Voluntary exercise in mice fed an obesogenic diet alters the hepatic immune phenotype and improves metabolic parameters – an animal model of life style intervention in NAFLD

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.

Exercise-Induced Benefits on Glucose Handling in a Model of Diet-Induced Obesity Are Reduced by Concurrent Nicotinamide Mononucleotide

“…Potential explanations for this are that in the present study the HFD did not reduce liver NAD + levels, that the dose of NMN was insufficient, or there was too little fat accumulation in the liver, as our previous work demonstrated NMN only reduced liver triglycerides in the most obese mice, following exposure to HFD both in utero and post-weaning [36]. Consistent with animal and human studies [37,38] our data show exercise reduced hepatic triglyceride levels, potentially through increasing beta-oxidation and inhibiting lipogenesis [37,39,40]. NMN appeared to dampen this benefit and other measures in this study, explored below.…”

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

“…Gehrke et al [125] recently investigated eight to ten week-old wild-type C57BL/6 male mice that were fed an obesogenic diet (fructose/glucose supplementation in drinking water). In this study, mice were either challenged with voluntary wheel running or were kept on a sedentary lifestyle intervention [125].…”

“…Gehrke et al [125] recently investigated eight to ten week-old wild-type C57BL/6 male mice that were fed an obesogenic diet (fructose/glucose supplementation in drinking water). In this study, mice were either challenged with voluntary wheel running or were kept on a sedentary lifestyle intervention [125]. Similar to well-known forced exercise models [126], voluntary wheel running protected these mice from HFD-induced pro-inflammatory and pro-fibrogenic states, as shown by decreased hepatic macrophage infiltration and improved fatty acid and glucose homeostasis.…”

“…These data were in line with Kawanishi et al [126], showing that exercise training reduced macrophage infiltration and adipose tissue inflammation by attenuating neutrophil infiltration in HFD-fed C57BL/6 mice. Thus, it is very likely that physical exercise exhibits beneficial effects and compensates for shortcomings of certain therapeutic approaches [125,126]. Models with circadian oscillations (e.g., Per1/2 -/or liver-specific Bmal1 knockout mice)…”

Dietary Intervention Accelerates NASH Resolution Depending on Inflammatory Status with Minor Additive Effects on Hepatic Injury by Vitamin E Supplementation

“…As disease prevalence is rapidly increasing, so is the need for finding effective pharmacological treatment modalities [ 4 , 16 ]. First line management in patients constitutes life style changes, where dietary restrictions and weight loss has been shown to induce positive effects on hepatic hallmarks of NASH in both patients and animal models [ 17 , 18 , 19 , 20 ]. However, to achieve an improvement of a minimum of “1” in hepatic inflammatory and fibrosis score, sustained weight loss above 10% has been shown to be necessary [ 21 , 22 ].…”