Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia

Abstract

BackgroundThe cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis.MethodsIl18−/− male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18+/+ male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively.ResultsCompared with Il18+/+ mice, BAT of Il18−/− mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5-expressing adipose precursor cells were extracted from Il18+/+ and Il18−/− mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18−/− BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18+/+ and Il18−/− mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the ‘Quantity of adipocytes’ identified three associated genes, apolipoprotein C3 (Apoc3), insulin-induced gene 1 (Insig1) and vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes’ size.ConclusionsThis study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1684-3) contains supplementary material, which is available to authorized users.

Analysis of genes linked to depressive‑like behaviors in interleukin‑18‑deficient mice: Gene expression profiles in the brain

“…In our previous study, it was hypothesized that IL-18 may serve as a novel option for treatment of metabolic disorders, such as diabetes mellitus and dyslipidemia, and for neuropsychiatric disorders, such as MDD (9,11,12). The results of the present study support the notion that IL-18 may serve as a novel treatment strategy of metabolic and neuropsychiatric disorders, including MDD.…”

“…An inactive 24-kDa precursor form of IL-18 is cleaved by activated caspase-1 to a mature 18-kDa active form (4)(5)(6)(7). In addition to its role as an inflammatory cytokine, IL-18 also serves a role in energy metabolism, and in the central nervous system it is involved in psychiatric disorders such as depression (8)(9)(10)(11)(12). Regarding energy homeostasis, IL-18 deficiency induces bulimia, corpulency and insulin resistance which resembles type 2 diabetes mellitus (8).…”

“…In the present study, candidate genes which may be involved in the induction of depressive-like behavioral changes were identified by comparing gene expression in the brains of Il18 +/+ and Il18 -/mice. At 12 weeks of age, a time at which Il18 -/mice start to exhibit depression-like behavioral changes, the genes with a |>1.5|-fold change were identified and analyzed using Ingenuity ® Pathway Analysis (IPA) as described previously (10,11). Subsequently, to explore candidate genes associated with depression at 12 weeks of age, microarray analysis was performed to compare expression at 6 and 12 weeks of age to screen for effector genes that induce depression.…”

Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases

“…Indeed, C57BL7 mice deficient for IL-18 are extremely sensitive to obesity but also exhibit larger brown adipocytes and a higher UCP-1 expression in BAT compared to wild-type littermates [240]. To support the role of IL-18 in this process, exogenous administration of IL-18 in these mice restores the adipocyte size as well as the expression of UCP-1 [240]. The precise action of IL-18 is likely to be complex and possibly independent from the IL-18 receptor (IL-18r).…”

Targeting programmed cell death in metabolic dysfunction-associated fatty liver disease (MAFLD): a promising new therapy

“…It is worth noting that the IL-18 and IL-1β released by MAFLD during pyroptosis seem to be a double-edged sword [ 113 ]. Studies by Yamanishi et al have demonstrated that IL-18 is essential for normal lipid metabolism in the liver and that its deficiency causes fat accumulation [ 120 ]. However, IL-1β is considered a pro-inflammatory cytokine that promotes the development of MAFLD.…”