Role of Immune System in Obesity-related Inflammation and Cardiometabolic Risk

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to learn more about how the body stores fat in and around organs (for example in the liver) and why this affects some people's health more than others. Understanding this may lead to better treatments for diseases such as diabetes and cardiovascular disease.

Detailed Description
-----------------
The purpose of this study is to determine the specific cellular and organ system metabolic and immunologic alterations that are associated with insulin resistance and inflammation in order to identify putative mechanisms and novel bio-markers involved in the pathogenesis and progression of inflammatory and cardiometabolic diseases.

Official Title
-----------------
Role of Immune System in Obesity-related Inflammation and Cardiometabolic Risk

Conditions
-----------------
Non-alcoholic Fatty Liver Disease, Metabolic Syndrome, Metabolically Abnormal Obesity, Metabolically Normal Obesity, Obesity

Intervention / Treatment
-----------------
* Other: Weight loss


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Lean, metabolically healthy group - Body mass index (BMI) 18.5-24.9 kg/m2, HbA1C ≤5.6%, fasting plasma glucose concentration <100 mg/dl, 2-h OGTT plasma glucose concentration <140 mg/dl and intrahepatic triglyceride (IHTG) content ≤5%. Obese, metabolically healthy group - BMI ≥30 kg/m2, HHbA1C ≤5.6%, fasting plasma glucose concentration <100 mg/dl, 2-h OGTT plasma glucose concentration <140 mg/dl and intrahepatic triglyceride (IHTG) content ≤5%. Obese, metabolically healthy group - BMI ≥30 kg/m2, IHTG content ≥5.6% and HbA1C ≥5.7% or fasting plasma glucose concentration ≥100 mg/dl or 2-h OGTT plasma glucose concentration ≥140 mg/dl. Lean, scheduled for inguinal hernia, hysterectomy or myomectomy surgery - BMI 18.5-24.9 kg/m2, HbA1C ≤5.6%, fasting plasma glucose concentration <100 mg/dl, 2-h OGTT plasma glucose concentration <140 mg/dl and IHTG content ≤5%. Obese, scheduled for bariatric and gallbladder surgery - BMI ≥35.0kg/m2 Exclusion Criteria: active or previous history of liver diseases other than NAFLD history of alcohol abuse currently consuming ≥20 g alcohol/day severe hypertriglyceridemia (>300 mg/dL) smoke tobacco cancer diagnosis within the previous 5 years medications that might confound the study results pregnancy or lactation exercise >2 h/week

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Lean, metabolically normal<br>Subjects with body mass index 18.5 - 24.9 kg/m² and normal fasting blood glucose and oral glucose tolerance and liver fat. | |
| No Intervention: Obese, metabolically normal<br>Subjects with body mass index ≥30.0 kg/m² and normal fasting blood glucose and oral glucose tolerance and liver fat. | |
| No Intervention: Obese, metabolically abnormal<br>Subjects with body mass index ≥30.0 kg/m² and impaired fasting or oral glucose tolerance and increased liver fat. | |
| Experimental: Obese, scheduled for bariatric surgery<br>Subjects with a body mass index ≥35.0 kg/m² undergoing bariatric surgery | Other: Weight loss<br>* Bariatric surgery-induced weight loss to achieve  20%-30% reduction in initial body weight<br>|
| No Intervention: Obese, scheduled for gallbladder surgery<br>Subjects with a body mass index ≥35.0 kg/m² undergoing gallbladder surgery | |
| No Intervention: Lean, scheduled for inguinal hernia, hysterectomy or myomectomy surgery<br>Subjects with body mass index 18.5 - 24.9 kg/m² and normal fasting blood glucose and oral glucose tolerance and liver fat. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity | Insulin sensitivity assessed in vivo by using a hyperinsulinemic-euglycemic clamp procedure with stable isotope tracer infusion | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TNF-alpha | TNF-alpha is a marker of inflammation | Baseline | 
| Interleukin-6 (IL-6) | Interleukin-6 is a marker of inflammation | Baseline | 
| Liver tissue inflammation | Liver immune cell content | Baseline | 
| Abdominal adipose tissue inflammation | Subcutaneous, omental and transverse mesocolic adipose tissue | Baseline only in participants scheduled for bariatric surgery | 
| Abdominal adipose tissue inflammation | Subcutaneous and omental adipose tissue | Baseline only in participants scheduled for gallbladder, inguinal hernia, hysterectomy or myomectomy surgery | 
| Upper vs lower adipose tissue inflammation | Immune cell content in abdominal and femoral subcutaneous adipose tissue | Baseline (All groups) | 
| Exosome-mediated intercellular signaling | Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood, subcutaneous, omental and transverse mesocolic adipose tissue and liver. | Baseline only in participants scheduled for bariatric surgery | 
| Exosome-mediated intercellular signaling | Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood, subcutaneous and omental adipose tissue | Baseline only in participants scheduled for gallbladder, inguinal hernia, hysterectomy or myomectomy surgery | 
| Exosome-mediated intercellular signaling | Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and abdominal and femoral subcutaneous adipose tissue. | Baseline only in all participants | 
| Change in exosome-mediated intercellular signaling | Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue | Before and after 20-30% weight loss ( 3-4 months) in participants scheduled for bariatric surgery | 
| Hepatic PNPLA3 synthesis rate | Synthesis rates assessed by stable isotope techniques in the fasted vs the fed states | Baseline only in people scheduled for gallbladder or bariatric surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NAFLD, Obesity, Metabolic syndrome