IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (−2.7 ± 8.2% in the placebo vs. −20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity

Il-6 receptor blockade increases circulating adiponectin levels in people with obesity:An explanatory analysis

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (−2.7 ± 8.2% in the placebo vs. −20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity

S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes

OBJECTIVE: The multifunctional Ca2+-binding protein S100A4 (also known as Mts1 and Fsp1) is involved in fibrosis and tissue remodeling in several diseases including cancer, kidney fibrosis, central nervous system injury, and pulmonary vascular disease. We previously reported that S100A4 mRNA expression was increased in hypertrophic rat hearts and that it has pro-cardiomyogenic effects in embryonic stem cell-derived embryoid bodies. We therefore hypothesized that S100A4 could play a supportive role in the injured heart. METHODS AND RESULTS: Here we verify by quantitative real-time PCR and immunoblotting that S100A4 mRNA and protein is upregulated in hypertrophic rat and human hearts and show by way of confocal microscopy that S100A4 protein, but not mRNA, appears in cardiac myocytes only in the border zone after an acute ischemic event in rat and human hearts. In normal rat and human hearts, S100A4 expression primarily colocalizes with markers of fibroblasts. In hypertrophy elicited by aortic banding/stenosis or myocardial infarction, this expression is increased. Moreover, invading macrophages and leucocytes stain strongly for S100A4, further increasing cardiac levels of S100A4 protein after injury. Promisingly, recombinant S100A4 protein elicited a robust hypertrophic response and increased the number of viable cells in cardiac myocyte cultures by inhibiting apoptosis. We also found that ERK1/2 activation was necessary for both the hypertrophy and survival effects of S100A4 in vitro. CONCLUSIONS: Along with proposed angiogenic and cell motility stimulating effects of S100A4, these findings suggest that S100A4 can act as a novel cardiac growth and survival factor and may have regenerative effects in injured myocardium

GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study

Aims/hypothesis IL-6 is a cytokine with various effects on metabolism. In mice, IL-6 improved beta cell function and glucose homeostasis via upregulation of glucagon-like peptide 1 (GLP-1), and IL-6 release from muscle during exercise potentiated this beneficial increase in GLP-1. This study aimed to identify whether exercise-induced IL-6 has a similar effect in humans. Methods In a multicentre, double-blind clinical trial, we randomly assigned patients with type 2 diabetes or obesity to intravenous tocilizumab (an IL-6 receptor antagonist) 8 mg/kg every 4 weeks, oral sitagliptin (a dipeptidyl peptidase-4 inhibitor) 100 mg daily or double placebos (a placebo saline infusion every 4 weeks and a placebo pill once daily) during a 12 week training intervention. The primary endpoints were the difference in change of active GLP-1 response to an acute exercise bout and change in the AUC for the concentration-time curve of active GLP-1 during mixed meal tolerance tests at baseline and after the training intervention. Results Nineteen patients were allocated to tocilizumab, 17 to sitagliptin and 16 to placebos. During the acute exercise bout active GLP-1 levels were 26% lower with tocilizumab (multiplicative effect: 0.74 [95% CI 0.56, 0.98], p = 0.034) and 53% higher with sitagliptin (1.53 [1.15, 2.03], p = 0.004) compared with placebo. After the 12 week training intervention, the active GLP-1 AUC with sitagliptin was about twofold that with placebo (2.03 [1.56, 2.62]; p < 0.001), while GLP-1 AUC values showed a small non-significant decrease of 13% at 4 weeks after the last tocilizumab infusion (0.87 [0.67, 1.12]; p = 0.261). Conclusions/interpretation IL-6 is implicated in the regulation of GLP-1 in humans. IL-6 receptor blockade lowered active GLP-1 levels in response to a meal and an acute exercise bout in a reversible manner, without lasting effects beyond IL-6 receptor blockade. Funding Danish National Research Foundation. Danish Council for Independent Research. Novo Nordisk Foundation. Danish Centre for Strategic Research in Type 2 Diabetes. European Foundation for the Study of Diabetes. Swiss National Research Foundation