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 6–12 months (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±4.4 kg (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±98 mmol/L*min; p=0.009) and enhanced pancreatic β-cell function (insulinogenic index: +0.8±0.9 pmol/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 6–12 month follow-up visit, body weight was reduced by 34.8±10.8 kg (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±5.3 mg/dL; p=0.002), and increased serum adiponectin (+1,358±1,406 pg/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.

Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

“…There may also be changes in serum levels of the insulin sensitizing hormone adiponectin following bariatric surgery. While Sams et al (407) observed significant increases in circulating adiponectin two weeks following surgery, our studies revealed no improvement one to 12 months post-surgery (162, 254). …”

“…Clear reductions in CRP are more apparent three to four months post-operatively, when presumably surgery-related inflammation has subsided (52, 202, 488), even though this is not seen in all studies (310, 483). Six to 12 months post-surgery, CRP, IL-6, PAI-1, and MCP-1 consistently are reduced relative to pre-surgery levels (6, 28, 108, 157, 162, 181, 199–202, 254, 310, 323, 327, 368, 468, 483, 489). There may also be changes in serum levels of the insulin sensitizing hormone adiponectin following bariatric surgery.…”

“…Substantial weight loss over 6–12 months following bariatric surgery, for example, was associated with an about three-fold increase in the number of ATMs (measured by flow cytometry) in SAT (162). Interestingly, in that and another study (254), we consistently observed a massive, several-fold increase in the number of neutrophils into SAT.…”

“…Nijhuis et al noted an absence of neutrophils outside of the adipose tissue vasculature, based on IHC staining for myeloperoxidase (343). In contrast, we recently isolated and identified neutrophils, based on the co-expression of CD15 and CD16 by flow cytometry, from the SVC of adipose tissue, and reported that their numbers are substantially increased following weight loss (162, 254). Accumulation of several of the less abundant myeloid cell types, such as mast cells, dendritic cells, and eosinophils, is also influenced by increased adiposity.…”

“…Following bariatric surgery, systemic inflammation appears to persist at least through the first month, as indicated by circulating CRP, IL-6, and PAI-1 concentrations at or near pre-surgery levels (162, 254, 310, 368). Clear reductions in CRP are more apparent three to four months post-operatively, when presumably surgery-related inflammation has subsided (52, 202, 488), even though this is not seen in all studies (310, 483).…”