사람에서 Wnt 신호계의 활성화에 의한 지방세포 분화 억제와 당대사 이상과의 연관성 = The Relation between Inhibition of Adipocyte Differentiation by Activation of Wnt signaling and impaired glucose metabolism in Human

다국어 초록 (Multilingual Abstract)

Objectives: The differentiation of preadipocyte to mature adipocyte includes activation of adipogenic gene expression and induction of insulin sensitivity. Wnt signaling, primarily mediated by Wnt10b in human, functions as a promoter of preadiocyte growth and proliferation, although it also functions as a potent inhibitor of adipogenesis. Therefore, this study was undertaken to determine the effect of Wnt signaling on the degree of adipocyte differentiation and glucose metabolism.
Methods: Adipose tissue was obtained during surgery from omental fat deposits in twenty one patients who underwent elective abdominal surgery at Hanyang University Hospital. All patients were divided into NGT patients (n = 12) and patients with impaired glucose metabolism (n = 9) based on the level of the fasting plasma glucose. Tissue expression level of transcription factors for adipocyte differentiation, early and late adipocyte -specific genes, and genes for Wnt signaling and CyclinD1 were investigated in NGT patients and patients with impaired glucose metabolism through real-time quantitative PCR analysis.
Results: To control for the effect of visceral adiposity on the development of impaired glucose metabolism, all patients were subdivided into low and high visceral adiposity according to the median value of V/S ratio (0.85). Among adipocyte-specific genes, expression of genes for insulin sensitivity, such as adiponectin and GLUT4 was reduced in patients with impaired glucose metabolism than NGT patients. Gene expression of Wnt10b and CyclinD1 was significantly higher in patients with impaired glucose metabolism than NGT counterparts.
Conclusions: The major role of Wnt/β-catenin signaling in human adipose tissue seems to selectively inhibit genes for insulin sensitivity such as adiponectin and GLUT4, which require C/EBPα as wells as PPARγ.

국문 초록 (Abstract)

목적: 비만은 인슐린 저항성을 유발하는 중요한 인자이지만, 한국인에서 제2형 당뇨병이 있는 65%의 환자들은BMI 기준을 25 kg/m2로 낮추더라도 비만하지 않다. 인슐린의 표적 세포 중 하나인 지방세포는 분화할수록 지방이축적되고 당을 흡수하는 능력이 증가한다. 인간에서 Wnt10b에 의해 매개되는 Wnt signaling의 활성화는 지방세포전구세포의 분열과 증식을 유발하지만 분화를 억제하는 것으로 알려져 있어 연구자는 인간에서 Wnt signaling의활성화 정도와 지방세포 분화 정도 그리고 당 대사와의 연관성을 알아보고자 하였다.
방법: 한양대병원 일반외과에서 선택적인 복부 수술을 시행한 21명의 환자들에서 내장 지방조직을 채취하였다.
이 환자들을 공복 혈당을 기준으로 정상군과 비정상 당 대사군 (공복혈당 장애와 제2형 당뇨병)으로 나누어 정량적중합효소반응을 통해 Wnt10b, β-catenin, Cyclin D1 (G1/S 세포주기 조절자), 지방세포 분화의 전사인자와 성숙한지방세포 특이적 유전자의 발현 정도 차이를 관찰하였다.
결과: 양 군 간에 내장 지방량의 차이를 보정하기 위해 V/S비 (visceral/subcutaneous fat ratio)의 중앙값인 0.85 를 기준으로 나누어 정상군과 비정상 당 대사군의 유전자 발현양의 차이를 비교하였다. 높은 내장 지방량을 가진환자들 중 비정상 당대사 군에서 PPARγ에 의해 그 발현이 조절되는 지방형성에 관여하는 유전자인 aP2의 발현이증가하였으나, 발현을 위해 PPARγ뿐만이 아니라 C/EBPα도 필요로 하는 인슐린 감수성을 개선하는 유전자인adiponectin과 GLUT4의 발현은 유의하게 감소하였다. 높은 내장 지방량을 가진 환자들 중 비정상 당대사 군에서Wnt10b와 Wnt signaling에 의해 활성화되는 Cyclin D1의 발현이 유의하게 증가하였다.
결론: 인간의 내장 지방세포에서 Wnt signaling의 활성화는 지방세포 형성과정에서 PPARγ에 의한 C/EBPα의활성화를 선택적으로 억제함으로써 인슐린 감수성에 관여하는 adiponectin과 GLUT4의 발현을 억제하는 것으로 생각된다.

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