Short- and long-term effects of high-fat diet feeding and voluntary exercise on hepatic lipid metabolism in mice Saki Yoshimura a , Shihoko Nakashima b , Yuki Tomiga c , Shotaro Kawakami d , Yoshinari Uehara b, c , Yasuki Higaki b, c, * a Graduate School of Sports and Health Science, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka, 814-0180, Japan b Faculty of Health and Sports Science, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka, 814-0180, Japan c The Fukuoka University Institute for Physical Activity, 8-19-1 Nanakuma, Johnan-ku, Fukuoka, 814-0180, Japan d Department of Rehabilitation, Fukuoka University Chikushi Hospital, 1-1-1 Zokumyoin, Chikushino, Fukuoka, 818-0067, Japan article info Article history: Received 24 October 2018 Accepted 5 November 2018 Available online xxx Keywords: High-fat diet Voluntary exercise Fatty liver disease Time dependent abstract Exercise is an effective tool for improving high-fat diet induced fat accumulation in the liver. However, the process of fat accumulation in the liver and the efficacy of early intervention with exercise remain unclear. The aim of this study was to investigate the short- and long-term effects of high-fat diet feeding and voluntary exercise on hepatic lipid metabolism in mice. Male C57BL/6J mice aged 6 weeks were randomly divided into two groups, the control group and high-fat diet feeding group, and fed a normal or high-fat diet for 12 weeks. After 6 weeks, mice in the high-fat diet feeding group were further divided into no exercise group and voluntary exercise training group, with mice in the exercise group provided a running wheel for 6 weeks. Body weight, food intake, and wheel rotation counts were measured every second day for 12 weeks. We found that voluntary exercise for 1 week (short-term exercise) significantly reduced fat accumulation in the liver by downregulating the expression of hepatic lipogenesis-associated proteins and upregulating the expression of hepatic lipolysis-associated proteins, as determined through western blotting and histology. Further, voluntary exercise for 6 weeks (long-term exercise) down- regulated the expression of hepatic lipogenesis-associated proteins. These results suggest that hepatic lipogenesis and/or hepatic lipolysis mediate the beneficial effects of voluntary exercise on hepatic fat accumulation. © 2018 Elsevier Inc. All rights reserved. 1. Introduction There has been a recent increase in diet-induced fatty liver disease worldwide. In Japan, the number of patients with fatty liver disease increased 2.7-fold between 1994 and 2004 [1], and, glob- ally, prevalence has been predicted at about 25% [2,3], indicating that this increase is not only a concern for Japan [4]. Fat accumu- lation in the liver causes hepatic dysfunction, inflammation and fibrosis, finally leading to cirrhosis and hepatocellular carcinoma. Early detection of fat accumulation in the liver and early inter- vention strategies (e.g., exercise) are important to prevent and improve fatty liver disease. To determine the process of fat accu- mulation in the liver and the efficacy of early intervention through exercise, it is necessary to examine the effects of a short- and a long-term intervention under high-fat diet (HFD) feeding with exercise training. Furthermore, it is important to assess how the balance between lipogenesis and lipolysis of fat in the liver is altered during the stages of fat accumulation. Fat accumulation in the liver by HFD feeding has been linked with enhanced lipogenesis and suppressed lipolysis. A previous study showed that short-term HFD feeding increases mitochondrial b-oxidation and lipolysis in the liver [5]. Others have shown that the suppression of lipolysis [6] and the enhancement of lipogenesis [7] occur in the liver after 2 weeks of HFD feeding, resulting in an increase in fat accumulation in the liver. Kurosaka and colleagues [8] examined the effects of HFD feeding for 8 weeks and reported that HFD causes a decrease in mitochondrial b-oxidation in the liver, leading to a downregulation in lipolysis and an upregulation in lipogenesis. Physical activity and exercise are effective tools for improving obesity [9, 10] and hepatic function by reducing fat accumulation in Abbreviations: HFD, high fat diet. * Corresponding author. E-mail address: higaki@fukuoka-u.ac.jp (Y. Higaki). Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc https://doi.org/10.1016/j.bbrc.2018.11.026 0006-291X/© 2018 Elsevier Inc. All rights reserved. Biochemical and Biophysical Research Communications xxx (xxxx) xxx Please cite this article as: S. Yoshimura et al., Short- and long-term effects of high-fat diet feeding and voluntary exercise on hepatic lipid metabolism in mice, Biochemical and Biophysical Research Communications, https://doi.org/10.1016/j.bbrc.2018.11.026