Impact of Circadian Exercise on Metabolic Dysfunction-Associated Steatotic Liver Disease in Postmenopausal Women

N/ANot Yet RecruitingNCT07386665

Universidad de Almeria63 enrolled

Overview

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.

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 counseling. 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.

Eligibility

Sex: FEMALEMin age: 45 YearsMax age: 75 Years

Medical Language ↔ Plain English

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 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

Outcomes

Primary Outcomes

Hepatic fat content

Hepatic fat content will be quantified using MRI

Time frame: Change from baseline in the mean adipose tissue content at 12 weeks

Secondary Outcomes

Visceral adipose tissue

Visceral adipose tissue will be quantified using MRI

Time frame: Change from baseline in the mean adipose tissue content at 12 weeks

Intra-muscular adipose tissue

Intra-muscular adipose tissue, at the mid thigh, will be quantified using MRI

Time frame: Change from baseline in the mean adipose tissue content at 12 weeks

Body composition

Whole-body composition will be quantified using DXA. Fat mass (in kg), and lean mass (in kg) will be assessed

Time frame: Change from baseline in the whole-body composition at 12 weeks

Bone related parameters

Whole-body bone related parameters will be quantified using DXA. Bone mineral density and content (both in g/cm\^2) will be assessed

Time frame: Change from baseline in the whole-body mineral density and content at 12 weeks

Resting blood pressure

Systolic pressure (mmHg) and diastolic pressure (mmHg) will be measured.

Time frame: Change from baseline in the resting blood pressure related parameters at 12 weeks

Glucose metabolism

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

Time frame: Change from baseline in the glucose related parameters at 12 weeks

Energy metabolism

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

Time frame: Change from baseline in the energy metabolism related parameters at 12 weeks

Exercise performance

VO2max will be assessed following an incremental test to exhaustion. Muscular strength will be evaluated through 1-RM for both upper and lower body muscular strength

Time frame: Change from baseline in the exercise performance related parameters at 12 weeks

Heart rate and heart rate variability

Heart rate (maximum and minimum values) and heart rate variability will be assessed at both, rest and exercise periods

Time frame: Change from baseline in the heart rate and heart rate variability related parameters at 12 weeks

Body weight

Body weight (in kg) will be assessed using a scale.

Time frame: Change from baseline in the body weight at 12 weeks

Height

Height (in m) will be assessed using a stadiometer.

Time frame: Change from baseline in the height at 12 weeks

Body mass index

Body weight (in kg) and height (in m) will be combined to report BMI in kg/m\^2

Time frame: Change from baseline in the height at 12 weeks

Fasting glucose levels

Fasting blood samples will be analyzed to determine glucose levels (mg/dl).

Time frame: Change from baseline in the fasting glucose levels at 12 weeks

Fasting insulin levels

Fasting blood samples will be analyzed to determine insulin levels (µmol/L).

Time frame: Change from baseline in the fasting insulin levels at 12 weeks

Fasting HbA1c levels

Fasting blood samples will be analyzed to determine HbA1c levels (mmol/mol).

Time frame: Change from baseline in the fasting HbA1c levels at 12 weeks

Fasting cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels

Fasting blood samples will be analyzed to determine cholesterol, HDL, and LDL levels (mg/dl).

Time frame: Change from baseline in the fasting cholesterol, HDL, and LDL levels at 12 weeks

International Physical Activity Questionnaire

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