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

Abstract

ObjectiveWhile extensive research revealed that interleukin (IL)-1β contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences.Research design and methodsTo induce obesity and IR, control and IL-1α 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-1α for 24 hours and subjected to gene expression analysis.ResultsAlthough total body weight gain was similar, IL-1α 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-1α 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-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance.ConclusionsWe demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.

Sanye Tablet Ameliorates Insulin Resistance and Dysregulated Lipid Metabolism in High-Fat Diet-Induced Obese Mice

“…The IL-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine ( Cavalli et al, 2021 ). A recent report indicates a possible role of IL-1α in promoting adiposity-induced glucose intolerance and hepatic de-novo lipogenesis ( Almog et al, 2019 ). Here, our results demonstrate that SYT reduces circulatory inflammatory cytokines in HFD-induced obese mice.…”

Consumption of a high energy density diet triggers microbiota dysbiosis, hepatic lipidosis, and microglia activation in the nucleus of the solitary tract in rats

“…Interleukin 1α (IL-1α) is generally known as an epidermal pro-inflammatory cytokine 48 . It has also been shown that IL-1α knockout mice gained less body fat and did not develop glucose intolerance when fed a high fat diet for 16 weeks 49 . Consistent with prior reports 50 , our data showed that rats fed a high ED diet for 26 weeks have significantly higher levels of IL-1α than low ED fed rats.…”

Innate-Immunity Genes in Obesity

“…Its downstream cascade, just as IL-1β signal transduction, includes IL-1R1, IL1RAP, MyD88, and IRAK4 and leads to the launch of proinflammatory NF-κB and MAPK signaling pathways [178]. Mice with this gene knocked out exhibit reduced adiposity [65]. As in mice, a correlation of IL genes with obesity has been shown in humans.…”