Role NLRP3 Inflammasome in Weight Loss Following Sleeve Gastrectomy in Morbidly Obese Patients

Study Overview
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Brief Summary
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Epidemiological studies show a very rapid increase in the epidemic of obesity in the Caribbean population. 6 out of 10 adults are overweight and 1 out of 4 is obese. Most are women. Consequences : harm to health and possible reduction in life expectancy due to the association with many cardiovascular comorbidities. Adverse effects of obesity on the cardiovascular and endocrine systems are attributed a chronic low-grade inflammatory state in obese patients. Visceral adipose tissue is largely responsible for the inflammatory syndrome. Obesity can also induce the formation of multi-protein platforms called inflammasomes also activated by mitochondrial production. Morbid obesity treatment with sleeve gastrectomy is an effective long term therapeutic for weight loss but also beneficial in terms of insulin resistance and cardiovascular complications. Some patients nevertheless remain resistant to the beneficial cardio-metabolic effects of bariatric surgery. However, the mechanisms that regulate the extent of weight loss and its stabilization after bariatric surgery are still poorly understood. Our study aims to describe the evolution of postoperative weight loss and the place of preoperative inflammation in its amplitude. The hypothesis is that the level of inflammation in visceral fat before surgery determines the extent of postoperative weight loss in obese women who have undergone sleeve gastrectomy.

Detailed Description
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Epidemiological studies show a very rapid increase in the epidemic of obesity in the Caribbean population. The latest prevalence data in Martinique show that 6 out of 10 adults are overweight and 1 out of 4 is obese (Body Mass Index, BMI ≥ 30 kg/m2). Obesity with a BMI ≥ 35 kg/m2 is said to be morbid because of its association with numerous cardiovascular comorbidities. A balanced diet and physical activity are effective behavioural modalities for weight loss, which, even at low intensity, can reduce cardiovascular complications and the risk of death. However, many patients do not adhere to these constraints over a long period of time and about 50% of them regain weight after the first year. These observations highlight the value of alternative therapies with lasting effects on weight loss and the cardio-metabolic comorbidities of obesity. Bariatric surgery with vertical calibrated vertical gastroplasty with gastric resection (or sleeve gastrectomy) and Roux-en-Y gastric bypass are therapeutic options that are not only effective in the long term for weight loss but also beneficial in terms of insulin resistance and cardiovascular complications. Bariatric surgery is currently indicated for the treatment of morbid obesity with a BMI ≥ 40 kg/m2 or a BMI ≥ 35 kg/m2 in the presence of complications. Some patients nevertheless remain resistant to the beneficial cardio-metabolic effects of bariatric surgery. The reasons for this resistance are attributed to factors such as age > 60 years, female sex, BMI > 45 kg/m2, African-American or Hispanic origin, and history of type 2 diabetes. Regardless of these factors, several studies have pointed out that a chronic low-grade inflammatory state reduces the magnitude of weight loss and thus counters the beneficial cardio-metabolic effects of bariatric surgery. Visceral adipose tissue is largely responsible for the inflammatory syndrome in obese patients, via the activation of nuclear transcription factors (NFkB, in particular) that stimulate the synthesis of numerous mediators and pro-inflammatory cytokines. Obesity can also induce the formation of multi-protein platforms called inflammasomes, including the active assembly of inflammatory caspases (caspase-1, in particular) that cleave the pro-interleukins IL1β and IL18 into mature pro-inflammatory cytokines IL1β and IL18. The role of the inflammasome NLRP3 (NOD-like receptor family, pyrin domain containing 3) in the inflammatory response has been particularly studied in humans due to its association with multiple chronic inflammatory, infectious and cardio-metabolic pathologies. Among the biomolecules responsible for activation of the NLRP3 inflammasome during obesity are palmitate, sphingolipids and cholesterol crystals. The NLRP3 inflammasome is also activated by mitochondrial production of reactive oxygen species (ROS) and by mitochondrial DNA released from mitochondria damaged by lipo-toxicity phenomena associated with obesity. More generally, the mitochondrial dysfunction of the metabolic syndrome is considered to be the causal intracellular event of the deregulation of the inflammatory response mediated by the inflammasome.

Official Title
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Role of NLRP3 Inflammasome Activation of Adipose Tissue in the Progression of Weight Loss After Sleeve Gastrectomy in Morbidly Obese Patients.

Conditions
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Obesity Morbid, Obesity-Associated Insulin Resistance

Intervention / Treatment
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* Procedure: Sleeve gastrectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Being a woman between the ages of 18 and 45; Have been well informed about bariatric surgery and perioperative risks and have benefited from a multidisciplinary evaluation by a multidisciplinary team (RCP) ; Have a BMI greater than or equal to 40 kg/m2 or greater than or equal to 35 kg/m2 with at least one co-morbidity that can be improved after surgery (cardiovascular disease, sleep apnea and severe respiratory disorders, type 2 diabetes, osteoarticular diseases) Have been informed of the research on the samples taken during care; Having stated its decision not to object to the research on the samples taken during the treatment; To have accepted medical and surgical follow-up for 24 months; Patient under the general social security system. Exclusion Criteria: Being a pregnant or nursing woman; Being a type 1 diabetic; Have inflammatory bowel disease; Have severe and unstable eating disorders ; Have severe, uncontrolled cognitive, mental or psychological disorders; Have a cancerous pathology; Be addicted to alcohol and psychoactive substances (both legal and illegal); Have a life-threatening illness in the short or medium term; Have contraindications related to surgical operations in general such as general anaesthesia; Be under legal protection measures (guardianship, curators, safeguarding of justice), and person deprived of liberty.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Procedure: Sleeve gastrectomy|Measure of NLRP3 inflammasome preoperative activation level by the expression of NLRP3, IL-1β, IL18 and caspase-1 mRNAs in subcutaneous and visceral adipose tissue. of the epiploon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight loss (kg) at 12 months of sleeve gastrectomy | Magnitude of weight loss (kg) at 12 months of sleeve gastrectomy as a function of the level of preoperative activation of the NLRP3 inflammasome. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preoperative activation level of the NLRP3 inflammasome | Preoperative activation level of the NLRP3 inflammasome will be measured by the expression of NLRP3, IL-1β, IL18 and caspase-1 mRNAs in subcutaneous and visceral adipose tissue of the epiploon; expressed as mRNA copy number measured in quantitative RT-PCR (RT-qPCR) | 1 day | 
| Mitochondrial activity | Preoperative levels of oxygen consumption by the mitochondrial respiratory chain (pmol O2*s-1*mg-1 of dry tissue) | 1 day | 
| Pre and post operative inflammatory state | Pre- and post-operative plasma levels of CRP and proinflammatory cytokines IL-1β and IL18 (pg/mL). Postoperative measurements will be done up to 6 months after bariatric surgery. In addition, since fat tissue sampling is not justified postoperatively, activation of the NLRP3 inflammasome will be assessed indirectly by plasma concentrations of the cytokines IL-1β and IL18 | 24 months | 
| Pre and post-operative BMI | Weight and height will be combined to report BMI in kg/m^2) at pre- and post-operative | 24 months | 
| Pre and post-operative abdominal perimeter | Abdominal perimeter in centimeter at pre- and post-operative (24-month follow-up). | 24 months | 
| Pre and post-operative hip circumference | Hip circumference in centimeter at pre- and post-operative (24-month follow-up). | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, cardiovascular risk, diabetes