**3. Antiobesity drugs**

mia [69]. The levels of body weight, systolic blood pressure, serum TG and blood glucose in cp/cp rats being 1.43, 1.65, 25.4, and 1.25 times, respectively, compared with those in control

Renal lesions, including glomerular and tubular changes, are observed in cp/cp rats, from 24 to 36 weeks of age [71]. In light microscopy, cp/cp rats develop glomerular lesions, characterized by glomerular hypertrophy, mesangial expansion, and focal and segmental glomerular sclerosis. Also, interstitial lesions, such as tubular hypertrophy and atrophy, inflammation cell infiltration, and thickening of tubular basal membrane, are prominent. In electron microscopy, thickening of glomerular basal membrane (GBM) and glomerular epithelial injuries, such as pseudocyst formation, vacuolization, detachment from the GBM, podocyte depletion, and foot process effacement are observed. Retinal lesions in cp/cp rats are also reported [72]. In cp/cp rats at 24 weeks of age, partial capillary obstruction and acellular, tortuous, irregular capillaries are observed by light microscope. In electron microscopy, thickening and irregularity of the basement membrane along with remnants of pericytes or so-called ghost pericytes are

It is reported that cp/cp rats fed a diet of AIN-93G show NASH-like lesions after 23 weeks [73].

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

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

rats, Wistar Kyoto rats at 19 or 20 weeks of age [70].

56 Adiposity - Omics and Molecular Understanding

observed. Neuropathy in cp/cp rats is not reported.

regarding microangiopathy and NASH.

**2.3. Nongenetic rodent model**

*2.3.1. Diet-induced obese models*

*2.2.7. WBN/Kob fatty rat*

#### **3.1. Protein tyrosine phosphatase 1B inhibitor**

PTP1B is a 50-KD cytosolic tyrosine dephosphorylase consisting of 435 amino acids that are ubiquitously expressed in organs throughout the body. Originally, PTP1B was known to dephosphorylate phosphorylated insulin receptor (IR) β subunit and IR substrate in order to negatively regulate insulin signal transmission [82]. PTP1B is also reportedly related to the negative regulation of leptin signal transmission and to dephosphorylate phosphorylated signal transducer and activator of transcription 3 (STAT3) [83]. Therefore, PTP1B inhibitors are expected to be developed as antiobesity drugs as well as antidiabetes drugs. PTP1B KO mice are protected from diet-induced obesity, and neuronal PTP1B KO mice also show increased leptin signaling in the hypothalamus, reductions in feeding, body weight and adiposity, and increases in energy expenditure [84].

Ito et al. reported the antiobesity effects of JTT-551, which was developed as a novel PTP1B inhibitor [85, 19]. The single administration of JTT-551 and leptin enhanced STAT3 phosphorylation in the hypothalamus of DIO mice, and the food intake resulted in a significant reduction as compared with that in the control group. The food intake in JTT-551 administration without leptin treatment did not result in the reduction. DIO mice at 8 weeks of age were given 10 or 100 mg/kg of JTT-551 contained in food for 6 weeks and the chronic effects were investigated. In the JTT-551 100 m/kg group, the cumulative calorie intake tended to decrease from 2 weeks after treatment and significantly decreased from 6 weeks after treatment. Body weight in JTT-551 treatment tended to decrease dose-dependently and the decreases in the JTT-551 100 mg/kg group were significant from 5 to 6 weeks after treatment. PTP1B inhibitor is a unique target that shows not only an improvement of glucose metabolism but also an antiobesity effect possibly by enhancement of leptin signaling.
