Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Abstract

The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide. Conclusion: Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents.

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

“…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.…”

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

“…While in response to a chow diet, MS-NASH mice [59] (formerly known as FATZO/Pco mice, a cross between wild-type C57BL/6J and obesity-prone AKR/J mice [60]) spontaneously develop obesity [61], feeding these mice a Western-type fructose-supplemented diet resulted in progressive features of NAFLD/NASH [59,62]. Given the concomitant dysregulation in metabolic status, these data point towards a novel tool for studying NAFLD with high translational value.…”