Abstract
Reproducible animal models to recapitulate the pathophysiology of non-alcoholic fatty liver disease (NAFLD) are urgently required to improve the understanding of the mechanisms of liver injury and to explore novel therapeutic options. Current guidelines recommend life-style interventions as first-line therapy for NAFLD and these types of intervention are considered standard-of-care. The current study establishes a reproducible mouse model of a life-style intervention in NAFLD using voluntary wheel running (VWR). Male C57BL/6J mice were fed a high-fat, high-carbohydrate diet (HFD) to induce NAFLD or a corresponding control diet for 12 weeks. Starting at week 9 of the obesogenic NAFLD diet, mice were randomized to either free access to a running wheel or being single caged resembling a sedentary (SED) life-style. VWR induced a transient weight reduction in HFD-fed mice up until week 10. In contrast to the SED mice, VWR mice exhibited normal ALT at the end of the intervention, while the metabolic alterations including elevated fasting glucose, insulin, triglyceride, and total cholesterol levels remained almost unchanged. Additionally, VWR prevented HFD-induced hepatic steatosis by alterations in key liver metabolic processes including the induction of fatty acid β-oxidation and lipogenesis inhibition following increased AMP-activated protein kinase (AMPK)-α activity. Phosphorylation of the serine kinase Akt in hepatic tissue was enhanced following VWR. Furthermore, VWR mice were protected from HFD-induced expression of pro-inflammatory cytokines, chemokines and liver macrophage infiltration. The SED/HFD group exhibited increasing activity of hepatic nuclear factor (NF)-κB p65, which was absent following exercise in the VWR/HFD group. In summary, in an obesogenic mouse model of NAFLD physical exercise improves fatty acid and glucose homeostasis and protects from macrophage-associated hepatic inflammation.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease at a global scale and increasing numbers are expected in Europe[1]
In foz/foz mice, which develop an obese phenotype from hyperphagia, adipose tissue inflammation, hepatic inflammation, fibrosis and muscle insulin sensitivity improved with exercise[16]
The aim was to provide a reproducible, well-characterized and applicable mouse model to reflect the current standard of care for non-alcoholic fatty liver disease (NAFLD) and which could be used in the context of studying the additional effects of therapeutic drug compounds in addition to life-style
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease at a global scale and increasing numbers are expected in Europe[1] This increase is linked to the epidemic of obesity, which arises in the context of intrinsic and extrinsic risk factors, including the type of diet and lifestyle, and genetic aspects[2]. Current US and EU-guidelines recommend weight loss through dietary changes and physical exercise[4,5] This is supported by a series of clinical studies in humans showing a reversal of steatohepatitis and regression of fibrosis with more than 7% of weight reduction[6,7,8]. We explored the applicability and effectiveness of VWR compared to sedentary life-style on changes in the hepatic metabolism and immune phenotype in a well-established obesogenic high-fat, high-carbohydrate diet (HFD) model of NAFLD18. The aim was to provide a reproducible, well-characterized and applicable mouse model to reflect the current standard of care for NAFLD and which could be used in the context of studying the additional effects of therapeutic drug compounds in addition to life-style
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
