*2.2.7. WBN/Kob fatty rat*

WBN/Kob fatty rat is a new congenic strain for the *fa* allele of the leptin receptor gene, and the homozygous rat provides a model of type 2 diabetes with obesity [74]. Male and female WBN/ Kob fatty rats show inflammatory cell infiltration of the pancreas and impaired glucose tolerance at 7 weeks of age. Furthermore, the rats developed diabetes with pancreatitis at 3 months of age. From 7 to 12 weeks of age, the body weight and body mass index (BMI) of male WBN/Kob fatty rats are significantly greater than those of lean rats. Female WBN/Kob fatty rats have a significantly greater body weight and BMI than lean rats from 5 to 32 weeks of age. Male WBN/Kob fatty rats show hyperinsulinemia until 8 weeks of age, but after 8 weeks their insulin levels decrease with the increase of blood glucose levels. There has been no report regarding microangiopathy and NASH.

#### **2.3. Nongenetic rodent model**

#### *2.3.1. Diet-induced obese models*

Diet-induced obesity (DIO) animal model is a created model to study obesity and its comorbidities, such as insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and atherosclerosis. In this model, an animal is fed a HF diet or HF/high sucrose or fructose diet for long term. As a result, it becomes obese with several glucose and lipid metabolic abnormalities, such as impaired glucose tolerance, increased fasting glucose level, hyperlipidemia, and hyperinsulinemia. The DIO models have become one of the most important tools for understanding the relationship of high-calorie Western diets and the development of obesity [75]. In recent years, Western diet-loaded genetic animal models have investigated to elucidate the pathophysiology of obese related diseases including NAFLD/NASH and pancreatic lesion with diabetes and develop the new therapies of the diseases [76].

HF diet-induced obesity models are commonly used to gain a greater understanding of pathophysiology in obesity and develop antiobesity drugs. When choosing the HF diet, the fat level in diet should be taken into consideration. The low-fat diet has about 10% of the calories coming from fats, while the HF diet has about 30–50% of the calories coming from fats, and the very HF diet contains greater than 50 kcal% fats. When those diets are used to induce obesity, there is a dose response for body weight [77]. The source of dietary fat is also important. The rodents fed diets with fish oil do not gain so much weight and are more insulin sensitive as compared with those fed saturated fats [78]. Moreover, there are variable responses in physiological parameters, such as glucose tolerance, insulin resistance, and blood lipid levels, on strain and gender [79]. HF diet promotes the incidence of diabetes, and induces NASH-like lesions in genetic obese models. It is reported that HF diet-fed db/db mouse shows NASH-like lesions [29].

In rodent models, high-fructose or/and sucrose diets elevates triglyceride and glucose production in liver, and this increased availability of nutrients leads to insulin resistance and hypertriglyceridemia [80]. Unless fed for a prolonged period of time, these high-fructose or/and sucrose diets do not appear to lead to excessive weight gain [81]. Since high-fructose or/and sucrose diets induce the elevation of lipid production in liver, these diets may be more effective to produce NASH-like hepatic lesions.
