Suppression of Anti-Inflammatory Mediators in Metabolic Disease May Be Driven by Overwhelming Pro-Inflammatory Drivers

Abstract

Obesity is a multifactorial disease and is associated with an increased risk of developing metabolic syndrome and co-morbidities. Dysregulated expansion of the adipose tissue during obesity induces local tissue hypoxia, altered secretory profile of adipokines, cytokines and chemokines, altered profile of local tissue inflammatory cells leading to the development of low-grade chronic inflammation. Low grade chronic inflammation is considered to be the underlying mechanism that increases the risk of developing obesity associated comorbidities. The glucocorticoid induced protein annexin A1 and its N-terminal peptides are anti-inflammatory mediators involved in resolving inflammation. The aim of the current study was to investigate the role of annexin A1 in obesity and associated inflammation. To achieve this aim, the current study analysed data from two feasibility studies in clinical populations: (1) bariatric surgery patients (Pre- and 3 months post-surgery) and (2) Lipodystrophy patients. Plasma annexin A1 levels were increased at 3-months post-surgery compared to pre-surgery (1.2 ± 0.1 ng/mL, n = 19 vs. 1.6 ± 0.1 ng/mL, n = 9, p = 0.009) and positively correlated with adiponectin (p = 0.009, r = 0.468, n = 25). Plasma annexin A1 levels were decreased in patients with lipodystrophy compared to BMI matched controls (0.2 ± 0.1 ng/mL, n = 9 vs. 0.97 ± 0.1 ng/mL, n = 30, p = 0.008), whereas CRP levels were significantly elevated (3.3 ± 1.0 µg/mL, n = 9 vs. 1.4 ± 0.3 µg/mL, n = 31, p = 0.0074). The roles of annexin A1 were explored using an in vitro cell based model (SGBS cells) mimicking the inflammatory status that is observed in obesity. Acute treatment with the annexin A1 N-terminal peptide, AC2-26 differentially regulated gene expression (including PPARA (2.8 ± 0.7-fold, p = 0.0303, n = 3), ADIPOQ (2.0 ± 0.3-fold, p = 0.0073, n = 3), LEP (0.6 ± 0.2-fold, p = 0.0400, n = 3), NAMPT (0.4 ± 0.1-fold, p = 0.0039, n = 3) and RETN (0.1 ± 0.03-fold, p < 0.0001, n = 3) in mature obesogenic adipocytes indicating that annexin A1 may play a protective role in obesity and inflammation. However, this effect may be overshadowed by the continued increase in systemic inflammation associated with rapid tissue expansion in obesity.

Oxidative Stress Responses in Obese Individuals Undergoing Bariatric Surgery: Impact on Carcinogenesis

“…The inflammation markers that showed an increase in their plasma concentrations were IL-10, ANXA-1, and adiponectin; CRP and leptin showed reductions three months after surgery, showing the presence of mild systemic inflammation after three months [ 56 ]. Moreover, an increase in adiponectin and IL-10 expression was observed in a morbidly obese population one year after performing the surgical procedure (sleeve gastrectomy or Roux-en-Y gastric bypass) [ 57 ]. Conversely, the levels of IL-6, leptin, and resistin decreased [ 49 ].…”

“…Conversely, the levels of IL-6, leptin, and resistin decreased [ 49 ]. Interestingly, when a multivariate analysis correlating the decrease in these inflammatory markers following weight loss was performed, only IL-10 did not show a positive correlation [ 57 ]. Therefore, most inflammatory markers showed an increase in their post-surgery levels; however, IL-6 showed a variable trend in the results, and in most studies, it was lower.…”