Cardiometabolic Diseases, Exercise, Metabolic Dysfunction-Associated Steatotic Liver Disease
Conditions
Keywords
Exercise, Metabolism, Health, Women
Brief summary
Type of Study: Clinical Trial Goal: The goal of this clinical trial is to investigate how performing exercise at different times of day (morning vs. evening) affects liver fat, cardiometabolic health, and gut microbiota in postmenopausal women. Participant Population/Health Conditions: The study will involve 63 sedentary postmenopausal women (aged 45-75) diagnosed with metabolic dysfunction-associated steatotic liver disease. Main Questions: The main questions this study aims to answer are: * Does morning exercise reduce hepatic fat more effectively than evening exercise? * How does time-of-day-specific exercise influence cardiometabolic markers? * Do changes in gut microbiota contribute to the metabolic effects of exercise timing? Participants Will: Be randomized into one of three groups: morning exercise, evening exercise, or a usual-care control group. Follow the assigned regimen for 12 weeks. The exercise groups will perform supervised aerobic and resistance training three times per week. Provide blood, stool, and imaging data before and after the intervention to determine the effects of the intervention. Comparison Group: Researchers will compare the effects of morning vs. evening exercise (and usual care) on hepatic fat reduction and cardiometabolic improvement, as well as changes in gut microbiota.
Detailed description
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one in three adults and is a major contributor to the growing burden of cardiometabolic disease. Exercise is one of the most effective interventions for improving cardiometabolic health, reducing hepatic fat, and enhancing metabolic flexibility. However, the timing of exercise -a modifiable behavioral factor- may play a crucial yet underexplored role in determining its physiological benefits. Preclinical studies have shown that circadian rhythms regulate key metabolic processes, including lipid metabolism and glucose homeostasis. Moreover, recent findings suggest that exercise performed at different times of day may elicit different responses, influencing the regulation of hepatic fat and systemic inflammation. These effects may be mediated, in part, through gut microbiota, which modulate host metabolism via the gut-liver axis. However, the interaction between exercise timing and gut microbiota in human physiology -particularly in women- remains poorly understood. This knowledge gap is particularly critical in postmenopausal women, a population that experiences profound metabolic changes due to hormonal decline, including increased hepatic and visceral fat, chronic inflammation, and reduced insulin sensitivity. These alterations significantly elevate the risk for MASLD and other cardiometabolic diseases. Yet, postmenopausal women are consistently underrepresented in clinical trials exploring exercise interventions. Based on emerging scientific evidence, the investigators hypothesize that morning exercise may lead to greater reductions in hepatic fat and improvements in cardiometabolic health compared to evening exercise in postmenopausal women with MASLD. Furthermore, the investigators propose that these effects may be partially mediated by exercise-induced changes in gut microbiota composition and function. Thus, the main objective of the project is to investigate whether the timing of exercise modulates hepatic fat reduction, cardiometabolic adaptation, and gut microbiota remodeling in postmenopausal women with MASLD. To achieve this, the project will implement a randomized controlled trial in which 63 sedentary postmenopausal women diagnosed with MASLD will be randomly allocated into one of three groups: (i) morning exercise (07:00h), (ii) evening exercise (19:00h), or (iii) a usual-care control group receiving lifestyle recommendations. Participants in the intervention groups will complete a 12-week supervised training program, combining aerobic and resistance exercise (3 sessions/week, 60-90 minutes per session), in accordance with WHO recommendations. Before and after the intervention, biological samples, magnetic resonance imaging, and metabolic assessments will be collected. The study will employ advanced multi-omics analyses, including metabolomics and semi-targeted metagenomics, to explore how gut microbiota changes relate to improvements in metabolism.
Interventions
BEHAVIORALMorning exercise group
Participants perform supervised exercise sessions at 07:00h
BEHAVIORALEvening exercise group
Participants perform supervised exercise sessions at 19:00h
BEHAVIORALUsual-care control group
Participants receive lifestyle recommendations without exercise
Sponsors
Universidad de Almeria
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Women aged 45-75 years, postmenopausal for at least two years (stage +1a) * Body Mass Index (BMI) \> 25 and \< 40 kg/m² * Diagnosed hepatic steatosis (via ultrasound hyperechogenicity, FibroScan CAP score \>280, or histological confirmation) * Sedentary lifestyle (no regular structured exercise) * Willingness to be randomized and adhere to study procedures, including all assessments and visits * Sufficient Spanish proficiency to understand and follow study instructions * Consent to store biological samples for future research * Participants should have a healthy circadian rhythm
Exclusion criteria
* Contraindications for MRI (e.g., claustrophobia, pacemaker, metal implants) * History of major cardiovascular, endocrine, neurological, or kidney disease, or any clinical abnormalities (to be judged by the study physician) * First-degree family history of sudden cardiac death * Alcohol or substance abuse * Psychiatric, psychotic, eating, or sleep disorders (to be judged by the study physician) * Prior bariatric surgery, diagnosed HIV/AIDS, or inflammatory/autoimmune diseases * Cancer or any medical condition where exercise is contraindicated (to be judged by the study physician) * Recent or unstable metabolic conditions (e.g., diabetes, recent medication changes, or use of drugs affecting metabolism) * Recent (\<3 months) use of antibiotics, statins, glucocorticoids, hormonal therapies, amiodarone, or myelosuppressive agents * Participation in weight-loss programs or special diets (e.g., ketogenic, high-carb) * Shift workers or caregivers with frequent nocturnal disruptions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic fat content | Change from baseline in the mean adipose tissue content at 12 weeks | Hepatic fat content will be quantified using MRI |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visceral adipose tissue | Change from baseline in the mean adipose tissue content at 12 weeks | Visceral adipose tissue will be quantified using MRI |
| Intra-muscular adipose tissue | Change from baseline in the mean adipose tissue content at 12 weeks | Intra-muscular adipose tissue, at the mid thigh, will be quantified using MRI |
| Body composition | Change from baseline in the whole-body composition at 12 weeks | Whole-body composition will be quantified using DXA. Fat mass (in kg), and lean mass (in kg) will be assessed |
| Bone related parameters | Change from baseline in the whole-body mineral density and content at 12 weeks | Whole-body bone related parameters will be quantified using DXA. Bone mineral density and content (both in g/cm\^2) will be assessed |
| Resting blood pressure | Change from baseline in the resting blood pressure related parameters at 12 weeks | Systolic pressure (mmHg) and diastolic pressure (mmHg) will be measured. |
| Glucose metabolism | Change from baseline in the glucose related parameters at 12 weeks | Glucose metabolism (mg/dl) will be assessed via an oral glucose tolerance test with serial glucose measurements. Continuous glucose monitoring systems will be used to monitor 24-hour glycemic fluctuations (mg/dl) under free-living conditions |
| Energy metabolism | Change from baseline in the energy metabolism related parameters at 12 weeks | Resting energy expenditure and exchange ratio will be determined using indirect calorimetry. Exercise energy expenditure and exchange ratio will be assessed during a steady-state submaximal exercise at 40-60% of VO2max |
| Cardiorespiratory Fitness | Change from baseline in the cardiorespiratory fitness at 12 weeks | VO₂max will be assessed following an incremental test to exhaustion. |
| Muscular strength | Change from baseline in the muscular strength related parameters at 12 weeks | Muscular strength will be evaluated using 1-RM and/or maximal isometric strength tests for both upper and lower body strength. |
| 30 seconds sit-to-stand test | Change from baseline in the sit-to-stand related parameters at 12 weeks | The 30-s sit-to-stand test will be conducted for evaluating the functional physical fitness (lower body strenth). |
| Heart rate and heart rate variability | Change from baseline in the heart rate and heart rate variability related parameters at 12 weeks | Heart rate (maximum and minimum values) and heart rate variability will be assessed at both, rest and exercise periods |
| Body weight | Change from baseline in the body weight at 12 weeks | Body weight (in kg) will be assessed using a scale. |
| Height | Change from baseline in the height at 12 weeks | Height (in m) will be assessed using a stadiometer. |
| Body mass index | Change from baseline in the height at 12 weeks | Body weight (in kg) and height (in m) will be combined to report BMI in kg/m\^2 |
| Fasting glucose levels | Change from baseline in the fasting glucose levels at 12 weeks | Fasting blood samples will be analyzed to determine glucose levels (mg/dl). |
| Fasting insulin levels | Change from baseline in the fasting insulin levels at 12 weeks | Fasting blood samples will be analyzed to determine insulin levels (µmol/L). |
| Fasting HbA1c levels | Change from baseline in the fasting HbA1c levels at 12 weeks | Fasting blood samples will be analyzed to determine HbA1c levels (mmol/mol). |
| Fasting cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels | Change from baseline in the fasting cholesterol, HDL, and LDL levels at 12 weeks | Fasting blood samples will be analyzed to determine cholesterol, HDL, and LDL levels (mg/dl). |
| Relative abundance of specific bacterial taxa - fecal microbiota composition | Change from baseline in the fecal microbiota at 12 weeks | Fecal samples will be collected before and after the exercise intervention to analyze the composition of the fecal microbiota. Percentage of total sequences assigned to specific taxa (e.g., Firmicutes, Bacteroidetes, Akkermansia) will be determined, and results will be expressed as percentage of total sequences (i.e., %) and/or relative abundance (i.e., proportion). |
| Alpha diversity of the fecal microbiota - fecal microbiota diversity | Change from baseline in the fecal microbiota at 12 weeks | Fecal samples will be collected before and after the exercise intervention to analyze the diversity of the fecal microbiota. Assessment of microbial richness and evenness within each sample will be determined, and results will be expressed as score on the Shannon Index / Simpson Index / observed OTUs. |
| Concentration of specific metabolites - fecal microbiota function | Change from baseline in the fecal microbiota at 12 weeks | Fecal samples will be collected before and after the exercise intervention to analyze the functional profile of the fecal microbiota (i.e., the concentration of metabolites). Quantification of metabolites (e.g., short-chain fatty acids \[SCFAs\]) will be determined, and results will be expressed as micromoles per gram of feces, millimolar, counts per million, or relative abundance of functional genes. |
| International Physical Activity Questionnaire | Change from baseline in the questionnaire score at 12 weeks | The International Physical Activity Questionnaire (IPAQ) will be used for quantifying total physical activity in Metabolic Equivalent of Task-minutes per week (MET-min/week). In this questionnaire, a higher score indicates a greater volume of physical activity |
| Morningness-Eveningness Questionnaire | Change from baseline in the questionnaire score at 12 weeks | The Morningness-Eveningness Questionnaire (MEQ) will be used for determining the individual's circadian typology. In this questionnaire, a higher score indicates a stronger "morning-type" preference and a lower score signifies an "evening-type" preference |
| Pittsburgh Sleep Quality Index Questionnaire | Change from baseline in the questionnaire score at 12 weeks | The Pittsburgh Sleep Quality Index (PSQI) will be used to assess subjective sleep quality and disturbances over a one-month period. In this questionnaire, a higher score represents poorer sleep quality; a score exceeding 5 typically denotes clinically poor global sleep quality. Additionally, participants will complete a sleep diary to record their daily sleep patterns and determine the actual hours of rest. |
| Three-Factor Eating Questionnaire | Change from baseline in the questionnaire score at 12 weeks | The Three-Factor Eating Questionnaire (TFEQ) or TFEQ-R18 will be used for measuring three components of eating behavior (Cognitive Restraint, Emotional Eating, and Uncontrolled Eating). In this questionnaire, elevated subscale scores indicate more disordered or problematic eating patterns |
| Perceived Stress Scale Questionnaire | Change from baseline in the questionnaire score at 12 weeks | The Perceived Stress Scale (PSS) will be used for measuring the degree to which life situations are appraised as stressful. In this questionnaire, a higher total score indicates a higher level of perceived psychological stress |
| Depression, Anxiety, and Stress Scale Questionnaire | Change from baseline in the questionnaire score at 12 weeks | The Depression, Anxiety, and Stress Scale (DASS-21) will be used for providing three independent severity subscales (Depression, Anxiety, and Stress). In this questionnaire, an increased score on any subscale signifies a greater severity of symptomatology and a diminished mental health status |
| Beck Depression Inventory Questionnaire | Change from baseline in the questionnaire score at 12 weeks | The Beck Depression Inventory (BDI-II) will be used for measuring depressive symptom severity. In this questionnaire, a higher score correlates directly with greater depressive symptom severity |
| Profile of Mood States Questionnaire | Change from baseline in the questionnaire score at 12 weeks | The Profile of Mood States (POMS) will be used for assessing transient mood states. In this questionnaire, higher scores on negative subscales indicate a poorer mood state, while an increased score on the Vigor scale indicates a more favorable mood |
Countries
Spain
Outcome results
None listed