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

Abstract

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 μg/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-1β, tumor necrosis factor α (TNFα), 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-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1α 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 TNFα and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity.

• Authors: Dov B Ballak, Suzhao Li, Giulio Cavalli, Jonathan L Stahl, Isak W Tengesdal, Janna A van Diepen, Viola Klück, Benjamin Swartzwelter, Tania Azam, Cees J Tack, Rinke Stienstra, Thomas Mandrup-Poulsen, Douglas R Seals, Charles A Dinarello
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 37 Pg. 14224-14236 (09 14 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 30006351 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Ballak et al.

Chemical References

• Biomarkers
• Cytokines
• IL37 protein, human
• Inflammation Mediators
• Interleukin-1
• Receptors, Interleukin-1 Type I
• Recombinant Proteins

Topics

• Adipose Tissue (metabolism)
• Animals
• Biomarkers (blood)
• Cytokines (biosynthesis)
• Diet, High-Fat
• Glucose Tolerance Test
• Humans
• Inflammation Mediators (metabolism)
• Insulin Resistance
• Interleukin-1 (genetics, therapeutic use)
• Metabolic Syndrome (drug therapy, metabolism, physiopathology)
• Mice
• Mice, Transgenic
• Obesity (physiopathology)
• Receptors, Interleukin-1 Type I (antagonists & inhibitors)
• Recombinant Proteins (genetics, therapeutic use)