Development of a new modified western diet to induce NASH with obesity and insulin resistance in mice

Background & aims: The alarming increase of obesity becomes a major global health issue. Obesity is often associated with insulin resistance, type II diabetes and non-alcoholic fatty liver disease (NAFLD) and may result in the metabolic syndrome. There are many contributing factors to obesity, but diet is one of the most relevant. Feeding studies with rodents like mice were often used to investigate the mechanisms leading to obesity and its associated co-morbidities, but the applied diets often did not induce the same phenotype like in human metabolic syndrome. High fat diets with saturated fatty acids induce obesity, insulin resistance and steatosis in mice, however mice do not develop hepatic steatosis with inflammation (NASH). Methionine- and choline-deficient diets as well as diets high in cholesterol and cholate induce NASH, but mice lose weight and are not insulin-resistant. Here we designed a new modified western diet that caused obesity, insulin resistance and NASH in mice.

Methods: Male C57BL/6 mice were fed chow a high fat diet (HFD) (25 g/100 g lard) or a modified western diet (mWD) containing high fat (25 g/100 g soybean oil) and cholesterol for 20 weeks.

Results: Mice fed a mWD significantly gained weight and increased their body fat mass 2.5-fold compared to chow fed mice. In an oral glucose intolerance test mice fed a mWD or a HFD were glucose intolerant with slightly increased insulin levels. In comparison to chow fed animals, serum parameters for liver inflammation like ASAT, ALAT and cholinesterase were elevated after feeding a mWD but after feeding HFD. Histological scoring of the liver revealed steatohepatitis (NASH) in mWD-fed mice and only steatosis without inflammation in HFD-fed mice. Gene expression analysis detected an up-regulation of chemokines (CCL2), pro-inflammatory cytokines (IL-1β, TNFα) and immune cell infiltration (CD68) in livers of mWD-fed, but not HFD-fed mice. Still, both mWD and HFD feeding was accompanied by enhanced expression of markers of hepatic insulin resistance (PTP1B, FGF21).

Conclusion: In contrast to mice, which receive a high fat diet based on saturated fatty acids, mice fed a modified western diet with high amounts of unsaturated fatty acids and cholesterol developed obesity, insulin resistance and hepatic inflammation. Mice fed a mWD therefore are a potential better model for human metabolic syndrome and NASH than mice fed a HFD.

Corresponding author: Henkel, Janin

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