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

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 fact...

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Bibliographic Details
Published in:Laboratory investigation 2019-01, Vol.99 (1), p.4-16
Main Authors: Poekes, Laurence, Gillard, Justine, Farrell, Geoffrey C., Horsmans, Yves, Leclercq, Isabelle A.
Format: Article
Language:English
Subjects:
Acetanilides - pharmacology
Acetanilides - therapeutic use
Adipose tissue
Adipose tissue (brown)
Adipose Tissue, Brown - drug effects
Adrenergic beta-3 Receptor Agonists - pharmacology
Adrenergic beta-3 Receptor Agonists - therapeutic use
Animal models
Animals
Body weight
Body weight loss
Caloric Restriction
Cirrhosis
Diabetes mellitus
Diet
Diet, High-Fat - adverse effects
Dietary restrictions
Dioxoles - pharmacology
Dioxoles - therapeutic use
Drug Evaluation, Preclinical
Fatty liver
Glucose
Glucose tolerance
High fat diet
Inflammation
Injury prevention
Lipids
Liver
Liver - drug effects
Liver cirrhosis
Liver diseases
Metabolic syndrome
Metabolic Syndrome - drug therapy
Mice
Non-alcoholic Fatty Liver Disease - diet therapy
Non-alcoholic Fatty Liver Disease - drug therapy
Non-alcoholic Fatty Liver Disease - etiology
Pathology
Rodents
Steatosis
Thermogenesis
Thiazoles - pharmacology
Thiazoles - therapeutic use
Weight loss
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Summary: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. Defective thermogenic response to calorie overload contributes to obesity and, in foz/foz mice, to nonalcoholic steatohepatitis (NASH). Activation of brown adipose tissue function by b3AR-agonists together with moderate calorie restriction improves the obese phenotype and resolves NASH pathology. This identifies the brown adipose tissue as a target for adjuvant therapy for NASH.
ISSN:0023-6837
1530-0307
DOI:10.1038/s41374-018-0120-x