will be converted into fat in the liver
as fructose is a better substrate for fatty acid synthesis
compared to glucose . Thus, fructose is the main
active ingredient contributing to the development of MetS
in animals after sucrose consumption.
An animal study showed that administration of 30 %
sucrose in drinking water led to the development of
MetS in male Wistar rats with increased body weight,
systolic blood pressure, insulin, triacylglycerol, total
cholesterol, low density lipoproteins (LDL) cholesterol, and free
fatty acids . Besides, high sucrose supplementation is
widely used for induction of whole body insulin resistance
in rats, whereby high levels of plasma insulin was detected
[45–48]. Concomitantly, animals treated with 32 %
sucrose in drinking water exhibited hyperglycemia,
hypertriglyceridemia, hypercholesterolemia, and increased body
weight . Another study by Pang et al.  reported
that rats responded to sucrose supplementation (77 %) by
a significant elevation in systolic blood pressure, plasma
insulin, and triglycerides.
However, Kasim-Karakas et al.  revealed that only
fructose-feeding increased fasting non-esterified fatty acids
and triglycerides levels in the plasma and liver of Golden
Syrian hamsters. However the increment was not found in
sucrose-fed hamsters. Moreover, impaired glucose
tolerance, significant increase of body weight and body fat were
only detected in fructose-fed (15 %) rats, but not in other
groups fed with a soft drink (10 % sucrose) and a diet soft
drink (without calories) . Fructose and sucrose
supplementation also invoked distinct responses in two
different animal models, i.e. Sprague-Dawley and spontaneous
hypertensive rats, which represented environmentally and
genetically acquired MetS respectively. Fructose enrichment
in Sprague-Dawley rats caused hyperinsulinemia,
hypertriglyceridemia, hypercholesterolemia, hypertension, and
insulin resistance. Meanwhile, sucrose enrichment in
spontaneous hypertensive rats only increased blood
pressure and worsened insulin resistance .
These paradoxical outcomes accumulated from
previous studies implied that high content of sucrose will
ensure the success of MetS development in animal models.
However, fructose appeared to be more superior than an
equivalent amount of sucrose in inducing MetS because
fructose exists as a free molecule while sucrose contains
only 50 % fructose and 50 % glucose.
Fats are one of the three main macronutrients and are
the most calorically dense macronutrient . Fats, also
known as triglycerides, are composed of esters of three
fatty acid chains and glycerol. Lipid metabolism begins
with the process of lipolysis. Plenty of glycerol and fatty
acids diffuse freely into the bloodstream. Plasma free
fatty acids are major substrates for hepatic
VLDLtriglycerides production . Approximately 70 % of
released free fatty acids will be re-esterified (lipogenesis)
to form triglycerides . The rate of re-esterification is
dependent on the rate of glycerol-3-phosphate
production through glycolysis and the rate of fatty acid release
from adipocytes . The coupled actions of free and
re-esterified fatty acids (triglycerides) form VLDL, which
assists fats to circulate in the water-based solution of the
Many researchers have employed different types of
high-fat diets that vary between 20 and 60 % of total
energy. The source of the fat component may be either
plant-derived oils (e.g. corn, safflower or olive oil) or
animal-derived fats (e.g. beef tallow and lard) .
Highfat diets have been extensively used to induce MetS in
experimental animals. More specifically, high-fat diets have
been widely used to induce obesity in animals [56, 57].
Studies have also indicated that high-fat diet is effective in
promoting hyperglycemia, insulin resistance, dyslipidemia
and increased free fatty acids in the blood, either
independently or concurrently .
A comprehensive study by Ghibaudi et al.  aimed to
assess the chronic effect of dietary fats with different fat
content (10, 32 and 45 %) on body adiposity and
metabolism in rats. The findings demonstrated that energy intake,
weight gain, fat mass, plasma glucose, cholesterol,
triglycerides, free fatty acids, leptin, and insulin levels increased
dose-dependently with increased dietary fat. Apart from
that, mice fed with high-fat (60 %) diet exhibited greatly
increased body mass, total fat pads, plasma triglyceride, high
density lipoproteins (HDL) cholesterol, and LDL
cholesterol levels . Another animal model fed with high-fat
diet displayed elevation of total cholesterol, LDL
cholesterol, and unesterified cholesterol . Later investigation
has found that high-fat intake augmented body weight,
total cholesterol, and leptin levels in male C57BL/6 J mice
. Another recent study indicated that mice fed with
high-fat diet had increased body weight, plasma lipids,
plasma insulin, and insulin resistance compared to mice fed
with standard chow . To conclude, the increased
formation of VLDL helps to distribute assembled triglycerides
synthesized by the liver resulting from overconsumption of
high-fat diet. A high level of VLDL cholesterol can cause
obesity, dyslipidemia and the build-up of cholesterol in
arteries. The accumulation of triglycerides in the liver can
cause insulin resistance.
A summary on the effects of different nutrients on
whole body metabolism has been illustrated (Fig. 1).
The lipotoxicity hypothesis (overproduction and
accumulation of triglycerides in the non-adipose tissue
such as liver, muscle, and pancreas) is the common
criteria seen in the effect of different diets in the
development of MetS. It is alarming that MetS can be
Lipolysis Acyl glycerol Lipogenesis
Hepatic insulin resistance
Fig. 1 Summary of the effects of different diets on whole body metabolism. a High-fructose diet intake interferes glycolytic pathway by bypassing
the rate-controlling step, the conversion of glucose-6-phosphate into fructose-1,6-bisphosphate. Phosphofructokinase acts as a negative regulator
for glucose metabolism and allows fructose to enter the glycolytic pathway continuously to produce pyruvate, lactate, glycerol and acyl-glycerol.
b When plenty of glucose is available during high dietary carbohydrate, glucose utilizing pathways are initiated: breakdown of glucose by glycolysis,
conversion of glucose into glycogen via glycogenesis, and production of insulin which acts on adipose tissue to promote fatty acids synthesis.
c Consumption of high-sucrose diet: sucrose separates into fructose and glucose molecules and enters their specific mechanisms as stated
earlier. d Fats undergo lipolysis, glycerol and fatty acids are released into the blood. However, fatty acids released during lipolysis are re-esterified to
form triglyceride. Overproduction of triglyceride through excessive intake of various nutrients is likely to cause accumulation of triglyceride in the liver,
which will further lead to hepatic insulin resistance (reduced insulin sensitivity)
by these seemingly
Genetic models of MetS
In addition to diet-induced MetS animal model, genetic
animal models are imperative in order to investigate the
pathogenesis of MetS caused by genetic factors. These
genetic models of MetS are time-saving because the
duration for the development of MetS is significantly
shortened compared to diet-induced MetS.
Originally, leptin- or leptin receptor-deficient rodent
models are used as genetically obese and diabetic
experimental models. Numerous animal models are developed,
such as leptin-deficient (ob/ob) mice, leptin
receptordeficient (db/db) mice, Zucker fatty (ZF) rats, Zucker
diabetic fatty (ZDF) rats, DahlS.Z-Leprfa/Leprfa (DS/
obese) rats, Goto-Kakizaki (GK) rats, obese spontaneous
hypertensive rat (Koletsky rat), and the POUND mice™.
Leptin, serving as an anti-obesity hormone by binding to
leptin receptor, is secreted by mature adipocytes in
proportion with the size of fat depots . Circulating
leptin is taken up into the hypothalamus to decrease
food intake and eating appetite to increase energy
expenditure via several signaling pathways. Thus, the
occurrence of obesity in these models is basically owing
to the abnormalities in leptin signaling, which result in
hyperphagia (great desire on food), uncontrolled
appetite, and reduced energy expenditure .
Leptin-deficient (ob/ob) and leptin receptor-deficient
(db/db) mice are the models of single autosomal
recessive mutation on leptin gene (chromosome 6) and leptin
receptor gene (chromosome 4) respectively.
Leptindeficient (ob/ob) mice develop obesity, hyperinsulinemia
and hyperglycemia with the absence of hypertension and
dyslipidemia. Both hypertension and dyslipidemia did
not develop even after 38 weeks of age . Whereas
leptin receptor-deficient (db/db) mice develop obesity,
hyperglycemia, and dyslipidemia without hypertension
[66, 67]. Hence, both of these animal models are
excellent models for obesity and type II diabetes, but not for
MetS. Zucker fatty rat, also known as leptin
receptordeficient obese rat, carries a missense mutation in the
leptin receptor gene with homozygous fa allele,
hallmarked by an increased circulating leptin level .
Obesity developed in these rats as early as between 3 to
5 weeks of life . Instead of being genetically obese,
ZF rats demonstrated hyperinsulinemia, insulin
resistance, mild glucose intolerance, dyslipidemia, and
hypertension [70, 71]. A variant of Zucker rat, known as
Zucker Diabetic Fatty rat, is a selective inbred rat strain
derived from ZF rat with high glucose levels . Zucker
Diabetic Fatty rats display hyperphagia caused by a
nonfunctioning leptin receptor . Moreover, ZDF rats
recapitulate several phenotypes of type II diabetes
(impaired glucose metabolism, hyperglycemia, and
hyperinsulinemia) resulting from the defects of GLUT-2 and
GLUT-4 transporter. Long-term severe diabetes leads to
mild cardiac diastolic dysfunction in ZDF rats .
Hattori et al.  introduced a new animal model of
MetS, namely DahlS.Z-Leprfa/Leprfa (DS/obese) rat strain,
which was established from a cross between Dahl
saltsensitive rats and ZF rats. Higher systolic blood pressure,
body weight, visceral fat mass, subcutaneous fat mass, and
ratio of LDL cholesterol to HDL cholesterol levels
were detected in DS/obese rats compared to
DahlS.ZLepr+/Lepr+ (DS/lean) rats fed on a normal diet,
whereas fasting serum glucose concentration remained
unchanged. After that, Murase et al.  further
confirmed this strain of rat as a MetS animal model because
female DS/obese rats developed elevated systolic blood
pressure, body weight, insulin, triglycerides, LDL:HDL
cholesterol ratio, visceral and subcutaneous fat mass.
Goto-Kakizaki (GK) rat, a leptin resistant animal
model, is considered as one of the best non-obese inbred
model of type II diabetes . They spontaneously
develop hyperleptinemia, hyperphagia, hyperglycemia,
decreased β-cell function, increased gluconeogenesis,
and accumulation of visceral fat [77, 78]. Goto-Kakizaki
rat was established through repetitive selective breeding
of Wistar rats with glucose intolerance over several
generations [79, 80]. In light of the difficulties to access
human pancreatic islet defect, this specific animal
model representing human type II diabetes provide an
opportunity to study the disease intensively. However,
GK rats only act as genetic model representing
certain aspects of MetS thus not a suitable animal model
to represent MetS.
Spontaneous hypertensive rat (SHR) was generated
from outbreed between Wistar Kyoto male rats with
noticeable elevated blood pressure and females with slight
elevation of blood pressure, followed by selective inbreed
of the offspring with highest blood pressure . The
SHR is used as an experimental model for genetically
induced hypertension. A study by Potenza et al. 
demonstrated that 12-week-old SHRs were
hypertensive, hyperinsulinemic, and insulin resistant compared
to Wistar-Kyoto rats. Spontaneously hypertensive rats
generally do not develop hypercholesterolemia and
hyperlipidemia unless they are put on a special diet regimen,
such as high-cholesterol or high-fructose high-fat diet
[83, 84]. Modification of SHR, known as obese SHR
or Koletsky rat, was obtained by crossing a female SHR
with a normotensive Sprague-Dawley male. Koletsky rats
carry a nonsense mutation in the leptin receptor and
possess interesting phenotypes, including obesity at 5 weeks
of age, hypertriglyceridemia even with standard diet,
hyperinsulinemia with normal blood glucose, and severe
hypertension at 3 months of age . Koletsky rats have
been suggested as a more appropriate animal model for
MetS compared to SHRs. The POUND mouse (C57BL/
6NCrl-Leprdb-lb/Crl) was established in the last decade as
another model fulfilling all the MetS criteria in a single
animal. The animals were fed with Purina Diet ad libitum
and showed obesity at 1 month of age, hyperinsulinemia
and hyperglycemia at 18 weeks of age, increased leptin
levels at 17–18 weeks of age, as well as increased
cholesterol levels at 14 weeks of age .
Amongst all these leptin- and leptin receptor-related
rodent models, ZF rats, ZDF rats, DS/obese rats,
Koletsky rats and POUND mice are suitable models of
MetS because these rats display all the conditions of
MetS (Table 4). Genetic models are beneficial in
elucidating the plausible molecular mechanisms involved in
the development of certain disease states. However,
there were only nine mutations have been identified in
the leptin gene in 2014 and mutations were more
prevalent in consanguineous marriages . Thus mutations
of leptin or leptin receptor rarely occur in humans,
implying that they do not actually resemble the human
disease state in real life.
Drug/chemically-induced model of MetS
Endogenous glucocorticoids are naturally occurring stress
hormones secreted by the adrenal glands. Glucocorticoids
bind to its receptors (glucocorticoid and mineralocorticoid
receptors) to exert their effects on different tissues .
Apart from that, exogenous glucocorticoids are used as
medicine to treat a wide range of human diseases, such as
autoimmune disease and cancer. It is also used to prevent
rejection in organ transplantation. However,
glucocorticoid treatment brings about undesirable side effects such as
body weight gain, glucose intolerance, impaired calcium
homeostasis, osteoporosis, cataracts and central nervous
system effects . Both endogenous and exogenous
glucocorticoids have been used to develop MetS in animal
Glucocorticoids cause MetS by acting directly on
different tissues and organs (e.g. fat, liver, muscles, and
kidneys) via several mechanisms: (1) glucocorticoids
stimulate the differentiation of pre-adipocytes into
mature adipocytes; (2) glucocorticoids increase lipolysis to
release free fatty acids; (3) glucocorticoids increase
proteolysis in muscle to increase free amino acids. Amino
acid-induced mammalian target of rapamycin complex-1
(mTORC1) activation causes phosphorylation of insulin
Table 4 Metabolic changes in genetic models of MetS
Leptin receptor-deficient Obesity, type II
(db/db) mice diabetes
Fatty (ZDF) rat
The POUND mouse™
Pre-diabetes/metabolic Mutation in leptin receptor
syndrome (deletion of axon 2 on
Autosomal recessive mutation (a) Obese & increased body weight
on leptin gene (chromosome 6) (Age: 4 weeks)
(b) Hyperinsulinemia & hyperglycemia
(Age: 4 weeks)
(c) Impaired glucose tolerance
(Age: 12 weeks)
(d) Reduced blood pressure
(e) Does not develop dyslipidemia
Autosomal recessive mutation (a) Obese & increased body weight
on leptin receptor gene (Age: 6 weeks)
(chromosome 4) (b) High fasting blood glucose
(Age: 8 weeks)
(c) Hyperinsulinemia & impaired
glucose tolerance (Age: 12 weeks)
(d) Unchanged blood pressure
(e) Increased triglycerides, total cholesterol,
LDL cholesterol, and free fatty acid
(Age: 13 weeks)
Non-functional leptin receptor (a) Obese (Age: 3–5 weeks)
(b) Hyperinsulinemia, insulin resistance,
hyperglycemia (Age: 13–15 weeks)
(c) Mild hypertension (Age: 12–14 weeks)
(d) Hypercholesterolemia, hypertriglyceridemia
(Age: 20 weeks)
of leptin receptor
(a) Obese (Age: 18 weeks)
(b) Hyperinsulinemia (Age: 18 weeks)
(c) Unchanged serum glucose concentration
(d) Hypertension (Age: 11–12 weeks)
(e) Hypercholesterolemia & hypertriglyceridemia
(Age: 18 weeks)
(b) Hyperinsulinemia, insulin resistance &
mild hyperglycemia (Age: 4 weeks)
(c) Hyperlipidemia (Age: 8 weeks)
(d) Unchanged blood pressure (Age: 14 months)
(a) Hyperinsulinemia, insulin resistance
(Age: 12 weeks)
(b) Severe hypertension (Age: 4 weeks)
(a) Obese, increased abdominal fat
(Age: 5 weeks)
(b) Hyperinsulinemia, insulin resistance
(Age: 16–18 weeks)
(c) Normal fasting blood glucose
(d) Severe hypertension (Age: 12 weeks)
(e) Hyperlipidemia (Age: 16–18 weeks)
(a) Obese (Age: 4 weeks)
(b) Hyperinsulinemia, hyperglycemia
(Age: 18 weeks)
(c) Increased leptin levels (Age: 17–18 weeks),
(d) Hypercholesterolemia (Age: 14 weeks)
Zucker fatty (ZF) rat
Missense mutation on leptin
Goto-Kakizaki (GK) rat
receptor substrate-1 (IRS-1), leading to the occurrence
of insulin resistance; (4) glucocorticoids promote
gluconeogenesis in liver and cause hyperglycemia; and (5)
non-specific binding of glucocorticoids to its receptor
in the kidneys causes an increase in sodium retention,
potassium excretion, water retention, and plasma
volume concomitantly with elevation of blood pressure
[87, 88, 90].
Using laboratory animals, glucocorticoid-induced MetS
has been done through various approaches, such as
feeding [87, 91], daily intraperitoneal injections , or
surgically implanted glucocorticoid pellets [93, 94]. All these
different routes of administration of glucocorticoids
resulted in almost similar outcomes. Mounting levels of
corticosterone enhanced food intake, weight gain, abdominal
fat accumulation, severe fasting hyperglycemia, insulin
resistance, impaired glucose tolerance, hypertension,
dyslipidemia, as well as deposition of lipids in visceral adipose,
hepatic tissue and skeletal muscle in animals. Meanwhile,
the removal of corticosterone reversed all these adverse
Antipsychotic drugs are medications used to treat
neuropsychiatric disorders, for examples, schizophrenia,
depression, and bipolar disorder . Antipsychotic drugs have
been associated with a high incidence of MetS, evidenced
by body weight gain, increased visceral fat, impaired
glucose tolerance, and insulin resistance in animal studies
[96, 97]. However, the exact underlying mechanism
involved in antipsychotic-induced MetS still remains an
enigma. The proposed mechanism available currently is
that the weight gain caused by antipsychotic treatment
contributes to the development of diabetes and
dyslipidemia . Latest evidence demonstrated that
administration of the second generation antipsychotic, olanzapine,
via intraperitoneal injection or oral gavage interacted with
gut microbiota and caused body weight gain, increased
plasma free fatty acids, infiltration of macrophages in
adipose tissue, and deposition of visceral fat in both rat
and mouse models [97, 99]. Since antipsychotic drugs are
important as treatment for psychiatric diseases, ongoing
research is necessary to elucidate the plausible
mechanisms involved in antipsychotic-induced MetS so that this
side-effect can be avoided. The comparison between
various types of MetS animal model has been summarized
Other animal models of MetS
Other animal models of MetS are available despite those
typical laboratory rodent models, such as the use of guinea
pig, swine, Nile rat, and Sand rat. A male Hartley guinea pig
model of MetS was successfully developed by exposure to
high-fat, high-sucrose or high-fat high-fructose diet for
150 days [100, 101]. Additionally, Ossabaw swine model of
MetS was developed after fed with high-fat, high-cholesterol
atherogenic diet, evidenced by obesity, elevated arterial
pressure, glucose intolerance, and hyperinsulinemia . Nile
rat (Arvicanthis niloticus) was introduced as a novel model
of MetS that experiences onset of hyperglycemia,
hypertension, dyslipidemia, and abdominal fat accumulation by age
of one when rats were given laboratory chow diet .
Sand rat (Psammomys obesus), found mostly in North
Africa, spontaneously develops obesity and diabetes under
laboratory diets . These MetS features have not been
observed among the wild type of Nile and Sand rats.
➢ Suitable for the investigations ➢ Delayed onset of MetS
of non-genetic lifestyle-dependent ➢ A lengthy duration of diet regimen
MetS in humans (usually takes up to 16 weeks)
➢ Inexpensive (dependent on
the kind of diet)
Genetic model of MetS
Examples: ZF rat, ZDF rat,
DS/obese rat, Koletsky rat,
➢ Severe and spontaneous
➢ Suitable for the investigations
of drug-related MetS in human
➢ Do not resemble the criteria of
MetS in humans with intact leptin
➢ Mutation in leptin or leptin
receptor gene rarely occur in humans
➢ Mutations/deficiencies in animals
are not easily manipulated
➢ Delayed onset of MetS
In conclusion, the advantage of using animal models to
study MetS is the ability to monitor histological, functional,
biochemical, and morphological changes of MetS, which is
difficult to conduct in humans. Subsequent studies are
encouraged using combination or modification of existing
established methods in order to successfully develop an
animal model of MetS with the desired metabolic changes.
Apart from pathophysiological similarity with human MetS,
an excellent animal model should also be reproducible,
simple, reliable, and affordable with minimal disadvantages.
CVD: Cardiovascular disease; db/db mice: leptin receptor-deficient mice; DS/
lean rats: DahlS.Z-Lepr+/Lepr+ rats; DS/obese rats: DahlS.Z-Leprfa/Leprfa rats;
GLUT-2: glucose transporter-2; GLUT-4: glucose transporter-4; GK rats:
GotoKakizaki rats; HDL: High density lipoproteins; IDF: International Diabetes
Federation; IRS-1: Insulin receptor substrate-1; LDL: Low density lipoproteins;
MetS: Metabolic syndrome; mTORC1: Mammalian target of rapamycin
complex-1; NCEP ATP III: National Cholesterol Education Programme Adult
Treatment Panel III; ob/ob mice: Leptin-deficient mice; SHR: Spontaneous
hypertensive rat; VLDL: Very low density lipoproteins; WHO: World Health
Organization; ZDF rats: Zucker diabetic fatty rats; ZF rats: Zucker fatty rats
Availability of data and materials
Deposition of data and data sharing are not applicable to this review as no
datasets were generated or analyzed.
SKW performed literature search and drafted the manuscript; KYC, FHS, FA,
and SIN provided critical review for the manuscript; SIN gave final approval
for the publication of this manuscript.
The authors declare no competing interests.
Consent for publication
All contributing authors declare their consent for the final accepted version
of manuscript to be considered for publication in Nutrition and Metabolism.
Ethics approval and consent to participate
Ethics approval and consent to participate are not applicable to this review.
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