Metabolic Phenotyping for Personalized Obesity Therapy

Summary

This study aims to develop a simple, clinically applicable method for metabolic phenotyping to personalize obesity therapy in morbidly obese individuals. The underlying concept is that the way a person's resting metabolic rate (RMR) responds to a 24-hour fast can help distinguish between two metabolic phenotypes. Individuals with a "thrifty" metabolism show a significant drop in RMR during fasting, which may make them less responsive to conventional weight loss interventions. In contrast, those with a "spendthrift" metabolism exhibit little to no drop-or even a slight increase-in RMR, suggesting they may lose weight more readily. The trial is designed as a prospective, single-center, longitudinal cohort study involving 20 morbidly obese patients (BMI \>40 kg/m²) who are already participating in a multimodal obesity therapy program. The study is divided into three phases. In the baseline phase, participants undergo comprehensive screening, which includes physical examinations, blood tests, and body composition assessments. RMR is measured using indirect calorimetry both before and after a 24-hour fasting period, and a device (Lumen™) is used to assess whether the body is primarily burning carbohydrates or fats. After the fasting measurements, participants perform a low-protein meal test by consuming a specially calibrated chocolate beverage. Their RMR is then monitored at several time points to determine the energy required for digestion. Following this, the study moves into the very-low-calorie diet (VLCD) phase, where participants consume approximately 800 kcal per day using formula meals tailored to meet their nutritional needs despite the calorie restriction. During this 12-week phase, changes in body weight, composition, and metabolic parameters are closely monitored. The final phase of the study is a 12-week weight maintenance period, during which the focus is on sustaining the achieved weight loss. In addition to RMR and dietary assessments, advanced techniques such as metabolomics are employed. Blood, urine, and saliva samples are collected to analyze metabolic profiles and identify potential hormonal biomarkers-such as leptin, FGF21, and adrenaline-that could further differentiate the "thrifty" and "spendthrift" phenotypes. Body composition is also assessed using methods like bioimpedance analysis (BIA), quantitative magnetic resonance imaging (qMR), and air displacement plethysmography (BodPod). By correlating the changes in RMR with metabolic and hormonal markers, the study tests the hypothesis that individuals with a marked RMR decrease during fasting (the "thrifty" phenotype) may experience less weight loss during a hypocaloric diet compared to those with minimal RMR change (the "spendthrift" phenotype). If validated, this approach could allow clinicians to predict weight loss outcomes more accurately and tailor obesity treatments to the individual's unique metabolic profile.

Eligibility

Inclusion Criteria:

* Morbid obesity (BMI \> 40 kg/m²)
* Currently undergoing a multimodal obesity therapy program at the Department of Internal Medicine I at the University Hospital Schleswig-Holstein (UKSH), Campus Kiel

Exclusion Criteria:

* Type 1 or Type 2 diabetes mellitus, or fasting blood glucose \>125 mg/dL, or HbA1c \>6.5%
* Conditions affecting appetite or energy expenditure (e.g., Cushing's syndrome, uncontrolled hyper-/hypothyroidism, diabetes mellitus)
* Gastrointestinal diseases that may impair nutrient absorption (e.g., inflammatory bowel disease, malabsorption syndromes, peptic ulcers)
* Psychiatric disorders that influence eating behavior (e.g., active depression, anorexia nervosa, bulimia nervosa, borderline personality disorder)
* Acute, unstable cardiovascular disease requiring hospitalization within the last 6 months (e.g., stent implantation)
* Cancer requiring treatment within the past 5 years
* Chronic kidney disease at Stage IV or worse according to NKF criteria
* Active infectious disease (e.g., HIV, hepatitis)
* Active nicotine use
* Drug use (e.g., amphetamines, cocaine, heroin, marijuana)
* Regular intense physical activity (≥1 hour of sport per day)
* Non-MRI-compatible metallic implants (e.g., joint replacements, metal plates)
* Pregnancy or breastfeeding
* Use of weight-loss medications
* Clinically relevant claustrophobia
* Any other condition not specified above that, in the judgment of the investigator, could interfere with study participation or compromise patient safety

Conditions2

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