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.
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).
Fasting glucose: 100-125 mg/dL
Triglycerides: ≥ 150 mg/dL
BMI ≥ 30.0 kg/m² (obesity).
Any weight-related or clinical condition that, in the judgment of the principal investigator, contraindicates participation.
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).
Parallel
Group 1: Exercise + thermogenic supplement (EX-TS)
Dietary supplementParticipants 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 of the set) and, 3) coordination and agility exercises block. Participants will undergo a standardized dietary control plan based on Individualized energy deficit equivalent to 0.7% of body weight per week, adjusted using the Harris-Benedict equation, and macronutrient distribution: protein: 2 g/kg; fat: 0.8 g/kg; remaining energy intake allocated to carbohydrates.
Group 2: Exercise + placebo supplement (EX-PL)
Dietary supplementParticipants 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.
Change in body composition via Dual-Energy X-ray Absorptiometry (DXA)
Whole body and segmental composition will be assessed through Dual-Energy X-ray Absorptiometry (DXA). Parameters analyzed will be: total and regional fat mass and lean mass
Change in fat distribution via Dual-Energy X-ray Absorptiometry (DXA)
Android/gynoid fat distribution will be analyzed through Dual-Energy X-ray Absorptiometry (DXA).
Change in hormonal biomarkers (glucagon-like peptide-1;GLP-1)
glucagon-like peptide-1 (GLP-1) will be collected through a blood sample in the morning in a fasted state to assess hormonal state
Change in hormonal biomarkers (acylated ghrelin)
Acylated ghrelin levels will be collected through a blood sample in the morning in a fasted state to assess hormonal state
Change in body composition via bioelectrical impedance analysis (BIA)
Whole body fat-free mass will be assessed through bioelectrical impedance analysis (BIA)
Changes in distance covered/aerobic capacity
Distance covered/aerobic capacity will be assessed through the 6- Minute walking test
Changes in lower limb strength
Lower limb strength will be assessed through the 30-second Chair Stand Test
Changes in agility and dynamic balance
Agility and dynamic balance will be assessed through the Timed Up and Go Test
Adherence to supplement and exercise
Adherence to supplement and exercise will be assessed through ad hoc questionnaire
Demographic characteristics (age)
Age will be assessed.
Demographic characteristics (sex)
Sex will be assessed.
Demographic characteristics (Body mass index, BMI)
Body mass index (BMI; weight/height2) will be assessed.
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