Increased non-shivering thermogenesis had preventive but no therapeutic effects on non-alcoholic steatohepatitis

Abstract

Background and Aims: Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease spectrum. No treatment has been proven efficacious except for lifestyle modifications coupling physical exercise with weight reduction. We recently identified defective adaptive thermogenesis as a contributing factor to obesity and metabolic syndrome in foz/foz mice. We now aim to test whether increased non-shivering thermogenesis prevent and/or improve pre-existing NASH in mice. Methods: A HFD for 4 or 8weeks induced a metabolic syndromewith fatty liver or NASH, respectively in male foz/foz mice. Mice were randomized and treated with a beta 3-adrenergic receptor (B3AR) POSTER PRESENTATIONS Journal of Hepatology 2017 vol. 66 | S333–S542 S433 agonist (CL-316,243–1mg/kg/day) to enhance thermogenic capacities or with vehicle (untreated) together with HFD for 2 or 4 weeks, respectively. C57Bl6 and db/db mice were fed a methionine and choline deficient (MCD) diet to induce NASH and treated with B3AR agonist for 4 additional weeks (n = 6–8/group). Results: In foz/foz mice with metabolic syndrome and liver steatosis, B3AR agonist improved brown adipose tissue (BAT) function assessed by increased cAMP and UCP1 BAT contents and upregulation of thermogenic genes (UCP1, DIO2). It also caused browning of white adipose tissue. All this resulted in increased tolerance to cold exposure and was associated with a better glucose tolerance (p < 0.05), a decreased NAS score (2 ± 1.3 vs 3.7 ± 1.6; p < 0.05) and decreased transaminases levels (p < 0.05) with no change in body weight. When treatment was initiated after the onset of NASH (NAS score = 5 ± 1.15) in foz/foz mice, B3AR agonist treatment restored BAT function, induced a slight 2%weight loss (p < 0.05), increased glucose tolerance (p < 0.001) but had no on impact liver pathology (NAS score 5.6 ± 2.1 vs 6.7 ± 1.3; ALT 286 ± 117 vs 396 ± 190 U/L) compared to untreated mice. Similarly, B3AR agonist has no therapeutic effect when administrated for 4 weeks on MCD-induced NASH whether in C57Bl6 or in obese and diabetics db/db mice. Conclusions: B3AR agonist treatment improved BAT function and glucose tolerance, prevented the progression of a simple steatosis to NASH but was not sufficient to cure a pre-established NASH, supporting previous observation that control over metabolic syndrome is insufficient to treat NASH. In our study, B3AR agonist caused no major weight loss and therefore, it will be of interest to evaluate whether BAT stimulation offers an additional advantage over weight loss therapy in NASH management. Show more