90-OR: High-Fat Diet Acutely Decreases Adipose Immunosuppressive T Regulatory Cells Leading to Insulin Resistance

Adipose resident T lymphocytes (ARTs) are known metabolic mediators in mice. In particular, immunosuppressive regulatory T cells (Tregs) protect against insulin resistance. However, little is known about ARTs in humans or the effect of human weight gain on the AT immunoenvironment. We obtained visceral AT (VAT) and subcutaneous AT (SAT) biopsies from obese (n=83, BMI 48.9±8.5 kg/m²) and lean (n=15, BMI 23.6±1.9 kg/m²) patients undergoing elective surgery. A separate group of lean metabolically healthy patients (n=15, BMI 22.4 ± 1.8 kg/m²) underwent baseline and repeat SAT biopsies and hyperinsulinemic clamps before and after 2 weeks of a high-fat diet (HFD) overfeeding protocol (additional 1,320 kcal/day:>50% total fat:>10% saturated fat). Adipocytes were isolated for gene expression and flow analysis. Tregs (CD4+CD25+FOXP3+) as percent (%) of CD4+ cells were substantially increased in lean compared to obese SAT (22.1±15.0% vs. 7.3±3.8%; p<0.001) and VAT (18.9±16.8% vs. 3.9±2.7%; p<0.001) and negatively correlated with BMI and insulin sensitivity. After HFD, there was a significant increase in BMI (p<0.001) and fasting glucose (p<0.001), but no change in fasting insulin or HOMA-IR. We noted a dramatic overall decline in SAT Tregs after HFD (7.5 ± 1.0% to 3.3 ± 0.5%, p<0.001), with all participants experiencing a decrease. The post-surgical change in SAT %Tregs positively correlated with the change in insulin sensitivity (M value) by hyperinsulinemic-euglycemic clamp (p=0.003, r=+0.797), so that those subjects with the greatest decline in Tregs had the largest decline in insulin sensitivity. This relationship persisted despite adjusting for, age, gender, pre-intervention BMI, and the change in weight from pre to post intervention (p=0.012). Our data thus demonstrates that Tregs decline in response to acute overfeeding, potentially contributing to development of insulin resistance. These results highlight a role for adipose tissue Tregs in human metabolism.