Harnessing Macrophage Lysosomal Lipid Metabolism in Obesity

Harnessing Macrophage Lysosomal Lipid Metabolism in Obesity-Associated Diseases

The goal of this study is to evaluate the role of transcription factor EB (TFEB) in adipose (fat) tissue macrophages (ATM) in regulating adipose tissue and systemic metabolic function in obesity. The investigators will assess the differences in ATM lipid metabolism in people with metabolically abnormal obesity and lean individuals.

Both groups will have:

• screening visit
• imaging (body composition testing - dual-energy x-ray absorptiometry (DEXA) scans, magnetic resonance imaging [MRI] and magnetic resonance spectroscopy [MRS] scans)
• Overnight visit with intravenous infusion (IV), muscle, and fat tissue biopsies Participants with obesity will complete meetings with study team members for a weight loss intervention to achieve a 10% body weight loss.

Inclusion Criteria :

• age: ≥18 but ≤70 years
• not pregnant or breastfeeding
• weight stable and sedentary before enrollment
• no use tobacco products, excessive amounts of alcohol, or dietary supplements, or medications known to or suspected to affect glucose and lipid metabolism (aside from certain medications used to treat diabetes in the metabolically abnormal obesity [MAO]-Type 2 Diabetes group)
• no evidence of significant organ system dysfunction or disease (e.g. chronic severe kidney disease, cancer)
• participants must fulfil all of the following group-specific inclusion criteria below:

Lean group:

• Body mass index (BMI) ≥18.5 but <25.0 kg/m2
• Intrahepatic triglyceride (IHTG) content <5%
• fasting blood glucose concentration: <100 mg/dl
• blood glucose concentration 2 h after a 75 g oral glucose challenge: <140 mg/dl
• Hemoglobin A1C (HbA1c) <5.7 %

Metabolically normal obesity (MNO) group:

• BMI ≥30.0 but <45.0 kg/m2
• IHTG content <5%
• fasting blood glucose concentration: <100 mg/dl
• blood glucose concentration 2 h after a 75 g oral glucose challenge: <140 mg/dl
• HbA1c <5.7 %

Metabolically abnormal obesity (MAO)-insulin resistance and non-alcoholic fatty liver disease (NAFLD) group:

• BMI ≥30.0 but <45.0 kg/m2
• IHTG content >7.5%
• fasting blood glucose concentration: ≥100 but <126 mg/dl
• blood glucose concentration 2 h after a 75 g oral glucose challenge: ≥140 but <200 mg/dl
• HbA1c: ≥5.7 but <6.4 %

MAO-type 2 diabetes group:

• BMI ≥30.0 but <45.0 kg/m2
• clinical diagnosis of type 2 diabetes or fasting blood glucose concentration >126 mg/dl or blood glucose concentration 2 h after a 75 g oral glucose challenge>200 mg/dl or HbA1c >6.4 % without medication if not diagnosed and medically treated for diabetes

Exclusion Criteria:

- Individuals that do not meet all inclusion Criterion