Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse

Abstract

Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia. Since many clinical studies have established a close link between higher body weight and the development of type 2 diabetes, we investigated whether time to progression to type 2 diabetes or disease severity in FATZO mice was dependent on weight gain in young animals. Our results indicate that lighter animals developed metabolic disturbances much slower and to a lesser magnitude than their heavier counterparts. Consumption of a diet containing high fat, accelerated weight gain in parallel with disease progression. A naturally occurring and significant variation in the body weight of FATZO offspring enables these mice to be identified as low, mid and high body weight groups at a young age. These weight groups remain into adulthood and correspond to slow, medium and accelerated development of type 2 diabetes. Thus, body weight inclusion criteria can optimize the FATZO model for studies of prevention, stabilization or treatment of type 2 diabetes.

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

“…The present data con rmed our previous report that MS-NASH mice possess all features of metabolic diseases [19,20] and NAFLD/NASH when on WDF [22], however, with a relatively long induction duration (~20 weeks), and moderate liver brosis (pathology score ~1). Low dose CCl 4 (0.08 mL/kg) accelerated the progression of NASH in ~8 weeks and exacerbated liver brosis by raising the pathology score to ~4, but did not signi cantly affect other liver pathology criteria of the NAS score in MS-NASH mice on WDF.…”

“…Male MS-NASH mice (formally FATZO) [18] were developed by Crown Bioscience as a new generation of mouse model presenting high translatable phenotypes in human diseases such as obesity, metabolic disorder, diabetes and NAFLD/NASH [19,20,22]. The animals for this study were bred and then housed individually in IVC cages (Taicang, China) or open ventilated cages (Indianapolis, IN) with room temperature maintained at 22-26 °C, a 12-hour light cycle (06:00-18:00), and distilled water ad libitum.…”

“…The is a new generation of animal model that spontaneously develops obesity, metabolic disorders and hyperglycemia under a standard chow diet in the presence of an intact leptin signaling pathway. They begin to exhibit glucose intolerance, insulin resistance and hyperinsulinemia as early as 6 weeks of age, but does not spontaneously develop NASH/NAFLD [19,20]. Western (high fat) diet supplemented with fructose (WDF) has been reported to induce NASH/NAFLD in murine models [11,16,21].…”

Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction

“…While the ob/ob mouse exhibits key aspects of human metabolic disease and, importantly, develops diet-induced NASH with consistent grade 2-3 fibrosis, most humans with NAFLD/NASH are likely hyperleptinemic as opposed to leptin-deficient. We therefore investigated the FATZO mouse, an inbred polygenic cross of AKR/J and C57BL6J strains with a predisposition to obesity and insulin resistance, but intact leptin axis[ 14 , 15 ].…”

“…Hepatic mitochondrial function and oxidative stress in metabolically-relevant, pre-clinical models of simple fatty liver vs NASH have not been fully assessed. Here, two pre-clinical mouse models of simple steatosis and NASH were investigated: ob/ob mice on NASH-inducing AMLN diet[ 13 ], and the recently described polygenic FATZO mouse which develops high-fat diet-induced obesity and impaired glucose tolerance and which retains an intact leptin axis[ 14 , 15 ]. Importantly, these models are readily available and rapidly and consistently develop clinically relevant disease.…”