Background: Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease in children and young people. NAFLD can progress to cirrhosis and is associated with cardiometabolic morbidity and mortality, often requiring liver transplant. Brown adipose tissue (BAT) expends energy for thermogenesis when activated by pharmacological agents, e.g. β3-adrenergic receptor agonists, or environmental signals such as cold exposure. We hypothesise that intermittent cold exposure (ICE), unlike persistent cold exposure, is clinically a feasible, non-invasive intervention which could be used alongside conventional therapies for NAFLD and associated cardiometabolic risk factors.
Methods: C57BL/6 mice were fed normal chow (NC) or a high-fat diet for 6 weeks until the mice were confirmed diet-induced obese (DIO) by significant weight gain and glucose intolerance. Mice were then exposed to 6°C for 3 hours over 4 consecutive days or housed at normal laboratory temperature (21°C) and sacrificed 24 h following the last cold exposure. Serum and hepatic lipid biochemistry were measured, alongside hepatic lipid droplet size and expression of fatty acid metabolism enzymes in BAT and liver.
Results: ICE significantly improves obesity and fatty liver disease markers in DIO mice. ICE reduced DIO mouse body weight and normalized liver weight relative to those housed at normal laboratory temperature (21°C). ICE significantly reduced hepatic lipid droplet content in DIO mice by 47%, including a 49% reduction in free fatty acid concentrations (P < 0.05), to levels comparable to NC mice. These changes correlated with a 2-fold increase in protein expression of BAT mitochondrial fatty acid oxidation enzyme, hydroxyacyl-CoA dehydrogenase (P < 0.001), whereas no change was observed in hepatic expression (P = 0.15).
Conclusion: This study demonstrates that in a mouse model, ICE is a feasible intervention to improve steatosis and associated metabolic markers of fatty liver disease through upregulation of BAT-mediated metabolism of lipids.