Gene Expression Profiling Reveals a Diverse Array of Pathways Inhibited by Nuclear Receptor SHP during Adipogenesis

Orphan receptor small heterodimer partner (SHP, NROB2) has been shown to be a metabolic regulator in pathways associated with several major aspects of the metabolic syndrome. However, the significance and transcriptional regulatory role of SHP in adipocyte differentiation remain unclear. Transcriptional profiles of 3T3-L1 preadipocytes and early differentiating preadipocytes in response to SHP were systemically surveyed using Affymetrix Genome Array representing well-characterized 14,000 genes. Analysis revealed about 963 genes that were up- or down-regulated by more than 2-fold during differentiation and/or by the overexpression of SHP. These genes were organized into 4 clusters that demonstrated concerted changes in expression of genes controlling various aspects of the cellular events and metabolism. Quantitative PCR was employed to further characterize gene expression and led to the identification of several key regulators and stimulators of the adipogenic program as potential new SHP targets. Overexpression of SHP inhibited the differentiation process as well as the accumulation of neutral lipids within the cells. Our data suggests that SHP may function as a molecular switch that governs adipogenesis and a potent adipogenic suppressor that maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors and stimulators. Developing SHP agonist may promise a future treatment for obesity.