Effects of intermittent fasting on liver physiology and metabolism in mice

Ma,Jianbo; Cheng,Yan; Su,Qiang; Ai,Wen; Gong,Ling; Wang,Yueying; Li,Linhao; Ma,Zhongren; Pan,Qiuwei; Qiao,Zilin; Chen,Kan

doi:10.3892/etm.2021.10382

Effects of intermittent fasting on liver physiology and metabolism in mice

Authors:
- Jianbo Ma
- Yan Cheng
- Qiang Su
- Wen Ai
- Ling Gong
- Yueying Wang
- Linhao Li
- Zhongren Ma
- Qiuwei Pan
- Zilin Qiao
- Kan Chen
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Affiliations: Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, Gansu 730030, P.R. China, Department of Cardiology, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, Guangdong 518102, P.R. China, Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China
Published online on: July 5, 2021 https://doi.org/10.3892/etm.2021.10382
Article Number: 950
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

A broad spectrum of health benefits from intermittent fasting have been reported in studies on animal models and human subjects. However, the underlying mechanisms of these beneficial effects remain largely elusive. The present study aimed to explore the effects and potential mode of action of intermittent fasting in mouse models with a focus on the liver. C57BL/6 mice were subjected to intermittent fasting or ad libitum feeding as controls. It was determined that 12 h of daily intermittent fasting for 30 days significantly reduced the cumulative food intake compared with that in mice with ad libitum feeding. Fasting resulted in a significantly reduced liver mass but only had a minimal effect on bodyweight. The effects on the liver by 30 days of fasting were not reversed by subsequent ad libitum refeeding for 30 days. Among the measured blood biochemical parameters, the levels of blood glucose were decreased, while the levels of alkaline phosphatase were increased in fasting mice. Of note, targeted metabolic profiling revealed global elevation of metabolites in the livers of fasting mice. These metabolic molecules included adenosine triphosphate, nicotinamide adenine dinucleotide phosphate (NADP), reduced NADP and succinate, which are essentially involved in the citric acid cycle and oxidative phosphorylation. Thus, it was concluded that daily 12 h of intermittent fasting for one month significantly reduced the liver weight of mice, which is associated with enhanced liver metabolism.

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1	de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN and Madeo F: The search for antiaging interventions: From elixirs to fasting regimens. Cell. 157:1515–1526. 2014.PubMed/NCBI View Article : Google Scholar
2	Longo VD and Panda S: Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab. 23:1048–1059. 2016.PubMed/NCBI View Article : Google Scholar
3	Mitchell SJ, Bernier M, Mattison JA, Aon MA, Kaiser TA, Anson RM, Ikeno Y, Anderson RM, Ingram DK and de Cabo R: Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metab. 29:221–228.e3. 2019.PubMed/NCBI View Article : Google Scholar
4	Lessan N and Ali T: Energy metabolism and intermittent fasting: The Ramadan perspective. Nutrients. 11(1192)2019.PubMed/NCBI View Article : Google Scholar
5	Patterson RE, Laughlin GA, LaCroix AZ, Hartman SJ, Natarajan L, Senger CM, Martínez ME, Villaseñor A, Sears DD, Marinac CR and Gallo LC: Intermittent fasting and human metabolic health. J Acad Nutr Diet. 115:1203–1212. 2015.PubMed/NCBI View Article : Google Scholar
6	Harney DJ, Hutchison AT, Hatchwell L, Humphrey SJ, James DE, Hocking S, Heilbronn LK and Larance M: Proteomic analysis of human plasma during intermittent fasting. J Proteome Res. 18:2228–2240. 2019.PubMed/NCBI View Article : Google Scholar
7	Patterson RE and Sears DD: Metabolic effects of intermittent fasting. Annu Rev Nutr. 37:371–393. 2017.PubMed/NCBI View Article : Google Scholar
8	Ahmad S and Chowdhury TA: Fasting during Ramadan in people with chronic kidney disease: A review of the literature. Ther Adv Endocrinol Metab. 10(2042018819889019)2019.PubMed/NCBI View Article : Google Scholar
9	Weindruch R and Sohal RS: Seminars in medicine of the Beth Israel deaconess medical center. Caloric intake and aging. N Engl J Med. 337:986–994. 1997.PubMed/NCBI View Article : Google Scholar
10	Baumeier C, Kaiser D, Heeren J, Scheja L, John C, Weise C, Eravci M, Lagerpusch M, Schulze G, Joost HG, et al: Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice. Biochim Biophys Acta. 1851:566–576. 2015.PubMed/NCBI View Article : Google Scholar
11	Belkacemi L, Selselet-Attou G, Bulur N, Louchami K, Sener A and Malaisse WJ: Intermittent fasting modulation of the diabetic syndrome in sand rats. III. Post-mortem investigations. Int J Mol Med. 27:95–102. 2011.PubMed/NCBI View Article : Google Scholar
12	Horne BD, Muhlestein JB and Anderson JL: Health effects of intermittent fasting: Hormesis or harm? A systematic review. Am J Clin Nutr. 102:464–470. 2015.PubMed/NCBI View Article : Google Scholar
13	Jane L, Atkinson G, Jaime V, Hamilton S, Waller G and Harrison S: Intermittent fasting interventions for the treatment of overweight and obesity in adults aged 18 years and over: A systematic review protocol. JBI Database System Rev Implement Rep. 13:60–68. 2015.PubMed/NCBI View Article : Google Scholar
14	Nair KS, Woolf PD, Welle SL and Matthews DE: Leucine, glucose, and energy metabolism after 3 days of fasting in healthy human subjects. Am J Clin Nutr. 46:557–562. 1987.PubMed/NCBI View Article : Google Scholar
15	Müller MJ, Enderle J, Pourhassan M, Braun W, Eggeling B, Lagerpusch M, Glüer CC, Kehayias JJ, Kiosz D and Bosy-Westphal A: Metabolic adaptation to caloric restriction and subsequent refeeding: The minnesota starvation experiment revisited. Am J Clin Nutr. 102:807–819. 2015.PubMed/NCBI View Article : Google Scholar
16	Mansell PI and Macdonald IA: The effect of starvation on insulin-induced glucose disposal and thermogenesis in humans. Metabolism. 39:502–510. 1990.PubMed/NCBI View Article : Google Scholar
17	Webber J and Macdonald IA: The cardiovascular, metabolic and hormonal changes accompanying acute starvation in men and women. Br J Nutr. 71:437–447. 1994.PubMed/NCBI View Article : Google Scholar
18	Haouari M, Haouari-Oukerro F, Sfaxi A, Ben Rayana MC, Kâabachi N and Mbazâa A: How Ramadan fasting affects caloric consumption, body weight, and circadian evolution of cortisol serum levels in young, healthy male volunteers. Horm Metab Res. 40:575–577. 2008.PubMed/NCBI View Article : Google Scholar
19	Kul S, Savaş E, Öztürk ZA and Karadağ G: Does Ramadan fasting alter body weight and blood lipids and fasting blood glucose in a healthy population? A meta-analysis. J Relig Health. 53:929–942. 2014.PubMed/NCBI View Article : Google Scholar
20	Sadeghirad B, Motaghipisheh S, Kolahdooz F, Zahedi MJ and Haghdoost AA: Islamic fasting and weight loss: A systematic review and meta-analysis. Public Health Nutr. 17:396–406. 2014.PubMed/NCBI View Article : Google Scholar
21	Charlton MR: Protein metabolism and liver disease. Baillieres Clin Endocrinol Metab. 10:617–635. 1996.PubMed/NCBI View Article : Google Scholar
22	Lawrence YA, Guard BC, Steiner JM, Suchodolski JS and Lidbury JA: Untargeted metabolomic profiling of urine from healthy dogs and dogs with chronic hepatic disease. PLoS One. 14(e0217797)2019.PubMed/NCBI View Article : Google Scholar
23	Besse-Patin A, Jeromson S, Levesque-Damphousse P, Secco B, Laplante M and Estall JL: PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin. Proc Natl Acad Sci USA. 116:4285–4290. 2019.PubMed/NCBI View Article : Google Scholar
24	Moore MC, Coate KC, Winnick JJ, An Z and Cherrington AD: Regulation of hepatic glucose uptake and storage in vivo. Adv Nutr. 3:286–294. 2012.PubMed/NCBI View Article : Google Scholar
25	Ramnanan CJ, Edgerton DS, Kraft G and Cherrington AD: Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes Metab. 13 (Suppl 1):S118–S125. 2011.PubMed/NCBI View Article : Google Scholar
26	Gibney MJ, Walsh M, Brennan L, Roche HM, German B and van Ommen B: Metabolomics in human nutrition: Opportunities and challenges. Am J Clin Nutr. 82:497–503. 2005.PubMed/NCBI View Article : Google Scholar
27	Hollywood K, Brison DR and Goodacre R: Metabolomics: Current technologies and future trends. Proteomics. 6:4716–4723. 2006.PubMed/NCBI View Article : Google Scholar
28	de Cabo R and Mattson MP: Effects of intermittent fasting on health, aging, and disease. N Engl J Med. 381:2541–2551. 2019.PubMed/NCBI View Article : Google Scholar
29	Golbidi S, Daiber A, Korac B, Li H, Essop MF and Laher I: Health benefits of fasting and caloric restriction. Curr Diab Rep. 17(123)2017.PubMed/NCBI View Article : Google Scholar
30	Johnson EL: Seizures and epilepsy. Med Clin North Am. 103:309–324. 2019.PubMed/NCBI View Article : Google Scholar
31	Guo ZV, Hires SA, Li N, O'Connor DH, Komiyama T, Ophir E, Huber D, Bonardi C, Morandell K, Gutnisky D, et al: Procedures for behavioral experiments in head-fixed mice. PLoS One. 9(e88678)2014.PubMed/NCBI View Article : Google Scholar
32	Tucci V, Hardy A and Nolan PM: A comparison of physiological and behavioural parameters in C57BL/6J mice undergoing food or water restriction regimes. Behav Brain Res. 173:22–29. 2006.PubMed/NCBI View Article : Google Scholar
33	Longo VD and Mattson MP: Fasting: Molecular mechanisms and clinical applications. Cell Metab. 19:181–192. 2014.PubMed/NCBI View Article : Google Scholar
34	Wegman MP, Guo MH, Bennion DM, Shankar MN, Chrzanowski SM, Goldberg LA, Xu J, Williams TA, Lu X, Hsu SI, et al: Practicality of intermittent fasting in humans and its effect on oxidative stress and genes related to aging and metabolism. Rejuvenation Res. 18:162–172. 2015.PubMed/NCBI View Article : Google Scholar
35	Manzanero S, Erion JR, Santro T, Steyn FJ, Chen C, Arumugam TV and Stranahan AM: Intermittent fasting attenuates increases in neurogenesis after ischemia and reperfusion and improves recovery. J Cereb Blood Flow Metab. 34:897–905. 2014.PubMed/NCBI View Article : Google Scholar
36	Farooq N, Priyamvada S, Arivarasu NA, Salim S, Khan F and Yusufi AN: Influence of Ramadan-type fasting on enzymes of carbohydrate metabolism and brush border membrane in small intestine and liver of rat used as a model. Br J Nutr. 96:1087–1094. 2006.PubMed/NCBI View Article : Google Scholar
37	Mohany M, Ashton N, Harrath AH, Nyengaard JR, Alomar SY and Alwasel S: A new model for fetal programming: Maternal Ramadan-type fasting programs nephrogenesis. J Dev Orig Health Dis. 9:287–298. 2018.PubMed/NCBI View Article : Google Scholar
38	Salim S, Farooq N, Priyamvada S, Asghar M, Khundmiri SJ, Khan S, Khan F and Yusufi AN: Influence of Ramadan-type fasting on carbohydrate metabolism, brush border membrane enzymes and phosphate transport in rat kidney used as a model. Br J Nutr. 98:984–990. 2007.PubMed/NCBI View Article : Google Scholar
39	Fernando HA, Zibellini J, Harris RA, Seimon RV and Sainsbury A: Effect of Ramadan fasting on weight and body composition in healthy non-athlete adults: A systematic review and meta-analysis. Nutrients. 11(478)2019.PubMed/NCBI View Article : Google Scholar
40	Sethi BK and Nagesh VS: Weight management in Ramadan. J Pak Med Assoc. 65 (5 Suppl 1):S54–S56. 2015.PubMed/NCBI
41	Hutchison AT and Heilbronn LK: Metabolic impacts of altering meal frequency and timing-does when we eat matter? Biochimie. 124:187–197. 2016.PubMed/NCBI View Article : Google Scholar
42	Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, Mosley M, Notterpek L, Ravussin E, Scheer FA, et al: Meal frequency and timing in health and disease. Proc Natl Acad Sci USA. 111:16647–16653. 2014.PubMed/NCBI View Article : Google Scholar
43	Marinac CR, Natarajan L, Sears DD, Gallo LC, Hartman SJ, Arredondo E and Patterson RE: Prolonged nightly fasting and breast cancer risk: Findings from NHANES (2009-2010). Cancer Epidemiol Biomarkers Prev. 24:783–789. 2015.PubMed/NCBI View Article : Google Scholar
44	Marinac CR, Nelson SH, Breen CI, Hartman SJ, Natarajan L, Pierce JP, Flatt SW, Sears DD and Patterson RE: Prolonged nightly fasting and breast cancer prognosis. JAMA Oncol. 2:1049–1055. 2016.PubMed/NCBI View Article : Google Scholar
45	Gill S and Panda S: A smartphone App reveals erratic diurnal eating patterns in humans that can be modulated for health benefits. Cell Metab. 22:789–798. 2015.PubMed/NCBI View Article : Google Scholar
46	Manoogian ENC and Panda S: Circadian rhythms, time-restricted feeding, and healthy aging. Ageing Res Rev. 39:59–67. 2017.PubMed/NCBI View Article : Google Scholar
47	Jain Gupta N and Khare A: Disruption in daily eating-fasting and activity-rest cycles in Indian adolescents attending school. PLoS One. 15(e0227002)2020.PubMed/NCBI View Article : Google Scholar
48	Chen K, Ma J, Jia X, Ai W, Ma Z and Pan Q: Advancing the understanding of NAFLD to hepatocellular carcinoma development: From experimental models to humans. Biochim Biophys Acta Rev Cancer. 1871:117–125. 2019.PubMed/NCBI View Article : Google Scholar
49	Fu L and Kettner NM: The circadian clock in cancer development and therapy. Prog Mol Biol Transl Sci. 119:221–282. 2013.PubMed/NCBI View Article : Google Scholar
50	Kim CW, Yun KE, Jung HS, Chang Y, Choi ES, Kwon MJ, Lee EH, Woo EJ, Kim NH, Shin H and Ryu S: Sleep duration and quality in relation to non-alcoholic fatty liver disease in middle-aged workers and their spouses. J Hepatol. 59:351–357. 2013.PubMed/NCBI View Article : Google Scholar
51	Maury E: Off the clock: From circadian disruption to metabolic disease. Int J Mol Sci. 20(1597)2019.PubMed/NCBI View Article : Google Scholar
52	Hunter AL and Ray DW: Circadian clock regulation of hepatic energy metabolism regulatory circuits. Biology (Basel). 8(79)2019.PubMed/NCBI View Article : Google Scholar
53	Christie S, Vincent AD, Li H, Frisby CL, Kentish SJ, O'Rielly R, Wittert GA and Page AJ: A rotating light cycle promotes weight gain and hepatic lipid storage in mice. Am J Physiol Gastrointest Liver Physiol. 315:G932–G942. 2018.PubMed/NCBI View Article : Google Scholar
54	Fleet T, Stashi E, Zhu B, Rajapakshe K, Marcelo KL, Kettner NM, Gorman BK, Coarfa C, Fu L, O'Malley BW and York B: Genetic and environmental models of circadian disruption link SRC-2 function to hepatic pathology. J Biol Rhythms. 31:443–460. 2016.PubMed/NCBI View Article : Google Scholar
55	Bertholdt L, Gudiksen A, Jessen H and Pilegaard H: Impact of skeletal muscle IL-6 on regulation of liver and adipose tissue metabolism during fasting. Pflugers Arch. 470:1597–1613. 2018.PubMed/NCBI View Article : Google Scholar
56	Marinho TS, Ornellas F, Barbosa-da-Silva S, Mandarim-de-Lacerda CA and Aguila MB: Beneficial effects of intermittent fasting on steatosis and inflammation of the liver in mice fed a high-fat or a high-fructose diet. Nutrition. 65:103–112. 2019.PubMed/NCBI View Article : Google Scholar
57	Johnstone A: Fasting for weight loss: An effective strategy or latest dieting trend? Int J Obes (Lond). 39:727–733. 2015.PubMed/NCBI View Article : Google Scholar
58	Barnosky AR, Hoddy KK, Unterman TG and Varady KA: Intermittent fasting vs daily calorie restriction for type 2 diabetes prevention: A review of human findings. Transl Res. 164:302–311. 2014.PubMed/NCBI View Article : Google Scholar
59	Carter S, Clifton PM and Keogh JB: The effects of intermittent compared to continuous energy restriction on glycaemic control in type 2 diabetes; a pragmatic pilot trial. Diabetes Res Clin Pract. 122:106–112. 2016.PubMed/NCBI View Article : Google Scholar