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

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.

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.

Eligibility Criteria:
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