Endocrine Abstracts

Introduction: Central obesity is a significant risk factor for type 2 diabetes mellitus (T2DM), with omental adipose tissue (AT) particularly involved in such risk. Additionally, obesity can cause low-level gut-derived endotoxemia, which may drive metabolic dysfunction in AT through mitochondrial damage and reduced BRITE (brown-in-white) adipocytes. Bariatric surgery reduces obesity and may prevent such dysfunction. This study investigated whether endotoxin: 1) impairs mitochondrial function and reduces browning in human AT, 2) has a depot specific effect on pathogenic risk, 3) has reduced impact following bariatric surgery.

Methods: Ex-vivo AT was collected from human abdominal subcutaneous (AbdSc) and omental (AbdOm) depots (n=134) from Caucasian women (lean:BMI=22.3±1.9 kg/m2, age=32.0±5.2, n=38; overweight (OW):BMI=27.3±1.4 kg/m2, age=31.5±7.5, n=40; obese (OB):BMI=38.1±6.1 kg/m2, age=40.8±12.9, n=63). Sub-cohort analysis of participants with severe obesity (BMI>35 kg/m2) examined AbdScAT pre- and post-bariatric surgery (BMI=42.2±5.6 kg/m2, age=54.5±5.9, n=26). Mitochondrial function and adipocyte browning genes, and serum endotoxin were assessed.

Results: With increased weight, rising endotoxin levels correlated with reduced mitochondrial fission and fusion in AbdOmAT, noted by FIS1 (P<0.05, r= -0.37, OW), DRP1 (P<0.05, r=-0.43, OB), and OPA1 (P<0.05, r=-0.39, OB); no such associations were observed in AbdScAT depot. Rising endotoxin levels also correlated with reduced BRITE gene expression in AbdOm from participants classed as overweight, indicated by Cidea (P<0.05, r=-0.3962), ELOVL3 (P<0.05, r=-0.42), PLIN5 (P<0.01, r=-0.46) and SLC27A2 (P<0.01, r= -0.48); this was not observed in AbdScAT. Endotoxin change with bariatric surgery negatively correlated with brown gene change (P<0.05).

Conclusion: These data suggest that gut-derived endotoxemia may impair mitochondrial function and reduce adipocyte browning in abdominal AT. This appears to preferentially impact AbdOmAT over AbdScAT, and may therefore have more profound metabolic consequences. Overall, these data highlight that reduced gut-derived endotoxin may improve AbdAT mitochondrial health and BRITE adipocyte development, and therefore lower metabolic risk.