TY - JOUR

T1 - Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue

AU - Ballak, Dov B.

AU - Li, Suzhao

AU - Cavalli, Giulio

AU - Stahl, Jonathan L.

AU - Tengesdal, Isak W.

AU - van Diepen, Janna A.

AU - Kluck, Viola

AU - Swartzwelter, Benjamin

AU - Azam, Tania

AU - Tack, Cees J.

AU - Stienstra, Rinke

AU - Mandrup-Poulsen, Thomas

AU - Seals, Douglas R.

AU - Dinarello, Charles A.

PY - 2018

Y1 - 2018

N2 - Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control. Transgenic mice expressing human interleukin 37 (IL-37), an anti-inflammatory cytokine of the IL-1 family, are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 g/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets. The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1, tumor necrosis factor (TNF), and CXC motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1, TNF, and IL-6 and reduced intracellular levels of IL-1 in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pm IL-37 reduced spontaneous release of TNF and 50% of lipopolysaccharide-induced TNF. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity.

AB - Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control. Transgenic mice expressing human interleukin 37 (IL-37), an anti-inflammatory cytokine of the IL-1 family, are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 g/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets. The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1, tumor necrosis factor (TNF), and CXC motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1, TNF, and IL-6 and reduced intracellular levels of IL-1 in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pm IL-37 reduced spontaneous release of TNF and 50% of lipopolysaccharide-induced TNF. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity.

KW - adipose tissue

KW - inflammation

KW - cytokine

KW - drug development

KW - insulin resistance

KW - glucose metabolism

KW - mouse

KW - type 2 diabetes

KW - cellular research

KW - mouse model

U2 - 10.1074/jbc.RA118.003698

DO - 10.1074/jbc.RA118.003698

M3 - Journal article

C2 - 30006351

VL - 293

SP - 14224

EP - 14236

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 37

ER -