Interleukin-1alpha deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice

Contains fulltext : 215650.pdf (publisher's version ) (Open Access)Objective: While extensive research revealed that interleukin (IL)-1beta contributes to insulin resistance (IR) development, the role of IL-1alpha in obesity and IR was scarcely studied. Using control, whole body IL-1alpha knockout (KO) or myeloid-cell-specific IL-1alpha-deficient mice, we tested the hypothesis that IL-1alpha deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences. Research design and methods: To induce obesity and IR, control and IL-1alpha KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1alpha for 24 hours and subjected to gene expression analysis. Results: Although total body weight gain was similar, IL-1alpha KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1alpha KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1alpha KO mice. Treatment with recombinant IL-1alpha elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1alpha did not show reduced adiposity and improved glucose tolerance. Conclusions: We demonstrate a novel role of IL-1alpha in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1alpha blockade could be used for treatment of obesity and its metabolic consequences