Impact of Metformin on Leptin Transport in Cerebrospinal Fluid of Obese Patients

Study Overview
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Brief Summary
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Obesity, a major health problem, is gradually transforming into a global epidemic. The current obesity treatment with long term efficacy is the bariatric surgery, however, the operative risk of this procedure is high and the post-operative iotrogeny may be important. Obesity is most often associated to the feeding behavior which depends on hypothalamic integration of peripheral signals such as leptin and glucose. High levels of circulating leptin are detected in obese patients. These elevated leptin levels fail to reduce appetite or increase energy expenditure. The mechanism underlying this non-integration of peripheral signals remains to be identified. The ratio of leptin levels in the cereprospinal fluid (CSF) and in the periphery is drastically decreased in obese patients when compared to lean individuals, therefore a defective transport of circulating leptin into the brain via the CSF is maybe linked to obesity.

Detailed Description
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We hypothesize that the alteration of leptin transport into the CSF of obese patients could be modulated by drugs such as metformin which is widely used worldwide to treat diabetes. This study is monocentric, prospective, one-arm type and interventional. The main objective isto evaluate the impact of metformin on the transport of leptin into the CSF of obese patients. We propose to show a variation of CSF leptin / serum leptin before and after metformin treatment and study its association with changes in hypothalamic metabolic activity, cognitive and appetite-related behaviors and ratio of other metabolic signals. This would support the hypothesis of modulation of resistance to peripheral leptin by metformin and thus uncover a new indication for metformin treatment towards the management of obesity. For this purpose, volunteers will be subjected to blood sampling via venipuncture, CSF collection via lumbar puncture, MRI assessments and questionnaires (cognitive tests, food survey and feeding behavior) before and after a 3-month metformin treatment.

Official Title
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Study of the Communication of the Hypothalamus With the Periphery: Impact of Metformin on Leptin Transport in the Cerebrospinal Fluid of Obese Patients. A Monocentric Prospective Study

Conditions
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Obesity Without Type 2 Diabetes, With BMI>30

Intervention / Treatment
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* Drug: Metformin Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults between 18 and 40 years old Body mass index >30 For childbearing age women: use of an effective contraceptive method for the duration of the study Patients willing to participate in the study and who have signed the informed consent form Patients with health insurance Exclusion Criteria: Genetic obesity Type 2 diabetes defined by 2 fasting blood glucose >1,26g/L or blood glucose >2 g/L at 120 min of oral glucose tolerance test with 75 g of glucose Patients already treated with metformin Type 1 diabetes Active neoplastic pathology, diagnosed < 5 years, or in treatment Neurological pathology (demyelinating, tumor, vascular) Adipose tissue pathology (lipodystrophy) History of bariatric surgery Contraindication to metformin Lumbar puncture contraindication MRI contraindication Person unable to consent, or benefiting from a legal protection regime (guardianship/curatorship/guardianship of justice) Pregnant or breastfeeding woman Contra-indication to impedance measurement Contraindication to indirect calorimetry: claustrophobia Taking a psychotropic drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obese patients<br>Patients with body mass index >30 | Drug: Metformin Oral Tablet<br>* Day 1 to day 3: 500 mg/day Day 4 to day 6: 500 mg/twice a day Day 7 to day 9: 500 mg three times a day Day 10 until next lumbar puncture : 850 mg three times a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cerebrospinal fluid /plasma leptin ratio |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cerebrospinal fluid /plasma glucose ratio |  | at day 0, 3 months | 
| cerebrospinal fluid /plasma glucagon like peptide 1 (GLP1) ratio |  | at day 0, 3 months | 
| cerebrospinal fluid /plasma insulin ratio |  | 3 months | 
| cerebrospinal fluid /plasma ghrelin ratio |  | at day 0, 3 months | 
| Cerebrospinal fluid levels of Agouti-Related Peptide (AgRP) |  | at day 0, 3 months | 
| Plasma levels of Agouti-Related Peptide (AgRP) |  | at day 0, 3 months | 
| Cerebrospinal fluid levels of proopiomelanocortin (POMC) |  | at day 0, 3 months | 
| Plasma levels of proopiomelanocortin (POMC) |  | at day 0, 3 months | 
| Cerebrospinal fluid levels of neuropeptide Y (NPY) |  | at day 0, 3 months | 
| Plasma levels of neuropeptide Y (NPY) |  | at day 0, 3 months | 
| Cerebrospinal fluid levels of leptin soluble receptor |  | at day 0, 3 months | 
| Plasma levels of leptin soluble receptor |  | at day 0, 3 months | 
| Apparent diffusion coefficient (ADC) | Apparent diffusion coefficient (ADC) is a measure of the magnitude of diffusion (of water molecules) within tissue, and is commonly clinically calculated using Magnetic resonance imaging (MRI). An ADC of a tissue is expressed in units of mm2/s | at day 0, 3 months | 
| Hypothalamic concentration of N-acetyl-aspartate (NAA) | This concentration will be measure by spectroscopy | at day 0, 3 months | 
| Hypothalamic concentration of creatine | This concentration will be measure by spectroscopy | at day 0, 3 months | 
| Hypothalamic concentration of Choline | This concentration will be measure by spectroscopy | 3 months | 
| Hypothalamic concentration of Glutamine / glutamate | This concentration will be measure by spectroscopy | at day 0, 3 months | 
| Hypothalamic concentration of gamma-aminobutyric acid (GABA) | This concentration will be measure by spectroscopy | at day 0, 3 months | 
| Weight |  | at day 0, 3 months | 
| Abdominal circumference |  | 3 months | 
| Percentage of body fat | This parameter will measure by bioelectrical impedance analysis (BIA). A weak electric current flows through the body and the voltage is measured in order to calculate impedance (resistance) of the body. | at day 0, 3 months | 
| Fat free mass (Kg) | This parameter will measure by bioelectrical impedance analysis (BIA). A weak electric current flows through the body and the voltage is measured in order to calculate impedance (resistance) of the body. | at day 0, 3 months | 
| Energy expenditure | This parameter will measure by indirect calorimetry (kCal / 24h) | at day 0, 3 months | 
| Score of the Three Factor Eating Questionnaire (TFEQ) | The TFEQ contains 51 items and measures three dimensions of eating behavior: cognitive restraint of eating' (Factor I - 21 items) disinhibition (Factor II - 16 items) hunger (Factor III - 14 items) Each item scores either 0 or 1 point. The minimum score for factors I-II-III is therefore 0-0-0, the possible maximum score 21-16-14 | 3 months | 
| Score of the Dutch Eating Behaviour Questionnaire (DEBQ) | This is a 33-item self-report questionnaire to assess three distinct eating behaviors in adults: (1) emotional eating, (2) external eating, and (3) restrained eating. Items on the DEBQ range from 1 (never) to 5 (very often), with higher scores indicating greater endorsement of the eating behavior. | at day 0, 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metformin, leptin, cerebrospinal fluid