The short-term and long-term effects of bariatric/metabolic surgery on subcutaneous adipose tissue inflammation in humans

Abstract

Context: The mechanisms mediating the short- and long-term improvements in glucose homeostasis following bariatric/metabolic surgery remain incompletely understood.

Objective: To investigate whether a reduction in adipose tissue inflammation plays a role in the metabolic improvements seen after bariatric/metabolic surgery, both in the short-term and longer-term.

Design: Fasting blood and subcutaneous abdominal adipose tissue were obtained before (n=14), at one month (n=9), and 6-12months (n=14) after bariatric/metabolic surgery from individuals with obesity who were not on insulin or anti-diabetes medication. Adipose tissue inflammation was assessed by a combination of whole-tissue gene expression and flow cytometry-based quantification of tissue leukocytes.

Results: One month after surgery, body weight was reduced by 13.5±4.4kg (p<0.001), with improvements in glucose tolerance reflected by a decrease in area-under-the-curve (AUC) glucose in 3-h oral glucose tolerance tests (-105±98mmol/L * min; p=0.009) and enhanced pancreatic β-cell function (insulinogenic index: +0.8±0.9pmol/mmol; p=0.032), but no change in estimated insulin sensitivity (Matsuda insulin sensitivity index [ISI]; p=0.720). Furthermore, although biomarkers of systemic inflammation and pro-inflammatory gene expression in adipose tissue remained unchanged, the number of neutrophils increased in adipose tissue 15-20 fold (p<0.001), with less substantial increases in other leukocyte populations. By the 6-12month follow-up visit, body weight was reduced by 34.8±10.8kg (p<0.001) relative to baseline, and glucose tolerance was further improved (AUC glucose -276±229; p<0.001) along with estimated insulin sensitivity (Matsuda ISI: +4.6±3.2; p<0.001). In addition, improvements in systemic inflammation were reflected by reductions in circulating C-reactive protein (CRP; -2.0±5.3mg/dL; p=0.002), and increased serum adiponectin (+1358±1406pg/mL; p=0.003). However, leukocyte infiltration of adipose tissue remained elevated relative to baseline, with pro-inflammatory cytokine mRNA expression unchanged, while adiponectin mRNA expression trended downward (p=0.069).

Conclusion: Both the short- and longer-term metabolic improvements following bariatric/metabolic surgery occur without significant reductions in measures of adipose tissue inflammation, as assessed by measuring the expression of genes encoding key mediators of inflammation and by flow cytometric immunophenotyping and quantification of adipose tissue leukocytes.

Keywords: Adipose tissue inflammation; Bariatric surgery; Insulin resistance; Metabolic surgery.

Figure 1

Glucose (A) and insulin (B) concentrations during oral glucose tolerance tests (OGTT) performed at baseline (●), and at one (■) and 12 (▲) months after bariatric/metabolic surgery. (A) Significant reductions in AUC glucose were observed at both one month (p=0.009) and 12 months (p<0.001) relative to baseline (pre-surgery). Glucose concentrations at the 120 min time point were similarly reduced at one month (*, p=0.020) and 12 months (**, p<0.001) relative to baseline (no statistical tests were conducted at other time points during the OGTT). (B) The rise in insulin secretion in the first 30 min relative to the rise in glucose concentrations (i.e., the insulinogenic index) was greater at one month (p=0.032) compared to baseline, but returned to baseline levels with a greater increase in insulin sensitivity by the 12-month time point.

Figure 2

Changes in circulating plasma markers and mRNA expression in subcutaneous adipose tissue from baseline (visit 1) to one (visit 2) and 12 (visit 3) months after bariatric/metabolic surgery. (A) No change in circulating CRP (●), IL-6 (■), and adiponectin (▲) within the first month of surgery. By 12 months, relative to baseline levels, circulating adiponectin exhibited a marked increase (*, p=0.003), while CRP (**, p=0.002) but not IL-6 (p=0.183) concentrations were significantly reduced. (B) There were no significant changes in mRNA expression patterns for TNFα (●), IL-1β (◆), IL-6 (■) and adiponectin (▼) in subcutaneous adipose tissue from baseline out to 12 months post-surgery, except for a downward trend in adiponectin expression (p=0.069).