Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice.
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.
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
Fahrettin
F
Haczeyni
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
Laurence
L
Poekes
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
Hans
H
Wang
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
Auvro R
AR
Mridha
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
Vanessa
V
Barn
Department of Medicine, VA Medical Center, University of Washington, Seattle, Washington, USA.
W
W
Geoffrey Haigh
Department of Medicine, VA Medical Center, University of Washington, Seattle, Washington, USA.
George N
GN
Ioannou
Department of Pathology, University of Washington, Seattle, Washington, USA.
Matthew M
MM
Yeh
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
Isabelle A
IA
Leclercq
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
Narcissus C
NC
Teoh
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
Geoffrey C
GC
Farrell
D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy*; D005260:Female; D007249:Inflammation / Q000188:drug therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy*; D015430:Weight Gain
C464660:obeticholic acid; D002635:Chenodeoxycholic Acid