Reprogramming Energy Homeostasis in Overweight Individuals Via Exercise, Cognitive, and Social Training (Resilient)

Reprogramming Energy Homeostasis in Overweight Children and Adults Trough Exercise, Cognitive Training and Social Interaction

The RESILIENT project is a clinical trial investigating leptin sensitivity in both children and adults with overweight or obesity. The study examines the additive effects of Cognitive Training (CT) and Social Training (ST) on leptin sensitivity, compared to stand-alone Intensive Health Behaviour Treatment (IHBT), which includes diet and Physical Activity (PA).

The intervention will last for 8 weeks, followed by a 12-week washout period. A multilevel assessment will be conducted, evaluating in vivo leptin sensitivity (through the ratio of leptin levels to caloric intake) as well as ex vivo molecular analysis of leptin signaling in Peripheral Blood Mononuclear Cells (PBMCs). Additionally, clinical, psychological, cognitive, and physiological assessments will be performed to assess the efficacy of each intervention. By investigating leptin resistance as a potential molecular bridge between metabolic dysregulation and cognitive dysfunctions, this study may contribute to the development of more effective, long-term treatments for obesity and overweight. Additionally, in vivo investigation of leptin sensitivity may be particularly important for providing evidence of the metabolic and cognitive effects necessary for developing novel anti-obesity treatments.

Study Overview

• Status: Recruiting
• Conditions: Childhood Obesity; Obesity and Overweight; Leptin Resistance
• Intervention / Treatment: Other: Nutritional Intervention; Other: Physical Activity training; Other: Cognitive training; Other: Social Training

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Melania Manco; Phone Number: +39 3317775547; Email: melania.manco@opbg.net

Study Locations

• Italy
  • Rome, Italy, 00146
    • Recruiting
    • Ospedale Pediatrico Bambino Gesù
  • Rome, Italy, 00165
    • Recruiting
    • Bambino Gesù Hospital and Research Institute,
    • Contact: Chiara Mennini; Phone Number: 06-68592572; Email: chiara.mennini@opbg.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• a condition of overweight or obesity
• Intelligence Quotient (IQ) ≥ 85

Exclusion Criteria:

• genetic or syndromic obesity;
• reduced mobility;
• systemic diseases;
• ongoing pharmacological treatment for chronic conditions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intensive Health Behavior Treatment group: Physical Activity and Diet; Participants will be provided with a personalized dietary plan and a Physical Activity training	Other: Nutritional Intervention; Participants will receive comprehensive dietary education from the nutritionists of the research team, aimed at improving their baseline diet by incorporating nutritional recommendations based on the Mediterranean diet and the Italian dietary guidelines for healthy eating.; Other: Physical Activity training; Participants will engage in a structured exercise program designed to improve motor competence and confidence. Tailored to each individual's baseline physical abilities and cardiorespiratory capacity, the program will focus on enhancing aerobic fitness, flexibility, and coordination.
Active Comparator: Cognitive Training group: Physical Activity, Diet and an online cognitive training; Participants will be provided with personalized dietary plan, a Physical Activity training, and an online cognitive training.	Other: Nutritional Intervention; Participants will receive comprehensive dietary education from the nutritionists of the research team, aimed at improving their baseline diet by incorporating nutritional recommendations based on the Mediterranean diet and the Italian dietary guidelines for healthy eating.; Other: Physical Activity training; Participants will engage in a structured exercise program designed to improve motor competence and confidence. Tailored to each individual's baseline physical abilities and cardiorespiratory capacity, the program will focus on enhancing aerobic fitness, flexibility, and coordination.; Other: Cognitive training; Participants will undergo an online cognitive training program, with a particular focus on memory enhancement.
Active Comparator: Social Training group: Physical Activity, Diet and cognitive training; Participants will be provided with personalized dietary plan, a Physical Activity training, and a peer interaction program in ecological context.	Other: Nutritional Intervention; Participants will receive comprehensive dietary education from the nutritionists of the research team, aimed at improving their baseline diet by incorporating nutritional recommendations based on the Mediterranean diet and the Italian dietary guidelines for healthy eating.; Other: Physical Activity training; Participants will engage in a structured exercise program designed to improve motor competence and confidence. Tailored to each individual's baseline physical abilities and cardiorespiratory capacity, the program will focus on enhancing aerobic fitness, flexibility, and coordination.; Other: Social Training; A peer interaction program within an ecological setting, meant as a natural context of daily life, will be offered to participants. The program aims to improve active listening skills, comprehension of various communication styles (passive, assertive, aggressive), and the efficient recognition and management of emotions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In Vivo Leptin Sensitivity	Leptin sensitivity will be evaluated as the ratio between caloric intake during an experimental meal and circulating leptin levels. Participants will receive a standardized breakfast and after 3 hours an ad libitum lunch, with detailed records of consumption, additional food requests, and portion sizes. Hunger and satiety will be measured using a 5-item Visual Analogue Scale (VAS) at multiple time points, recorded in millimeters. Energy and nutrient intake will be assessed using nutritional labels from each food item, and leptin sensitivity will be determined via plasma fasting.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Ex Vivo Leptin Sensitivity	Since direct assessment of leptin sensitivity in the central nervous system is not feasible in humans, peripheral leptin sensitivity ex vivo will be evaluated using Peripheral Blood Mononuclear Cells (PBMCs). PBMCs will be collected from the same individuals before and after the intervention and exposed to recombinant leptin to assess intracellular signalling activation. The primary leptin effector pathway is Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3), though Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activation has also been reported among others. The activation of these pathways will be measured using immunoassays such as Enzyme Linked Immunosorbent Assay (ELISA) and Western blot, quantifying the ratio of phosphorylated to total protein levels for each intracellular effector.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Insulin Sensitivity and Secretion	Insulin sensitivity and secretion will be assessed both during fasting and the oral glucose tolerance test (OGTT).	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Energy Metabolism	Energy metabolism, including resting metabolic rate and diet-induced thermogenesis, will be measured by indirect calorimetry.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Fat Mass (percentage)	Fat mass will be estimated using bioelectrical impedance analysis and expressed as a percentage of total body weight.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Fat Mass (kilograms)	Fat mass will be estimated using bioelectrical impedance analysis and expressed in kilograms.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-Verbal Fluid Intelligence	Assessed using the Colored Progressive Matrices (CPM), a standardized test that measures the ability to recognize patterns and solve problems without reliance on language. The outcome is the global Intelligent Quotient (IQ) score, with a mean of 100 and a standard deviation of 15, measured in standardized scores.	At baseline (T0)
Working Memory	Evaluated through the N-Back Task, a computerized assessment of both visuo-spatial and verbal working memory. In the visuo-spatial condition, participants view randomly positioned blue boxes and determine whether the current position matches the previous one. In the verbal condition, they listen to a stream of letters and identify whether each letter matches the one immediately preceding it. The task adapts dynamically, increasing in difficulty when accuracy reaches or exceeds 80%. The outcome metric is the accuracy percentage at each difficulty level, measured in percentage of correct responses.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Sustained Attention and inhibitory control	Measured using the Continuous Performance Test-II (CPT-II), a computerized assessment of sustained attention and inhibitory control. Participants respond to any letter except "X" (Go trials) and withhold responses when "X" appears (No-Go trials). Reaction times and response variability provide insights into attentional performance. The outcome metrics include accuracy, reaction time (RT) in milliseconds, and reaction time variability (RTV) in milliseconds.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Episodic Long-Term Memory	To assess episodic long-term memory, the Verbal and Visual-Spatial Learning tasks from the standardized Battery for the evaluation of Memory (PROMEA) will be administered. The Verbal Learning Task presents a list of 15 unrelated words across 3 trials, followed by delayed recall after 15 minutes. Similarly, the Visual-Spatial Learning Task involves recalling the placement of 15 objects in 4 quadrants during 3 trials, with delayed recall after 15 minutes. The outcome metrics include the number of words or objects recalled across trials and the delayed recall score, expressed in standard scores and percentile ranks.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Visual-Motor Integration	Assessed using the Test of Visual Motor Integration (VMI), which evaluates the coordination between visual perception and motor function. It consists of 3 components: Visual Motor Integration, requiring participants to copy increasingly complex forms; Visual Perception, involving the identification of matching forms among distractors; and Fine Motor Coordination, assessing precision in connecting dots within defined boundaries. The outcome includes raw scores converted to standard scores, with a mean of 100 and a standard deviation of 15, as well as percentile ranks.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Gross and Fine Motor Skills	Measured using the Movement Assessment Battery for Children-2 (MABC-2), which evaluates motor skills through 3 components: Manual Dexterity, assessing fine motor control; Aiming and Catching, measuring coordination between fine and gross motor movements; and Balance, which examines static and dynamic postural control through structured physical tasks. The outcomes are expressed as standard scores (mean = 100, SD = 15) and percentile ranks.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Short-Term Memory	Evaluated using the Battery for Neuropsychological Evaluation of Children Battery (BVN 5-11), including the Digit Span and Corsi Block-Tapping Tests. The Digit Span Test requires participants to repeat sequences of numbers in the same or reversed order, assessing verbal short-term memory. The Corsi Block-Tapping Test involves replicating sequences of tapped blocks to assess visuo-spatial short-term memory. The score is determined by the number of items correctly recalled, expressed as Z-scores based on a normative sample, where a Z-score of 0 indicates the average performance of the normative group.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Behavioral and Emotional Symptoms	Assessed using the Child Behavior Checklist for Ages 6-18 (CBCL 6-18), a standardized parent-report questionnaire, comprised of 8 syndrome scales (anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behaviour, and aggressive behaviour), 3 broadband scores (internalizing and externalizing problems, and total problem), Diagnostic and Statistical Manual of mental disorders (DSM)-oriented scales (affective problems, anxiety problems, somatic problems, attention deficit/hyperactivity problem, oppositional defiant problems, conduct problems), and the 2007 Scales (sluggish cognitive tempo, obsessive-compulsive problems, post-traumatic stress problems). For each subscale raw scores will be converted in T-scores (M = 50, SD = 10).	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Ankle Dorsiflexion	Ankle dorsiflexion will be evaluated using the Knee to Wall test, in which the participant places one foot touching the wall and gradually moves back until being able to touch the wall with the knee while keeping the heel on the ground.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Joint Mobility	Joint mobility will be assessed through a Scapular-Humeral Circumduction test, conducted with a calibrated stick, where the result is the last completed circumduction with extended arms.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Trunk Strength	Trunk strength will be assessed using the Trunk Lift test, in which participants lie prone on a mat and lift their upper body off the floor to their maximum height. The distance between the floor and the participant's chin will be measured.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Flexibility: Sit and Reach Test	In the Sit and Reach test, participants sit with their legs extended and feet dorsiflexed against a 30 cm support, then perform a forward trunk flexion. The result is measured as the distance between the fingertips and the toes.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Flexibility: Lateral Trunk Flexion Test	Flexibility will also be assessed using the Lateral Trunk Flexion test, which records the difference between the initial hand position and the maximum lateral flexion.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Quality of Life: Physical, Emotional, Social, and School Functioning	The Pediatric Quality of Life Inventory (PedsQL version 4) is a widely used tool in studies involving children with obesity to measure key dimensions of health and quality of life. It includes domains of Physical, Emotional, Social, and School Functioning. Both child self-report and parent-report formats will be administered. Total Score and Psychosocial Health Summary Score will be calculated as percentages. Higher percentages indicate better functioning across these domains.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Social Adaptive Skills	The social skill domain will be investigated through the standardized parent-reported Adaptive Behavior Assessment System, Second Edition (ABAS-II), which will provide the Social Adaptive Composite (SAC), which summarizes performance across the Leisure and Social skill areas. Raw scores will be converted into standardized weighted scores (M = 10, SD = 3) and standard scores (M = 100, SD = 15).	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Social Skills	The Social Responsiveness Scale (SRS) will be used as well. The SRS is a standardized parent-report measure frequently used with children and adolescents between the ages of 4 and 18 years to screen subtle social communication deficits. The SRS generates 5 subscales: social awareness, social cognition, social motivation and social communication. Raw scores will be converted to gender-normed T-scores (M = 50, SD = 10).	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Eating Behavior and Disorders	The Eating Disorders Questionnaire in Childhood (EDQ-C) is a standardized tool used for the early identification of eating disorders in children, assessing comorbidities with attachment patterns, anxiety and mood disorders, as well as relational and behavioural difficulties. It includes a self-report version for children aged 8 and older, and 2 parent-report forms based on the child's age (4-7 and 8-12 years). For each diagnostic category, raw scores will be calculated and converted into standard score and percentile ranks (< 90 = within normal range, > 95 = clinically significant, > 99 = pathological).	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Sleep Habits and Quality	To assess sleep habits and quality, the Sleep Disturbance Scale for Children (SDSC) will be employed. This standardized parent-report questionnaire evaluates various aspects of children's sleep, including duration, onset time, sleep disorders and an overall measure of sleep disturbances in children and adolescents aged 6 to 15 years. Six main areas are investigated by the following subscales: Disorders in Initiating and Maintaining Sleep (DIMS), Sleep Breathing Disorders (SBD), Arousal Disorders (DA), Sleep-Wake Transition Disorders (SWTD), Excessive Sleepiness (DES), and Nocturnal Hyperhidrosis (NH). For each subscale raw scores will be converted in T-scores (M = 50, SD = 10).	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Brain Function	Brain responses will be studied through vascular brain activity to a glucose challenge, measured using functional near-infrared spectroscopy (fNIRS) in children and functional MRI (fMRI) in adults.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Plasma Analysis	Plasma samples will be analysed for circulating levels of adipokines and cytokines (R&D Systems, Inc. 614 McKinley Place NE Minneapolis, MN 55413), including Brain-Derived Neurotrophic Factor (BDNF), a key regulator of neural plasticity and appetite suppression, Pro-OpioMelanoCortin (POMC) and its derivative Melanocyte-Stimulating Hormone (MSH), which play a central role in the anorectic response to leptin, eotaxin/CCL11, a proinflammatory chemokine linked to age-related cognitive decline, and Insulin-like Growth Factor-Binding Protein 2 (IGFBP2), a liver-derived protein regulated by leptin and involved in glucose homeostasis.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Gut Microbioma	The composition of the gut microbiota will be assessed using genomic analysis of stool samples collected from participants. Fresh stool samples will be collected by participants at home, immediately frozen at approximately -20°C, and transported in a refrigerated box to the biobank. Upon arrival, the samples will be stored at -80°C until DNA extraction.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Muscle Strength: Upper Limb Strength	Upper limb strength will be evaluated with a Floor Press test using calibrated dumbbells based on each participant's strength.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Muscle Strength: Handgrip Strength	Handgrip strength will be assessed using a dynamometer.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Lower Limb Explosive Strength	Lower limb explosive strength will be measured with the Standing Long Jump test, where participants jump as far as possible, landing with both feet together; the best of two attempts will be considered.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Abdominal Strength and Endurance	Abdominal strength and endurance will be assessed with a Sit-Up test, where participants lie supine with their legs bent at 90° and perform sit-ups, with the result being the maximum number of repetitions performed.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.
Balance	Balance will be assessed using the Single Leg Stance test, where participants maintain a single-leg stance within a shoe-sized rectangle for 60 seconds, with the number of falls recorded.	At baseline (T0), at the end of the 8-week intervention (T1, end of month 2), and 12 weeks after the intervention (T2, end of month 5) to verify the persistence of effects.

Collaborators and Investigators

• Sponsor: Bambino Gesù Hospital and Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: March 24, 2025
• First Submitted That Met QC Criteria: April 9, 2025
• First Posted (Actual): April 17, 2025

Study Record Updates

• Last Update Posted (Actual): April 17, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: physical activity; obesity; overweight; childhood obesity; leptin; cognitive training; energy expenditure; lifestyle modification; thermogenesis; environmental enrichment; social training; leptin sensitivity; leptin resistance
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity; Pediatric Obesity
• Other Study ID Numbers: PNRR-MAD-2022-12376459

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared upon reasonable request, subject to validation by the OPBG Ethics Committee, in compliance with GDPR and European regulations. Alternatively, aggregated data may be considered.
• IPD Sharing Time Frame: The time frame for data availability will be determined in accordance with GDPR and relevant European regulations.
• IPD Sharing Access Criteria: Access to the IPD and supporting information will be granted to the Principal Investigator (PI) of the research, Dr. Melania Manco (melania.manco@opbg.net).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No