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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Kyosuke Yamanishi, Seishi Maeda, Sachi Kuwahara-Otani, Takuya Hashimoto, Kaoru Ikubo, Keiichiro Mukai, Keiji Nakasho, Naomi Gamachi, Yosif El-Darawish, Wen Li, Daisuke Okuzaki, Yuko Watanabe, Hiromichi Yamanishi, Haruki Okamura, Hisato Matsunaga
• Journal: Journal of translational medicine (J Transl Med) Vol. 16 Issue 1 Pg. 314 (11 19 2018) ISSN: 1479-5876 [Electronic] England
• PMID: 30453990 (Publication Type: Journal Article)

Chemical References

• Interleukin-18
• Recombinant Proteins

Topics

• Adipogenesis (drug effects)
• Adipose Tissue, Brown (drug effects, growth & development, pathology)
• Adiposity
• Animals
• Cell Differentiation (drug effects)
• Dyslipidemias (metabolism, pathology)
• Fatty Liver (pathology)
• Interleukin-18 (deficiency, metabolism)
• Lipid Metabolism (drug effects)
• Male
• Mice, Inbred C57BL
• Recombinant Proteins (administration & dosage, pharmacology)
• Stem Cells (drug effects, metabolism)
• Thermogenesis (drug effects)