obeticholic-acid and Weight-Gain

To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis (NASH) in obese mouse models of biopsy-confirmed NASH.. Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression (RNA sequencing) and liver lipid biochemistry.. DIO-NASH and

Topics: Animals; Biopsy; Chalcones; Chenodeoxycholic Acid; Collagen Type I; Collagen Type I, alpha 1 Chain; Diet, High-Fat; Disease Models, Animal; Galectin 3; Lipid Metabolism; Liraglutide; Liver; Liver Cirrhosis; Male; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Propionates; Time Factors; Weight Gain

Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes.. OCA (1 mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. Adipose indices, glucose tolerance, and fatty liver pathology were studied. Experiments were repeated with OCA 10 mg/kg.. OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favor of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure number in visceral adipose tissue. foz/foz mice showed more crown-like structures in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10 mg/kg.. OCA improved adipose indices, glucose tolerance, and steatosis in a milder metabolic phenotype but failed to improve these factors in morbidly obese diabetic mice. These results help explain OCA's limited efficacy to reverse human NASH.

Topics: Adiposity; Animals; Chenodeoxycholic Acid; Diet, Atherogenic; Disease Models, Animal; Fatty Liver; Female; Inflammation; Liver; Mice; Mice, Inbred NOD; Mice, Obese; Obesity; Weight Gain