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.
a condition of overweight or obesity
Intelligence Quotient (IQ) ≥ 85
genetic or syndromic obesity;
reduced mobility;
systemic diseases;
ongoing pharmacological treatment for chronic conditions.
Factorial
Nutritional Intervention
Other interventionParticipants 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.
Physical Activity training
Other interventionParticipants 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.
Cognitive training
Other interventionParticipants will undergo an online cognitive training program, with a particular focus on memory enhancement.
Social Training
Other interventionA 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.
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.
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.
Insulin Sensitivity and Secretion
Insulin sensitivity and secretion will be assessed both during fasting and the oral glucose tolerance test (OGTT).
Energy Metabolism
Energy metabolism, including resting metabolic rate and diet-induced thermogenesis, will be measured by indirect calorimetry.
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.
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.
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.
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.
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