Effect of exercise and dietary intervention on serum metabolomics in men with insomnia symptoms: a 6-month randomized-controlled trial

Background Accumulating evidences have shown that lifestyle interventions such as exercise and diet are associated with improved sleep quality. However, the underlying molecular mechanisms remain unclear. Assessing exercise and diet intervention associated changes in circulating metabolomics profile in people with insomnia symptoms may help to identify molecular biomarkers that may link lifestyle changes to improved sleep outcomes. Methods The present study is a part of a 6-month randomized lifestyle intervention on sleep disorder subjects. Seventy-two Finnish men (aged: 51.6 ± 10.1 years; body mass index, BMI: 29.3 ± 3.9 kg/m2) with chronic insomnia symptoms who were assigned into different intervention groups completed this study (exercise n = 24, diet n = 27 and control n = 21). The exercise group was assigned to a progressive aerobic exercise training with intensity of 60 – 75% of estimated maximum heart rate, 3 – 5 times a week. The diet group aimed to reduce their total energy intakes by 300 to 500 kcal per day for the first three months. The control group were advised to maintain their current lifestyle. Sleep was assessed by using a non-contact sleep monitoring devise (Beddit sleep tracker). Blood samples were collected in the morning between 7:00 and 9:00 a.m. after overnight fasting. Gas Chromatography Time-Of-Flight Mass Spectrometry (GC-TOF-MS) method was used to determine the serum metabolites. Results Twenty-one metabolites were significantly changed in the exercise group, thirty-three metabolites in the diet group and five metabolites in the control group after intervention, respectively. The differential metabolites after exercise intervention were mainly related to glycerolipids and carbohydrates metabolism, while dietary intervention altered mainly amino acids metabolism and fatty acids metabolism related metabolites. We subsequently assessed the change of those metabolites with the change of sleep parameters and found that decreased alpha-ketoisocaproic acid (r = -0.52, p = 0.026) was correlated with improved sleep efficiency (SE) in the exercise group. Change of 3-hydroxybutric acid (r = -0.47, p = 0.025) and D-glucopyranose (r = -0.54, p = 0.006) correlated negatively with SE in the diet group. On the other hand, oxalic acid (r = 0.49, p = 0.021), D-glucopyranose (r = 0.43, p = 0.048), 4-deoxyerythronic acid (r = 0.60, p = 0.004) and tagatose (r = 0.51, p = 0.016) correlated positively with change of SOL, and 2-keto-isovaleric acid (r = 0.45, p = 0.029) correlated with TST in the diet group. Conclusion In conclusion, this study identified circulating metabolites that may represent a part of a biological mechanism through which lifestyle interventions are associated with improved sleep quality in people with insomnia. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN77172005 ### Funding Statement This study was supported financially by the by the Finnish Funding Agency for Technology and Innovation (TEKES2206/31/2010), the 111 Project (B17029) of Shanghai Jiao Tong University, the Shanghai Jiao Tong University Zhiyuan Foundation (Grant CP2014013), and China Postdoc Scholarship Council (201806230001). ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Availability of the data will follow the data management principles for research at the University of Jyväskylä https://www.jyu.fi/tutkimus/tutkimusaineistot/rdmenpdf. Established researchers wishing to collaborate will be given access to the de-identified data following approval of a signed research proposal.