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

• Published in: Journal of translational medicine 2018-11, Vol.16 (1), p.314-314, Article 314
• Main Authors: Yamanishi, Kyosuke, Maeda, Seishi, Kuwahara-Otani, Sachi, Hashimoto, Takuya, Ikubo, Kaoru, Mukai, Keiichiro, Nakasho, Keiji, Gamachi, Naomi, El-Darawish, Yosif, Li, Wen, Okuzaki, Daisuke, Watanabe, Yuko, Yamanishi, Hiromichi, Okamura, Haruki, Matsunaga, Hisato
• Format: Article
• Language: English
• Subjects: Accumulation; Adipocytes; Adipogenesis; Adipogenesis - drug effects; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - drug effects; Adipose Tissue, Brown - growth & development; Adipose Tissue, Brown - pathology; Adiposity; Animals; Apolipoproteins; Bioaccumulation; Body fat; Brown adipocytes; Brown adipose tissue; Calcitriol; Cell culture; Cell Differentiation - drug effects; Cytokines; Diabetes; DNA microarrays; Dyslipidemia; Dyslipidemias - metabolism; Dyslipidemias - pathology; Energy; Fatty acids; Fatty liver; Fatty Liver - pathology; Fibroblast growth factors; Genes; Immunology; Inflammation; Insulin; Insulin resistance; Interferon; Interleukin 1; Interleukin 18; Interleukin-18 - deficiency; Interleukin-18 - metabolism; Interleukin-18 knockout; Intravenous administration; Lipid metabolism; Lipid Metabolism - drug effects; Lipids; Liver; Liver diseases; Long-term effects; Male; Metabolic disorders; Mice; Mice, Inbred C57BL; Molecular modelling; Non-shivering; Obesity; Phosphorylation; Physiological effects; Physiology; Proteins; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Reverse transcription; Rodents; Shivering; Stem Cells - drug effects; Stem Cells - metabolism; Thermogenesis; Thermogenesis - drug effects; Vitamin D; Vitamin D3; Western blotting
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-018-1684-3

The 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. Il18 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. Compared 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. This 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.