The role of adipose tissue in the pathogenesis of non-alcoholic steatohepatitis

Abstract

The prevalence of the metabolic disorders, type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH) are rapidly increasing worldwide in parallel with increasing obesity rates. These obesity-related conditions are also associated with adipose tissue inflammation and dysfunction. In response to overfeeding, some individuals develop healthy obesity and are resistant to obesity-associated metabolic diseases; whereas others readily develop one or more of these disorders. The reasons for such disparity in responses to overfeeding are unclear. Fat aussie (foz/foz) mice have a spontaneous mutation in the Alms 1 gene, causing defective appetite regulation, overfeeding and obesity. Interestingly, after 24 weeks of age on high fat (HF) diet, female Balb/c foz/foz mice develop healthy obesity; whereas NOD.B10 foz/foz mice on HF diet develop obesity and both T2D and NASH. HF-fed NOD.B10 foz/foz mice also exhibit a relative defect in adipose tissue expansion (termed adipose restriction) compared to Balb/c foz/foz mice. We hypothesized that a primary defect in the adipose tissue response to overfeeding in the NOD.B10 foz/foz mice underlies its propensity to develop T2D and NASH, and that this defect would not be observed in diabetes and NASH-resistant Balb/c mice. The major aim of this study therefore, was to determine the role of adipose tissue in the development of T2D and NASH using NOD.B10 and Balb/c foz/foz mice. Female NOD.B10 and Balb/c wild-type and foz/foz mice were fed on chow or HF diet over an 8 week period, and mice length, weight, body composition, adipose tissue depots and liver weights, fed-state blood glucose and plasma insulin, intraperitoneal glucose tolerance, hepatic triacylglyceride (TG) content, plasma alanine transaminase, plasma adiponectin and monocyte chemoattractant protein-1 (MCP-1) levels, as well as the expression of genes associated with differentiation, function, inflammation and adipokine/chemokine production were measured at various time-points from 4 to 12 weeks of age. Obesity developed in HF-fed foz/foz mice of both strains. However, only HF-fed NOD.B10 foz/foz mice developed hyperglycaemia (from 6 weeks of age), profound hyperinsulinaemia (from 8 weeks), glucose intolerance (from 5 weeks), hepatomegaly with increased TG content (from 8 weeks) and NASH (at 12 weeks of age), whereas HF-fed Balb/c foz/foz mice only developed obesity and hepatic steatosis. Adipose tissue restriction was not clearly evident by 12 weeks of age, and although changes in the majority of measured adipose tissue genes at the mRNA level were similar in HF-fed foz/foz mice of both NOD.B10 and Balb/c strains, the diabetes prone HF-fed NOD.B10 foz/foz mice had increased expression of inflammation genes (in particular MCP-1) at 12 weeks of age. Taken together, glucose intolerance and hyperinsulinaemia precede the development of both adipose tissue inflammation and NASH in HF-fed NOD.B10 foz/foz mice. The results suggest, therefore, that adipose tissue most probably plays a secondary role in the pathogenesis of metabolic disorders associated with obesity. However, these findings do not preclude an important role of adipose inflammation and dysfunction in the progressive worsening of metabolic disorders in susceptible subjects. Show more