Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 37, Pages 14224-14236Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.003698
Keywords
adipose tissue; inflammation; cytokine; drug development; insulin resistance; glucose metabolism; mouse; type 2 diabetes; cellular research; mouse model
Categories
Funding
- National Institutes of Health (NIH) [AI-15614]
- Interleukin Foundation
- Glenn/AFAR postdoctoral fellowship
- Prof. Dr. Terpstra Award from the Dutch Union of Diabetes Research
- American Heart Association postdoctoral fellowship
- Colorado Clinical and Translational Sciences Institute (CCTSI) CO-Pilot Mentored Faculty award
- NIH [AI128443]
- MSD/EFSD program
- VIDI grant from the Netherlands Organization for Scientific Research
- NIH Grants [AG-013038, RO1 HL107120]
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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.
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