cl-316243 and mirabegron

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.

Topics: Acetanilides; Adipose Tissue, Brown; Adrenergic beta-3 Receptor Agonists; Animals; Caloric Restriction; Diet, High-Fat; Dioxoles; Drug Evaluation, Preclinical; Liver; Metabolic Syndrome; Mice; Non-alcoholic Fatty Liver Disease; Thiazoles

We report the use of β3 adrenergic receptor mediated activation of rat brain frontal cortex using mirabegron (a selective β3 adrenoceptor agonist), measured by (18)F-FDG PET/CT. Another β3 agonist, CL 316,243, did not have this effect due to impermeability through the blood brain barrier (BBB), while atomoxetine, a norepinephrine transporter blocker, did increase (18)F-FDG uptake in the frontal cortex. Mirabegron exhibited a dose-dependent increase in frontal cortex (18)F-FDG uptake. These findings suggest a possible use of selective β3 adrenoceptor agonists in reversing regional glucose hypometabolism in the brain.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Blood-Brain Barrier; Dioxoles; Fluorodeoxyglucose F18; Frontal Lobe; Male; Multimodal Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Thiazoles; Tomography, X-Ray Computed