*2.2.4. Wistar fatty rat*

In Wistar fatty rats, glucose intolerance accompanied by exaggerated insulin secretion and an increase of basal plasma glucose level are observed at 8 weeks of age, and an increase of basal plasma insulin level also increased at 14 weeks of age [64].

Kidney enlargement and glomerular hypertrophy are observed at 20 and 42 weeks of age in Wistar fatty rats [65]. In histopathological analyses, glomerular lesions, including mesangial area enlargement and tubular lesions, are observed. Intercellular adhesion molecular (ICAM)-1 expression on the glomeruli is significantly observed at 15 weeks of age, and progresses further at 29 weeks of age [66]. The other complications, such as retinopathy, neuropathy, and NASH, are not reported in Wistar fatty rats.

#### *2.2.5. Spontaneously Diabetic Torii (SDT) fatty rat*

Spontaneously Diabetic Torii fatty rats of both sexes show a significant hyperphagia and obesity after weaning, and especially, the increase of body weight in female rats is remarkable. In the male SDT fatty rats, the blood insulin levels increase after weaning, but the insulin levels decrease after 16 weeks of age. The female SDT fatty rats show hyperinsulinemia from 4 to 8 weeks of age, and the insulin levels decrease with aging. Serum glucose levels in SDT fatty rats of both sexes are elevated from 6 weeks, and the hyperglycemia is sustained for a long time afterwards.

With early incidence of diabetes mellitus, diabetic complications, such as nephropathy, retinopathy, and neuropathy, are observed at younger ages than the SDT rats [67, 68]. In histopathological analyses of the male rats, tubular lesions are observed after 8 weeks of age, and glomerular lesions are also observed after 16 weeks of age [67]. The glomerulosclerosis are observed from 16 weeks of age, and the nodular-like lesions are observed at 40 weeks of age. The renal tubular lesions, such as Armanni-Ebstein lesions and tubular dilation, are observed from 8 weeks of age. In histopathological analyses of the female rats, tubular lesions are observed from 16 weeks of age, and glomerular lesions are also observed from 32 weeks of age [68]. In lens of the male rats, histopathological changes, such as hyperplasia of epithelium and vacuolation of fiber, are observed after 8 weeks of age. Similar changes are observed after 16 weeks of age in the female SDT fatty rats. The male and female SDT fatty rats show the retinal lesions, such as folding and thickening, after 40 weeks of age [67, 68]. The decrease in caudal MNCV is observed at 24 weeks of age in the male SDT fatty rats [67]. In histopathological analyses, the male rats show the decrease in fiber number and the atrophy in myelinated nerve at 40 weeks of age.

It is reported that female SDT fatty rats fed a standard diet develop HASH-like hepatic lesions [4]. Hepatic lipid content significantly increases in female SDT fatty rats from 8 to 32 weeks of age. Histopathologically, severe hepatosteatosis accompanied by inflammation was observed from 8 weeks of age, and fibrosis started to occur at 32 weeks of age (**Figure 1**). Female SDT fatty rats have the potential to become an important animal model of NASH with diabetes and obesity.

**Figure 1.** Histological analysis of liver in female Spontaneously Diabetic Torii fatty and Sprague-Dawley (SD) rats[4]. Liver sections are from SDT fatty at 32 weeks of age (A, B) and SD at 40 weeks of age (C, D). Hematoxylin and eosin (HE) stain (A, C) and Sirius Red stain (B, D). Bar = 200 µm.

#### *2.2.6. cp/cp rat*

histological analyses from 24 to 28 weeks of age after the onset of diabetes, ZDF rats do not

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

Otsuka Long-Evans Tokushima fatty rats show an impaired glucose tolerance from 8 weeks of age, and the plasma glucose level becomes higher from 18 weeks of age [57]. In kidney of OLETF rats, pathological changes such as diffuse glomerulosclerosis and nodular lesion are observed [58]. The proliferation in mesangial cells is observed at 25 weeks of age, and the mesangial area enlargement is observed with extracellular matrix accumulation and GBM thickening after 40 weeks of age. Nodular-like lesions are observed after 65 weeks of age, and the lesions expand to the proliferated mesangial area. Tubular interstitial lesions, such as mononuclear cell filtration and fibrosis, are also observed. In the retinal capillaries after 56 weeks of age, the basement membranes are thicker, and the ratio of pericyte area decreases [59]. Regarding cataract, slight lens fiber swelling is observed in the anterior and/or posterior subcapsular regions at 40 weeks of age in OLETF rats [60]. In examination of peripheral nerve functions in OLETF rats, MNCV tends to decrease after about 40 weeks of age as compared

In NASH-like lesions of OLETF rats, there are some reports of MCD diet-induced steatohepatitis [62, 63]. The steatohepatitis is accelerated in OLETF rats after 8 weeks fed MCD diet. Furthermore, the MCD + HF diet leads to rapid development of precirrhosis in OLETF rats.

In Wistar fatty rats, glucose intolerance accompanied by exaggerated insulin secretion and an increase of basal plasma glucose level are observed at 8 weeks of age, and an increase of basal

Kidney enlargement and glomerular hypertrophy are observed at 20 and 42 weeks of age in Wistar fatty rats [65]. In histopathological analyses, glomerular lesions, including mesangial area enlargement and tubular lesions, are observed. Intercellular adhesion molecular (ICAM)-1 expression on the glomeruli is significantly observed at 15 weeks of age, and progresses further at 29 weeks of age [66]. The other complications, such as retinopathy,

Spontaneously Diabetic Torii fatty rats of both sexes show a significant hyperphagia and obesity after weaning, and especially, the increase of body weight in female rats is remarkable. In the male SDT fatty rats, the blood insulin levels increase after weaning, but the insulin levels decrease after 16 weeks of age. The female SDT fatty rats show hyperinsulinemia from 4 to 8 weeks of age, and the insulin levels decrease with aging. Serum glucose levels in SDT fatty rats of both sexes are elevated from 6 weeks, and the hyperglycemia is sustained for a long time

represent sympathetic neuroaxonal dystrophy [56].

54 Adiposity - Omics and Molecular Understanding

*2.2.3. Otsuka Long-Evans Tokusima fatty (OLETF) rat*

plasma insulin level also increased at 14 weeks of age [64].

neuropathy, and NASH, are not reported in Wistar fatty rats.

*2.2.5. Spontaneously Diabetic Torii (SDT) fatty rat*

with lean rats [61].

*2.2.4. Wistar fatty rat*

afterwards.

The LA/N-corpulent (LA/N-cp) rat is a normotensive strain derived from Koltesky's original mutant strain of the spontaneously hypertensive rat (SHR). When homozygous for the cp gene (cp/cp), the rats are hyperphagous, obesity, hyperinsulinemia, hyperglycemia, and dyslipidemia [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 rats, Wistar Kyoto rats at 19 or 20 weeks of age [70].

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

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