Hexosamine Biosynthetic Pathway對於脂肪細胞分化過程中所扮演的角色

Abstract

Obesity is a rapidly growing global threat against public health. The World Health Organisation (WHO) has defined obesity as a condition with excessive fat accumulation in the body. Increasing adipose tissue relates in adipokines secretion and involves in development of metabolic complications. However, regulation of adipocyte differentiation and adipokines secretion still need further clarified. O-linked N acetyl-glucosamine (O-GlcNAc) modification has been implicated in regulation of signaling pathway, cell function, cell cycle and gene expression in several cell types. Hexosamine biosynthetic pathway (HBP) generates the sugar nucleotide UDP-GlcNAc, which is the donor for O-GlcNAc modification of nucleocytoplasmic proteins. When the GFAT-1 (rate limiting enzyme of HBP) was overexpressed in mice, the mice developed fat cell hypertrophy and excess weight. The aim of this study is to investigate the pathophysiological role of HBP and protein O-GlcNAc modification on adipocyte by observing the expression of genes involving in early stage of differentiation and adipokines affecting late stage complications. Our results demonstrate that the O-GlcNAc modified proteins are increased in the process of 3T3-L1 preadipocyte differentiation since very early stage after induction. Genes involve in early stage of differentiation such as SREBP-1c, PPAR-γ, C/EBP-α, C/EBP-β, and C/EBP-δ are upregulated. Adiponectin, visfatin, apelin, retinol-binding protein-4 and angiotensinogen mRNAs are increased in mature adipocytes. However, blocking HBP by AZA or DON can decrease the end product of HBP—O-GlcNAc modification and prevents the differentiation of 3T3-L1 cells. Decreasing HBP activity also diminishes gene expressions which are necessary for adipocyte differentiation in early stage and prevents mRNA overexpression of above adipokines. The results suggest that HBP activation and change of protein O-GlcNAc modification maybe a novel pathway mediating differentiation and adipokine expression in adipocytes.