Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease.

Abstract

BACKGROUND AND AIMS:

Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD.

METHODS:

Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants.

RESULTS:

Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes.

CONCLUSIONS:

Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).

• Authors: Anja Fuchs, Dmitri Samovski, Gordon I Smith, Vincenza Cifarelli, Sarah S Farabi, Jun Yoshino, Terri Pietka, Shin-Wen Chang, Sarbani Ghosh, Terence M Myckatyn, Samuel Klein
• Journal: Gastroenterology (Gastroenterology) Vol. 161 Issue 3 Pg. 968-981.e12 (09 2021) ISSN: 1528-0012 [Electronic] United States
• PMID: 34004161 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Blood Glucose
• Cytokines
• Insulin
• Plasminogen Activator Inhibitor 1
• SERPINE1 protein, human

Topics

• Adult
• Animals
• Biomarkers (blood)
• Blood Glucose (metabolism)
• Cells, Cultured
• Cytokines (blood)
• Exosomes (immunology, metabolism)
• Female
• Hepatocytes (metabolism)
• Humans
• Insulin (blood)
• Insulin Resistance
• Liver (metabolism)
• Macrophages (immunology, metabolism)
• Male
• Memory T Cells (immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Muscle Fibers, Skeletal (metabolism)
• Non-alcoholic Fatty Liver Disease (blood, diagnosis, immunology, physiopathology)
• Obesity (blood, diagnosis, immunology, physiopathology)
• Plasminogen Activator Inhibitor 1 (blood)
• Subcutaneous Fat, Abdominal (immunology, metabolism)
• Tissue Culture Techniques