Effects of thermoneutral housing in a mouse model of non-alcoholic fatty liver disease
Résumé
Background and aims: Non-Alcoholic Fatty Liver Disease (NAFLD) including steatosis and its more advanced stage Non-Alcoholic SteatoHepatitis (NASH) is positively correlated with obesity and type 2 diabetes. Since there is currently no pharmacological treatment approved for NAFLD, developing relevant preclinical models to study the inflammatory component and the progression to the irreversible stages of the disease (NASH) is necessary. The early steps of NAFLD depend on excessive accumulation of fatty acids. The majority of lipids that accumulate in NAFLD originate from white adipose tissue (WAT) lipolysis. In this work, we evaluated the combined effect of thermoneutral housing and diet-induced obesity on obesity, diabetes and NAFLD. We also investigated the consequences for the metabolic dialogue between the liver and adipose tissues. Materials and methods: All experiments were carried out in accordance with the European Guidelines for the Care and Use of Animals for Research Purposes. C57Bl6/J male mice were housed at room temperature (RT=22°C, n=32) or at thermoneutrality (TN=30°C, n=32). In each group, half of the mice were fed a control diet (Chow, CD, n=16) or an obesogenic diet (Western Diet, WD, n=16) for 13 weeks. Half of mice housed at TN were treated with a β 3 -adrenergic receptor agonist (CL316243) to induce white adipose tissue lipolysis. Glucose and lipid metabolism were studied using glucose tolerance test and plasma biochemistry. Liver phenotype was analyzed by quantification of hepatic triglycerides and histology. Liver gene expression profiles was measured by microarray. Brown adipose tissue activation (BAT) was investigated by histology and gene expression profiling. Results: WD-fed mice showed significantly higher obesity, fasting blood glucose and HOMA-IR at TN than at RT. The number of hepatic genes significantly modulated upon WD was more than 2-fold higher in TN-housed mice compared to RT-housed mice with an overexpression of genes involved in inflammation and fibrosis in TN-vs. RT-housed mice. Accordingly, TN-housing induced signif- icantly higher hepatic triglyceride accumulation (steatosis), inflammation and fibrosis upon WD compared to RT-housed mice. In addition, stimulation with β 3 -adrenergic receptor agonist revealed that some hepatic responses such as FGF21 and ketone bodies production dependent on WAT lipolysis were intact. However, WD-fed mice showed significant changes in other hepatic gene expression, insulin level, altered BAT morphology and reduced expression of BAT activation markers upon β 3 -adrenergic stimulation. Conclusion: Thermoneutral housing exacerbates the metabolic and hepatic disturbances induced by a WD. This pre-clinical model reca- pitulates the different stages of the transition from steatosis to NASH in rodents and might be of medical interest for the study of new pharmacological molecules. It is known that β 3 -adrenergic stimulation results in a systemic response which involves WAT lipolysis, insulin secretion, fatty acid-mediated changes in liver gene expression and BAT activation. Our data reveal that in obesity, diabetes and NAFLD this inter-organ dialogue is altered.
