**3. Rat models**

three stages: (1) an early stage in response to a high-fat diet in which mice were sensitive to exogenous leptin; (2) a reduced stage of food intake when mice had an increase in milk production and still retained central leptin sensitivity; and (3) a stage of increased food intake

The hypercaloric diets (HCDs) induce hyperglycemia by inducing tolerance to glucose and increasing the levels of TAG, TNF-α and MCP-1/JEin plasma. Moreover, the HCD increases the MCP-1/JE levels in target organs such as the adipose tissue and liver. However, the HC diet also can increase TNF-α concentration in the liver [62]. It is important to mention that the HFD is more effective to induce the body weight gain as compared with the HCD because of the large storage capacities of the adipose tissue and the low satiating effects of HFD as compared to the low capacities of the glycogen stores and of the de novo

The metabolic syndrome (MetS) models are important to understand the pathophysiological basis of the MetS and how this syndrome increases the risk to the development of severe complications. The MetS animal model most commonly used is the obese mouse strains with several spontaneous mutations, which have been used for decades and are very well characterized. Moreover, inducing MetS with high-fat diet requires only some months, and these models are useful to study the effects of single genes by developing transgenic or gene knock-

This mouse homozygous mutation has an elevated serum cholesterol level of 200–400 mg/dl and they attain very high levels (>2000 mg/dl) when fed with a HFD. Normal levels of serum

The heterozygote mouse has increased the adipose tissue mass due to fat-cell hypertrophy and later develops insulin resistance and hyperglycemia. Heterozygote mice are also more susceptible to develop tumors than the normal mice, and their spleen cells cause a significantly lower graft versus host reaction. The level of malic enzyme in the liver is

These mouse models are extremely useful for research works on obesity, diabetes, dyslipidemia and hypertension. NON/ShitLtJ (nondiabetic obese) mice contain an MHC haplotype resistant to diabetes and demonstrate early impaired glucose tolerance in both genders. These

mice do not generate obesity when they are fed a diet containing 6% fat [68, 69].

and accompanied by reduced sensitivity to the central leptin [61].

112 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

outs to determine the influence of a gene on MetS [19, 65].

cholesterol in the mouse are 80–100 mg/dl [66].

*2.3.6.2. High carbohydrate-fed mice*

lipogenesis cost [63, 64].

**2.4. Other metabolic syndromes**

*2.4.1. B6.129S7-Ldlrtm1Her/J*

*2.4.2. B6.Cg-Ay/J*

elevated [67].

*2.4.3. NON/ShiLtJ*

#### **3.1. Type 2 diabetes**

#### *3.1.1. Goto-Kakizaki rats*

This rat strain was developed by the selective selection of Wistar rats for glucose intolerance over multiple generations, resulting in a polygenic strain that spontaneously develops hyperglycemia with problems in β-cell function. The hyperglycemia that these rats present is due to an increase of gluconeogenesis. Goto-Kakizaki (GK) rats have been considered one of the best nonobese T2D animal models. They are thin rats but present hyperglycemia and increased gluconeogenesis. GK rats present valuable characteristic tools that are commonly and functionally present in human diabetic patients [70, 71].

#### *3.1.2. Streptozotocin-treated rat*

This experimental model is useful for studying the regeneration of β cells in which damage to cells is caused by the injection of STZ. In this strain, regeneration of the cells is a complication, which is decreased in adult rats and thus presents a chronic pathological pattern like human T2D, glucose intolerance and low insulin in response to glucose [72, 73].

#### *3.1.3. Pancreatomized Sprague-Dawley rats*

To create this model of rats, Sprague-Dawley rats underwent simulated pancreatectomy. One week later, animals develop chronic hyperglycemia that is stable for several weeks without significant alterations in fatty acid levels. It is a strain used for the homeostatic control of the mass of the β cells to produce insulin in both the normal pancreatic growth and during the pathogenesis of diabetes. It is a multipurpose albino model, and primarily evidence of obesity is induced by diet, diabetes and oncology [74, 75].

#### **3.2. Diabetic nephropathy**

A very common treatment to obtain this model of rat is the application of streptozotocin, creating rats with diabetic conditions that develop kidney injury, similar to human diabetic nephropathy [76]. The mean urinary volume and protein excretion in these rats are greater than healthy rats; also, the kidney weight increases in this strain, as the immunoreactivity of endothelial nitric oxide in the renal cortex of these rats is much higher [77].

#### **3.3. Obesity**

#### *3.3.1. Obesity induced by diet*

#### *3.3.1.1. High-fat diet-fed rat*

The increase in weight induced by a high-energy diet causes certain defects in the neuronal response to negative feedback signals from circulating adiposity, such as insulin. Insulin resistance of peripheral tissue involves cellular inflammatory responses that are caused by excess lipids. This model consists of rats fed with a HFD, mainly provoking DIO that has become one of the most important tools to understand the interactions of diets high in saturated fat and the development of obesity [78].

[3] Lee D, Park J, Kay K, Chrlstakls N, Oltval Z, Barabásl A. The implications of human metabolic network topology for disease comorbidity. Proccedings of the National Academy of Sciences of the United States of America. 2008;**105**:9880-9885. DOI: 10.1073/

Rodent Models of Obesity and Diabetes http://dx.doi.org/10.5772/intechopen.74595 115

[4] Lera TA, Osburn AE. Genetic, endocrine & metabolic disorders. In: Osburn AE, editor. Oklahoma Notes (Clinical Sciences Review for Medical Licensure Developed at the University of Oklahoma College of Medicine). New York: NY; 1993. pp. 37-38. DOI:

[5] Taquchi A, Maruyama H, Nameta M, Yamamoto T, Marsuda J, Kulkarni AB, Yoshioka H, Ishii S.A symptomatic Fabry disease mouse model generated by inducing globotriosylceramide synthesis. The Biochmical Journal. 2013;**456**(3):373-383. DOI: 10.1042/BJ20130825

[6] Shedlovsky A, McDonald JD, Symula D, Dove WF. Mouse models of human phenylke-

[7] Resnick JL, Nicholls RD, Wevrick R. Prader-Willi syndrome animal models working group. Mammalian Genome. 2013;**24**(5-6):165-178. Published online 2013 Apr 23. DOI:

[8] Tang M, Siddiqi A, Witt B, et al. Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT)-deficient mouse model. European Journal of

[9] Jeyakumar M, Smith D, Eliott-Smith E, Cortina-Borja M, Reinkensmeier G, Butters T, Lemm T, Sandhoff K, Perry V, Dwek R, et al. An inducible mouse model of late onset Tay-Sachs disease. Neurobiology of Disease. 2002;**10**(3):201-210. DOI: 10.1006/nbdi.2002.0511

[10] Ged C, Mendez M, Robert E, Lalanne M, Lamrissi-Garcia I, Costet P, Daniel JY, Dubus P, Mazurier F, Moreau-Gaudry F, de Verneuil H. A knock-in mouse model of congenital erythropoietic porphyria. Genomics. 2006;**87**(1):84-92, ISSN 0888-7543. DOI: 10.1016/j.

[11] Raben N, Nagaraju K, Lee A, Lu L, Rivera Y, Jatkar T, Hopwood J, Plotz P. Induction of tolerance to a recombinant human enzyme, acid alpha-glucosidase, in enzyme deficient knockout mice. Transgenic Research. 2003;**12**(2):171-178. DOI: 10.1023/A:1022998010833

[12] Perl D, Schuchman E. Acid sphingomyelinase deficient mice: A model of types a and B Niemann-pick disease. Nature Genetics. 1995;**10**:288-293. DOI: 10.1038/ng0795-288

[13] Strauch O, Stypmann J, Reincheckel T, Peters C. Cardiac and ocular pathologies in a mouse model of mucopolysaccharidosis type VI. Pediatric Reearch. 2003;**54**(4):701-708.

[14] Cadone M, Polito VA, Pepe S, Mann L, D'Azzo A, Auricchio A, Ballabio A, Cosma MP. Correction of hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery. Human Molecular Genetics. 2006;**15**(7):1225-1236. DOI: 10.1093/hmg/ddl038

tonuria. Genetics. 1993;**134**(4):1205-12010. PMCID: PMC1205587

Human Genetics. 2014;**22**(10):1172-1179. DOI: 10.1038/ejhg.2014.12

pnas.0802208105

10.1007/978-1-4684-0450-0\_4

10.1007/s00335-013-9454-2

ygeno.2005.08.018

DOI: 10.1203/01.PDR.0000084085.65972.3F

#### *3.3.1.2. Cafeteria diet-induced obese rat*

In the above model, body weight increases dramatically and remains significantly elevated in CAF-fed rats. Also, hyperinsulinemia, hyperphagia, hyperglycemia and glucose intolerance are exaggeratedly elevated in CAF-fed rats compared with other models with HFD [79–81]. These models present increased adiposity and hepatosteatosis, brown fat and more inflammation in the adipose tissue and liver. A CAF-fed rat model provides a model of human metabolic syndrome with an exaggerated obesity phenotype with glucose intolerance [81]. With this model, it is possible to study the biochemical, genomic and physiological mechanisms of obesity and disease states related to metabolic diseases [79].
