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.

Highlights

  • The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflamma‐ tory factor; there is increasing evidence suggesting that it has non-immunological effects on physiological functions

  • The mRNA expression of Lep, peroxisome proliferator-activated receptor γ coactivator 1-β (Pgc1b), Elovl3, adrenergic receptor beta 3 (Adrb3), cluster of differentiation 36 (Cd36) and uncoupling protein 3 (Ucp3) was higher in cells from Il18−/− mice compared with cells from Il18+/+ mice, whereas CCAAT/enhancer binding protein beta (Cebpb) was unchanged, and type II iodothyronine deiodinase (Dio2) was significantly suppressed (Fig. 1e)

  • PR domain containing 16 (PRDM16)-dependent genes such as Pparg and peroxisome proliferator-activated receptor γ coactivator 1-α (Pgc1a), and in upregulated PRDM16-independent genes such as fibroblast growth factor 21 (Fgf21); (3) brown adipose tissue (BAT) in Il18−/− mice developed severe adiposity during growth compared with that in Il18+/+ mice; (4) several molecules related to adiposity were affected by IL-18 deficiency; and (5) some of these abnormal conditions were recovered by recombinant IL-18 (rIL-18) administration, which affected some of the identified molecules

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Summary

Introduction

The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflamma‐ tory factor; there is increasing evidence suggesting that it has non-immunological effects on physiological functions. 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. Previous studies have reported that IL-18-deficient mice developed hyperphagia, obesity and insulin resistance [9] These mice presented with dyslipidemia, non-alcoholic fatty liver diseases (NAFLD) and non-alcoholic steatohepatitis (NASH), and they were related to kidney function [10, 11]. The serum concentration of IL-18 was significantly higher in patients with type 2 diabetes mellitus and with metabolic syndrome than in healthy controls [12, 13]

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