Critical role of the HMGI(Y) proteins in adipocytic cell growth and differentiation

The high-mobility group I (HMGI) nonhistone chromosomal proteins HMGI(Y) an d HMGI-C have been implicated in defining chromatin structure and in regula ting the transcription of several genes. These proteins have been implicate d in adipocyte homeostasis: a severe deficiency of fat tissue is found in m ice with targeted disruption of the HMGI-C locus, and lipomagenesis in huma ns is frequently associated with somatic mutations of HMGI genes. The aim o f this study was to examine the role of HMGI(Y) proteins in adipocytic cell growth and differentiation. First, we found that differentiation of the pr eadipocytic 3T3-L1 cell line caused early induction of HMGI(Y) gene express ion. Suppression of HMGI(Y) expression by antisense technology dramatically increased the growth rate and impaired adipocytic differentiation in these cells. The process of adipogenic differentiation involves the interplay of several transcription factors, among which is the CCAAT/enhancer-binding p rotein (C/EBP) family of proteins. These factors are required for the trans criptional activation of adipocyte-specific genes. We also tested the hypot hesis that HMGI(Y) might participate in transcriptional control of adipocyt e specific promoters. We found that HMGI(Y) proteins bind C/EBP beta in viv o and in vitro. Furthermore, we show that HMGI(Y) strongly potentiates the capacity of C/EBP beta to transactivate the leptin promoter, an adipose-spe cific promoter. Taken together, these results indicate that the HMGI(Y) pro teins play a critical role in adipocytic cell growth and differentiation.