Oral Presentation Australian & New Zealand Obesity Society 2015 Annual Scientific Meeting

Obeticholic acid improves adipose morphometry/inflammation and metabolic function in diet-induced obesity but not in diabetic mice with nash (#30)

Fahrettin Haczeyni 1 , Laurence Poekes 2 , Vanessa Barn 1 , Auvro Mridha 1 , Matthew Yeh 3 , Geoffrey Haigh 4 , George Ioannou 4 , Narci Teoh 1 , Geoffrey Farrell 1
  1. Medical School, The Australian National University, Canberra, ACT, Australia
  2. Institute of Experimental and Clinical Research, Catholic University of Leuven, Brussels, Belgium
  3. Department of Pathology, University of Washington, Seattle, WA, USA
  4. VA Medical Center, University of Washington, Seattle, WA, USA

Obeticholic acid (OCA) reduces body weight and improves non-alcoholic fatty liver disease (NAFLD) activity score in patients with steatohepatitis (NASH), but the protective mechanisms and impact on NASH remains unresolved. There are complex interactions between adipose morphology and inflammation, glucose metabolism and NAFLD severity.

Alms1 mutant foz/foz mice exhibit hyperphagic obesity and hyperglycemia when fed an atherogenic diet (23% fat, 0.2% cholesterol). We studied the effects of OCA (10 mg/kg diet) on multiple adipose depots (periovarian/lumbar/mesenteric) and their stromal vascular fractions (SVFs), including morphometry and inflammation analyses. We particularly measured the number of macrophage coalescence as “crown-like structures” (CLS) and macrophage polarization. Metabolic and liver indices were also studied.

OCA reduced body weight in wildtype but not foz/foz mice. All mice had post-prandial hyperglycemia, which was worse in foz/foz mice; OCA corrected hyperglycemia only in wildtype mice. OCA reduced liver mass and steatosis in wildtype mice, but not in foz/foz. Atherogenic-fed wildtype mice developed milder forms of NAFLD, whereas foz/foz mice develop absolute NASH. Adiposity was less in OCA-treated wildtype mice in all compartments. OCA altered subcutaneous adipose morphometry in wildtype mice, with more small (healthy) adipocytes. In foz/foz mice, the average adipocyte volume did not change, but OCA decreased percentage of large adipocytes (<8000 µm2). The number of adipose CLSs decreased with OCA in wildtype but not foz/foz mice. OCA caused phenotypic switch to anti-inflammatory macrophages in wildtype adipose SVFs. Pro-inflammatory macrophages remained abundant in foz/foz mice.

OCA improved visceral adiposity and reduced adipose inflammation in atherogenic-fed wildtype mice, associated with improved glucose tolerance and NAFLD. Conversely, in atherogenic-fed foz/foz mice with established NASH, OCA regimen had no impact on the severer metabolic phenotype. These results may help explain the borderline efficacy of OCA against human NASH, with some improvement in steatosis score but no reversal of NASH pathology.