Energy -Sensing Metabolites in Caloric Restriction

Study Overview
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Brief Summary
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General integrated goal of the coordinated project: To elucidate the role of succinate and other metabolites derived from the intestinal microbiota such as Short Chain Fatty Acids (SCFAs), as energy sensing metabolites in the context of obesity and type 2 diabetes (T2D). Specific objectives of Subproject 1 (SP1): 1a. - To investigate whether intermittent fasting (IF) is better than Continued Daily Caloric Restriction (DCR) in terms of metabolic improvement through the study of: 1) the dynamics of gastrointestinal hormones and energy sensing metabolites, 2) the intestinal microbiome, 3) variability on succinate and SCFAs, MCFAs and Biliary Acid after weight loss; Methodology: clinical study: randomized, cross-over design, study participants (n=15) will consume either lifestyle recommendations for a healthy Mediterranean diet under a continued caloric restriction diet (DCR) or will undertake an intermittent (IF) protocol. Clinical, anthropometrical and functional studies. Metabolomics for gut derived metabolites in plasma. Enteroendocrine gastrointestinal dynamics. Metagenomic analysis.

Detailed Description
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To investigate whether IF is better than DCR in terms of metabolic improvement through the study of: the dynamics of gastrointestinal hormones and energy sensing metabolites the intestinal microbiome variability on succinate and SCFAs MCFAs and BA after weight loss Human study protocol: A pilot clinical trial in human study participants will be assayed. Participants for intermittent fasting (IF) will be asked to fast for 24 hours on two days of the week (2/5 protocol). 1A.-Design: Utilizing a randomized, cross-over design, study participants (n=15) will consume either lifestyle recommendations for a healthy Mediterranean diet under a continued daily caloric restriction diet (DCR) or will undertake an intermittent (IF) protocol. Each study period will be 8 weeks - total study period will be 16 weeks + a 4-week washout period between dietary exposures. The study participants will be adults who have obesity with a Body Mass Index (BMI)25 kg/m2 and 40 kg/m2 and have no contraindications for intermittent fasting (see inclusion and exclusion criteria below).

Official Title
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New Energy-sensing Metabolites: Beneficial Effects on Metabolic Health in Obesity Comparing Diary Caloric Restriction vs Intermittent Fasting. A Randomized Cross-over Study

Conditions
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Obesity, Insulin Sensitivity/Resistance, Diabetes Type 2

Intervention / Treatment
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* Other: dietary intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: White men and women between 18 and 65 years of age. BMI range between 25 and 40 kg/m2 Absence of underlying pathology in medical and physical examination, except for those related to excess weight. Signature of the informed consent for participation in the study. Exclusion Criteria: Serious systemic disease not related to obesity, such as cancer, kidney or severe liver disease. Systemic diseases with intrinsic inflammatory activity (autoimmune diseases such as rheumatoid arthritis and asthma) Pregnancy and lactation. Vegetarians or subjects subjected to an irregular diet. Patients with severe eating disorders. Patients with clinical symptoms and signs of infection in the previous month. Patients with chronic anti-inflammatory steroid treatments and/or nonsteroidal anti-inflammatory drugs. Recent antibiotic treatment. Psychiatric history. Uncontrolled alcoholism or drug abuse.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: clinical study: randomized, cross-over design, study participants will consume either lifestyle recommendations for a healthy Mediterranean diet under a continued caloric restriction diet (DCR) or will undertake an intermittent (IF) protocol
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: conventional caloric restriction diet<br>(DCR protocol): lifestyle recommendations for a healthy Mediterranean diet under a continued daily caloric restriction diet | Other: dietary intervention<br>* Chronic caloric restriction diet vs intermittent fasting on energy sensing metabolites and metabolic homeostasis<br>|
| Other: Intermitent fasting<br>Fasting for two days (non-consecutive) out of seven, with the fasting days separated by at least one day. | Other: dietary intervention<br>* Chronic caloric restriction diet vs intermittent fasting on energy sensing metabolites and metabolic homeostasis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate whether IF is better than DCR in terms of metabolic improvement through the study (change in the secretory pattern of glucose) | Plasma concentrations of glucose during a meal test | basal and after 8 weeks | 
| To investigate whether IF is better than DCR in terms of metabolic improvement through the study (change in the secretory pattern of insulin) | Plasma concentrations of insulin during a meal test | basal and after 8 weeks | 
| To investigate whether IF is better than DCR in terms of metabolic improvement through the study (change in the secretory pattern of glucose after crossing arm) | Plasma concentrations of glucose during a meal test | at beginning of week 12 vs week 20 | 
| To investigate whether IF is better than DCR in terms of metabolic improvement through the study (change in the secretory pattern of insulin after crossing arm) | Plasma concentrations of insulin during a meal test | at beginning of week 12 vs week 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1) the dynamics of gastrointestinal hormones and energy sensing metabolites | GLP-1; GLP-2 during a meal test | 8 weeks - 20 weeks | 
| 2) Analysis of microbial species in fecal samples (gut flora) | intestinal microbiome after each interventional period | 8 weeks - 20 weeks | 
| variability on succinate after weight loss | quantification of succinate | 8 weeks - 20 weeks | 
| variability on Short-chain fatty acids (SCFAs) after weight loss | quantification of SCFAs | 8 weeks - 20 weeks | 
| variability on Medium-chain fatty acids (MCFAs) after weight loss | quantification of MACFAs | 8 weeks - 20 weeks | 
| variability on biliary acids (BA) after weight loss | quantification of BA | 8 weeks - 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, intermittent fasting, energy-sensing metabolites, obesity