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Insulin-Like Growth Factor Binding Protein-3가 3T3-L1 지방세포의 adipokine과 유전자 발현에 미치는 영향

The Effect of IGFBP-3 on Adipokines and Gene Expression in Differentiated 3T3-L1 Adipocytes

김혜순
대한소아내분비학회 (Korean Society Of Pediatric Endocrinology)|2011.04|Annals of Pediatric Endocrinology & Metabolism|제16권 제1호|pp. 24-30

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주제분류소아과학

초록

목 적:Insulin like growth factor binding protein-3 (IGFBP- 3)는 지방세포에서 인슐린 저항성을 유발시키는 것으로 알려졌다. 이에 저자들은 IGFBP-3가 지방세포에서 분비되는 adipokine의 발현과 유전자 발현에 어떠한 영향을 주는지 알아보고자 하였다. 방 법:3T3-L1세포를 dexamethason, 3-isobutyl-1-methylzanthine, insulin을 3일간 첨가하여 분화시킨 후 분화된 성숙한 지방세포에 IGFBP-3 (0, 0.5, 1, 2 µg/mL)를 첨가하고 24시간 후 세포을 얻어 RNA를 추출한 후 leptin, resistin, adiponectin, TNF-α의 mRNA의 발현을 관찰하기위해 RT-PCR을 시행하였다. 또한 세포배양액에서 adiponectin, leptin, resistin 및 IL- 6 농도를 알아보기 위해서 multiplex ELISA assay를 시행하였다. cDNA microarray 실험를 이용하여 IGFBP-3에 의한 3T3- L1 지방세포의 유전자 발현의 변화를 관찰하였다. 결 과:IGFBP-3을 처리한 후 분화된 3T3-L1 세포내 leptin, resistin, adiponectin 및 TNF-alpha mRNA 발현은 IGFBP-3 농도 의존적으로 감소하였다. 분화된 지방세포에 다양한 농도의 IGFBP-3을 처리한 결과, 세포배양액 내 leptin, resistin 및 adiponectin 농도는 IGFBP-3에 의해 유의적으로 감소되었고, leptin의 분비는 IGFBP-3의 농도 의존적으로 50% 정도 까지 감소되었다. 그러나 adiponectin은 IGFBP-3 0.5 µg/mL와 1 µg/mL에서 30% 정도 감소되었다. Resistin의 분비는 IGFBP-3의 농도와 관계없이 40%정도 모두 감소되었다. Microarray를 이용하여 분화된 3T3-L1 지방 세포의 유전자 발현에 대한 IGFBP-3의 영향을 관찰한 결과, adipokine pathway에 관련 있는 Agrp이 1.51배, JAK2가 1.51배 증가되었다. 인슐린 pathway에 관련 있는 Rhoq 1.51배, adipokine pathway 에 관여하는 Acsl6 1.5배, toll-like receptor signaling pathway에 관여하는 Irak1의 발현이 1.5배 감소하였다. 결 론:IGFBP-3는 3T3-L1 성숙지방세포의 adipokine 유전자 발현과 분비에 영향을 미쳤을 뿐 아니라, 인슐린 저항성과 관계된 유전자들의 발현에도 영향을 주어 인슐린 저항성을 나타낼 것으로 생각된다.

Abstract

Purpose: IGFBP-3 leads to the induction of insulin resistance in 3T3-L1 adipocytes. We carried out a series of experiments to elucidate the effects of IGFBP-3 on adipokines and gene expressions. Methods: We treated fully differentiated 3T3-L1 adipocytes with IGFBP-3 (0.5, 1, and 2 µg/mL) for 1 day and measured the mRNA levels of adiponectin, leptin, resistin and TNF-α by RT-PCR and adiponectin, leptin, resistin, and IL-6 protein levels in the culture supernatant were measured using multiplex adipokine assay ELISA Kits (Linco Research, St. Charles, Missouri). Gene expression in 3T3-L1 adipocyte cells using microarray method was performed. Results:IGFBP-3 inhibited the expression of mRNA of adiponectin, leptin, resistin and TNF-α. IGFBP-3 at 0.5 and 1 µg/mL decreased adiponectin release, but IL-6 release was increased at 2 µg/mL IGFBP-3. Dose-dependent inhibition of leptin release by IGFBP-3 by 50%. Resistin release was decreased by 40%. The effect of IGFBP-3 on the gene expression in 3T3-L1 adipocyte cells using microarray assay related to increase of agouti realted protein (Agrp), Janus kinase 2 (JAK2) and decrease of ras homolog gene family (Rhoq), acyl-CoA synthetase long-chain family member 6 (Acsl6), and interleukin-1 receptor-associated kinase 1 (Irak1). Conclusion:IGFBP-3 regulates several adipokines gene expression which are known to modulate insulin sensitivity and that this regulation may be attributable to the insulin resistance effect of IGFBP-3 on adipocytes. (J Korean Soc Pediatr Endocrinol 2011;16:24-30)

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