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Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis

Laboratory Investigation (2018) | Download Citation


Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.

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The authors thank Natacha Feza-Bingi (UCL, Brussels, Belgium) and Mathilde Beka (UCL, Brussels, Belgium) for animal breeding, genotyping, and care; and Anne Bol (UCL, Brussels, Belgium) for PET/CT imaging. The work was financially supported by “Communauté française de Belgique – Actions de Recherche Concertées” (12/17-047) and unrestricted grants from Bristol-Myers Squibb Belgium, MSD Belgium, Gilead Belgium, Janssen Pharmaceutica Belgium, and Abbvie Belgium.

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  1. Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium

    • Laurence Poekes
    • , Justine Gillard
    •  & Isabelle A. Leclercq
  2. Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, ACT, Australia

    • Geoffrey C. Farrell
  3. Gastroenterology Unit, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

    • Yves Horsmans


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The authors have no conflict of interest in relation to this work to disclose.

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Correspondence to Isabelle A. Leclercq.

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