Effects of Physical Exercise and a Nutritional Supplement on Body Composition, Metabolic Function, and Overall Health in Adults With a Metabolically Challenging Profile

Official title

Effects of Physical Exercise and a Nutritional Supplement on Body Composition, Metabolic Function, and Overall Health in Adults With a Metabolically Challenging Profile.

Overview

Early-onset metabolic disturbances (such as mild hyperglycemia, subclinical dyslipidemia, excess body fat, and reduced functional capacity) represent one of the major public health challenges among middle-aged and older adults. Although body mass index (BMI) remains the primary clinical criterion for classifying excess weight, growing evidence indicates that BMI does not adequately discriminate cardiometabolic risk, particularly in individuals classified as overweight who present elevated body fat levels (Wu et al., 2024). Several studies have identified altered metabolic phenotypes that do not meet the criteria for obesity, including the so-called "metabolically unhealthy normal weight" (MUNW) or "metabolically unhealthy non-obese" phenotypes. These individuals are characterized by excess body fat, central adiposity, and alterations in glucose and lipid metabolism despite having a non-obese BMI (Stefan, 2020). This profile is associated with increased insulin resistance, low-grade systemic inflammation, and elevated cardiovascular risk, underscoring the need for targeted interventions in "metabolically challenged" individuals. Xiong et al. (2024) demonstrated that metabolic health status independently predicts cardiovascular risk, even when BMI is within non-obese ranges. This evidence supports the rationale of the present project: to intervene in a group of adults without clinical obesity (BMI \< 30 kg/m²) but presenting at least two indicators of mild metabolic dysfunction. Nutritional supplements with thermogenic properties that promote fat oxidation and satiety-such as phenylcapsaicin, an analog of capsaicin designed to improve bioavailability and reduce pungency, thereby enhancing tolerability in adults-may offer a promising complementary strategy. Recent studies have shown that low doses of phenylcapsaicin were sufficient to increase fat oxidation during exercise, reduce respiratory exchange ratio, and lower maximal heart rate during submaximal testing compared with placebo (Jiménez-Martínez et al., 2023a). Furthermore, additional research reported that phenylcapsaicin improved strength performance, reduced perceived exertion, and attenuated markers of muscle damage following resistance training (Jiménez-Martínez et al., 2023b). These findings suggest that thermogenic and fat-oxidation-enhancing supplementation may act as a safe and effective metabolic modulator, particularly when combined with exercise, positioning it as an innovative strategy for adults presenting mild metabolic risk. The present study would integrate: (1) a multicomponent functional exercise program designed to improve strength, balance, and aerobic capacity in older adults; (2) a thermogenic and fat-oxidation-enhancing nutritional supplement as a safe metabolic activation strategy; (3) a standardized dietary control protocol to isolate the specific effects of the supplementation; (4) dual-energy X-ray absorptiometry (DXA) for precise body composition assessment; (5) hormonal and lipid biomarkers to evaluate underlying physiological mechanisms; and (6) validated questionnaires addressing quality of life, sleep, and appetite to capture the holistic dimension of this stage of adulthood. This multidimensional approach would provide an innovative intervention for a growing yet underexplored population: non-obese but metabolically challenged adults at increasing cardiometabolic risk. References: * Jiménez-Martínez P, Sánchez-Valdepeñas J, Cornejo-Daza PJ, Cano-Castillo C, Asín-Izquierdo I, Alix-Fages C, Pareja-Blanco F, Colado JC. Effects of different phenylcapsaicin doses on neuromuscular activity and mechanical performance in trained male subjects: a randomized, triple-blinded, crossover, placebo-controlled trial. Front Physiol. 2023a Aug 2; 14: 1215644. * Jiménez-Martínez P, Cornejo-Daza PJ, Sánchez-Valdepeñas J, Asín-Izquierdo I, Cano-Castillo C, Alix-Fages C, Pareja-Blanco F, Colado JC. Effects of different phenylcapsaicin doses on resistance training performance, muscle damage, protein breakdown, metabolic response, ratings of perceived exertion, and recovery: a randomized, triple-blinded, placebo-controlled, crossover trial. J Int Soc Sports Nutr. 2023b Dec; 20 (1): 2204083. * Stefan N. Metabolically healthy and unhealthy normal weight and obesity. Endocrinol Metab (Seoul). 2020 Sep;35(3):487-493. * Xiong Q, Zang Y, Li J, An Y, and Yu S. Comparison of cardiovascular disease risk association with metabolic unhealthy obesity identified by body fat percentage and body mass index: Results from the 1999-2020 National Health and Nutrition Examination Survey. PLoS One. 2024 Aug 14; 19 (8): e0305592. * Wu Y, Li D, and Vermund SH. Advantages and limitations of the body mass index (BMI) to assess adult obesity. Int J Environ Res Public Health. 2024 Jun 10; 21 (6): 757.

Detailed description

The present project is designed as a longitudinal, randomized, controlled, parallel-group, triple-blind clinical trial, with a 12-week active intervention and pre- and post-intervention assessments.

The study will be conducted at a single center (single-center trial) and will include two parallel groups:

* Experimental group: multicomponent functional exercise + thermogenic and appetite-modulating nutritional supplement. * Control group: multicomponent functional exercise + placebo supplement (identical in appearance, without active ingredient).

Randomization will be performed using balanced block allocation, stratified by sex and baseline body fat percentage, with a 1:1 allocation ratio.

The study will be triple-blind:

* Participants, * The intervention and assessment team, * And the statistician responsible for data analysis will remain unaware of group allocation (experimental or control).

The design corresponds to a comparative efficacy trial aimed at evaluating the additional effect of the nutritional supplement compared to placebo, while maintaining identical exercise programming and dietary control in both groups. This approach allows isolation of the specific impact of the supplement on body composition, metabolic function, functional capacity, and perceived health in adults with a metabolically challenged profile but without clinical obesity.

As is standard practice, participants will be informed that their allocation may correspond to either the placebo or experimental group, without disclosure of their actual assignment.

As appropriate in experimental studies, standardized collection of biological samples and psychometric and perceived health data will be conducted at pre- and post-intervention time points to quantify changes in these metrics and analyze them as dependent variables of the applied protocol.

Interventions

• Dietary supplement Group 1: Exercise + thermogenic supplement (EX-TS)
  Participants in this group will receive an oral daily dose of the nutritional supplement with thermogenic and appetite-modulating effects in combination with a supervised multicomponent functional program (3 sessions per week, 60 minutes each) for 12 weeks, composed by three exercise blocks: 1) joint mobility and postural control exercises block, 2) functional strength block with three sets of two strength exercises using elastic bands at 70%-85 of 1RM (RPE 6-7 at the beginning and 9 at the end
• Dietary supplement Group 2: Exercise + placebo supplement (EX-PL)
  Participants in this group will receive a placebo supplement identical in appearance, color and taste to the active supplement, together with the same multicomponent functional exercise program and dietary control for 12 weeks.

Primary outcome measures

• Change in body composition via Dual-Energy X-ray Absorptiometry (DXA) [Time frame: Pre and post-intervention of 12 weeks]
• Change in fat distribution via Dual-Energy X-ray Absorptiometry (DXA) [Time frame: Pre and post-intervention of 12 weeks]
• Change in hormonal biomarkers (glucagon-like peptide-1;GLP-1) [Time frame: Pre and post-intervention of 12 weeks]
• Change in hormonal biomarkers (acylated ghrelin) [Time frame: Pre and post-intervention of 12 weeks]
• Change in hormonal biomarkers (leptin) [Time frame: Pre and post-intervention of 12 weeks]
• Change in metabolic biomarkers (glucose) [Time frame: Pre and post-intervention of 12 weeks]
• Change in metabolic biomarkers (total cholesterol) [Time frame: Pre and post-intervention of 12 weeks]
• Change in metabolic biomarkers (HDL cholesterol) [Time frame: Pre and post-intervention of 12 weeks]
• Change in metabolic biomarkers (LDL cholesterol) [Time frame: Pre and post-intervention of 12 weeks]
• Change in metabolic biomarkers (triglycerides) [Time frame: Pre and post-intervention of 12 weeks]

Secondary outcome measures (12)

• Change in body composition via bioelectrical impedance analysis (BIA) [Time frame: Pre and post-intervention of 12 weeks]
• Changes in distance covered/aerobic capacity [Time frame: Pre and post-intervention of 12 weeks]
• Changes in lower limb strength [Time frame: Pre and post-intervention of 12 weeks]
• Changes in agility and dynamic balance [Time frame: Pre and post-intervention of 12 weeks]
• Changes in handgrip strength [Time frame: Pre and post-intervention of 12 weeks]
• Changes in quality of life specific for older adults [Time frame: Pre and post-intervention of 12 weeks]
• Changes in general quality of life [Time frame: Pre and post-intervention of 12 weeks]
• Changes in general health perception [Time frame: Pre and post-intervention of 12 weeks]
• Change in sleep quality [Time frame: Pre and post-intervention of 12 weeks]
• Change in perceived insomnia [Time frame: Pre and post-intervention of 12 weeks]
• Change in eating behavior [Time frame: Pre and post-intervention of 12 weeks]
• Change in appetite behavior [Time frame: Pre and post-intervention of 12 weeks]

Eligibility criteria

Inclusion Criteria: Individuals will be eligible to participate in the study if they meet all of the following criteria:

• Age: Between 50 and 65 years at the time of screening.
• Weight status (non-obese): Body mass index (BMI) between 25.0 and 29.9 kg/m² (overweight range, without clinical obesity).
• Metabolically challenged profile (non-obese): Presence of at least two of the following criteria, in addition to the specified BMI range:

A) Altered body composition (primary criterion): Body fat percentage ≥ 30% in women or ≥ 25% in men, assessed by DXA.

B) Borderline metabolic markers (one or more):

• Fasting glucose: 100-125 mg/dL
• Triglycerides: ≥ 150 mg/dL
• HDL cholesterol: < 50 mg/dL in women or < 40 mg/dL in men
• LDL cholesterol: ≥ 130 mg/dL

C) Sedentary lifestyle:

Low or very low physical activity level, defined as ≤ 600 MET·min/week according to the IPAQ questionnaire.

• Clinical and functional status:

• Clinically stable condition, without acute disease or recent decompensation.
• Ability to perform moderate-intensity exercise three times per week, according to medical assessment.
• Previous treatment and lifestyle:

• No participation in structured exercise programs (≥ 2 days/week) during the previous 6 months.
• No intensive hypocaloric diets or medical weight-loss treatments during the previous 3 months.
• Administrative and ethical aspects:

• Ability to understand study explanations and follow instructions.
• Signed informed consent prior to initiation of any study procedures.

Exclusion Criteria: Individuals presenting any of the following conditions will be excluded from the study:

• Clinical obesity or anthropometric extremes:

• BMI ≥ 30.0 kg/m² (obesity).
• Any weight-related or clinical condition that, in the judgment of the principal investigator, contraindicates participation.
• Relevant or uncontrolled chronic diseases:

• Previous diagnosis of type 1 or type 2 diabetes mellitus.
• Moderate or severe cardiovascular disease (e.g., ischemic heart disease, heart failure, uncontrolled clinically significant arrhythmias).
• Moderate or severe renal, hepatic, or respiratory disease.
• Neurological or musculoskeletal disorders limiting or contraindicating the prescribed exercise program.
• Pharmacological treatments interfering with energy metabolism or body weight:

Current use (or use within the previous 3 months) of:

• Weight-loss medications or GLP-1 receptor agonists
• Systemic corticosteroids at moderate or high doses
• Thyroid hormones at non-replacement doses
• Anabolic agents or other drugs significantly affecting body composition
• Specific prior supplementation: Use of capsaicin, phenylcapsaicin, or other thermogenic or appetite-modulating supplements within the previous 3 months.
• Functional or cognitive limitations:

• Cognitive, psychiatric, or mental health disorders that may impair study comprehension or protocol adherence.
• Physical limitations preventing safe participation in exercise.
• Substance use:

• Alcohol consumption at levels considered high risk (> 20 g/day).
• Heavy smoking (> 10 cigarettes/day), unless deemed clinically stable by the investigator.
• Other exclusion criteria:

• Concurrent participation in another clinical trial or interventional study.
• Any other condition that, in the judgment of the principal investigator, may pose additional risk to the participant or significantly interfere with study outcomes.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Prevention

Study locations

Spain · 1 center

• Physical activity and Sport Science Faculty — Valencia

Identifiers

NCT: NCT07504068 · 2025-FIS-4275027

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗