*2.2.1. Zucker fatty (ZF) rat*

Zucker rats were originally bred to be a genetic model for research on obesity and hypertension. Two types of Zucker rat: a lean Zucker rat, denoted as the dominant trait (Fa/Fa) or (Fa/ fa); and the characteristically obese Zucker rat (ZF) rat, which is actually a recessive trait (fa/fa) of the leptin receptor [41, 42]. ZF rats show overt obesity with hyperphagia (mean ± standard deviation in body weights at 12 weeks of age: ZF rats, 476.4 ± 39.4 g vs. lean rats, 306.9 ± 21.9 g; mean ± standard deviation in body weights at 18 weeks of age; ZF rats, 634.8 ± 50.3 g vs. lean rats, 409.9 ± 33.5 g), and hyperinsulinemia (mean ± standard deviation in body weights at 6 weeks of age: ZF rats, 8.9 ± 1.9 ng/ml vs. lean rats, 1.1 ± 0.3 ng/ml; mean ± standard deviation in body weights at 18 weeks of age: ZF rats, 29.8 ± 12.4 ng/ml vs. lean rats, 2.7 ± 1.2 ng/ml). Blood glucose levels in ZF rats were comparable to those in lean mice from 8 to 12 weeks of age, but the glucose levels in ZF rats slightly increased as compared with those in lean rats after 12 weeks of age.

There are some reports of microangiopathy in ZF rats. Renal lesions, such as glomerular area expansion and tubular cast accumulation are observed at 24 weeks of age in ZF rats [43]. Decreased hind limb pressure pain threshold is an early indicator of insulinopenia and neuropathy, and the decreased pressure pain threshold is observed at 10 weeks of age in ZF rats [44]. Histological changes in retina of ZF rats are not reported, but some markers of inflammation, including nuclear factor (NF)-κβ, increased in the retina [45].

There are few reports of NASH-like lesions in ZF rats. Obese and hypertensive SHRSP-ZF rats treated with a high fat diet and carbon tetrachloride show the pathophysiological and histopathological characteristics of NASH [46].

## *2.2.2. Zucker diabetic fatty (ZDF) rat*

The db/db mice fed a standard diet show fatty liver, but do not represent NASH-like lesion. Like ob/ob mice, NASH-like lesion is induced in ob/ob mice by methionine-choline deficient

KK mouse, which is a spontaneously diabetic model, was established by Kondo et al. [31]. Furthermore, Nakamura et al. established KKAy mouse, which is an obese diabetic model, by

In KKAy mice, metabolic abnormalities, such as obesity, hyperinsulinemia, and hyperglycemia, are observed from 6 weeks of age, but the abnormalities are improved with aging [34].

Glomerular lesions, such as glomerulosclerosis, glomerular basement membrane (GBM) thickening, and nodular-like changes, are observed after 16 weeks of age [35]. Moreover, in retina of KKAy mice, the apoptosis cell number for retinal neural cells in the ganglion cell layer

In 1992, two inbred strains: Tsumura Suzuki obese diabetics and Tsumura Suzuki nonobese (TSNO) mice were established by selective breeding of obese mice in ddy strain [38, 39].

In the male TSOD mice, metabolic abnormalities, such as hyperinsulinemia, hyperglycemia, and dyslipidemia, are developed with the increase of body weight. In the examination of pancreatic islets, the hypertrophy is observed with the increase in number of β cells and the

In histopathological analyses in kidney, glomerular lesions, such as GBM thickening and mesangial area enlargement, are observed after 18 weeks of age [40]. The sensory neuropathy is observed after 12 months of age, and the motor neuropathy is also shown after 14 months of age. In histological analyses in sciatic nerves, a decrease in the density of nerve fibers is observed after 18 months of age. Moreover, the degenerative changes of myelinated fibers and the separation of myelin sheaths are observed with intralamellar edema and remyelination.

Zucker rats were originally bred to be a genetic model for research on obesity and hypertension. Two types of Zucker rat: a lean Zucker rat, denoted as the dominant trait (Fa/Fa) or (Fa/ fa); and the characteristically obese Zucker rat (ZF) rat, which is actually a recessive trait (fa/fa) of the leptin receptor [41, 42]. ZF rats show overt obesity with hyperphagia (mean ± standard deviation in body weights at 12 weeks of age: ZF rats, 476.4 ± 39.4 g vs. lean rats, 306.9

It is reported that NASH-like lesions are observed in KKAy mice fed a MCD diet [37].

introducing the yellow obese gene (Ay) into the KK mice [32, 33].

(MCD) and high-fat (HF) diets [29, 30].

52 Adiposity - Omics and Molecular Understanding

 *mouse*

increased with aging [36].

degranulation of β cells [38].

**2.2. Genetic rat model**

*2.2.1. Zucker fatty (ZF) rat*

*2.1.4. Tsumura Suzuki obese diabetics (TSOD) mouse*

Retinal lesions in TSOD mice are not reported.

*2.1.3. KKAy*

Zucker diabetic fatty rats derived from the ZF strain exhibit obesity with diabetes. It is reported that characteristics of the male ZDF rat maintained on Purina 5008 diet include obesity, hyperinsulinemia, and hyperglycemia beginning at 6–7 weeks of age [47]. Also, in our study, obesity and hyperinsulinemia were observed at 6 weeks of age (mean ± standard deviation in body weights: ZDF rats, 221.8 ± 9.3 g vs. lean rats, 157.6 ± 5.0 g; mean ± standard deviation in insulin levels; ZDF rats, 23.1 ± 4.3 ng/ml vs. lean rats, 1.1 ± 0.3 ng/ml). By 14 weeks of age, blood glucose levels steadily increase, reaching an average of approximately 800 mg/dl. Since the ZDF rats develop diabetes, the degree of obesity in ZDF rats is mild as compared with that in ZF rats (body weights at 9 weeks of age: ZDF rats, 314.3 ± 10.7 g vs. ZF rats, 414.6 ± 19.2 g vs. lean rats, 277.6 ± 11.9 g; body weights at 13 weeks of age: ZDF rats, 388.3 ± 17.7 g vs. ZF rats, 572.5 ± 33.2 g vs. lean rats, 352.0 ± 15.8 g).

In examination of renal lesion, pathological changes, such as glomerulosclerosis and tubulointerstitial scarring/inflammation are observed. ZDF rats at 8 weeks of age show neither glomerulosclerosis nor evidence of tubulointerstitial lesions. Renal hypertrophy is slightly observed at 12 weeks of age, and the renal hypertrophy is more prominent by 16 weeks of age [48]. Glomerulosclerosis commences after 20 weeks of age, and is associated with glomerular hypertrophy and mild mesangial expansion with podocyte injury [49]. Furthermore, tubulointerstitial scarring and inflammation are observed in ZDF rats at 22 weeks of age [50]. In ZDF rats, the retinal capillaries demonstrated hypercellularity, and the retinal capillary basement membrane thickness revealed thicker membrane as compared with lean rats [51, 52]. The blood-retinal barrier is broken at 26 weeks of age in ZDF rats, and the inflammatory state and cell death by apoptosis in retina are observed [53]. In examination of sciatic nerve functions in ZDF rats, motor nerve conduction velocity (MNCV) decreases after 12 weeks of age, and vascular relaxation of sciatic nerve is impaired after 8 weeks of age [54, 55]. In the histological analyses from 24 to 28 weeks of age after the onset of diabetes, ZDF rats do not represent sympathetic neuroaxonal dystrophy [56].

ZDF rats show fatty liver with insulin resistance, but the NASH-like lesions are not reported.
