Abstract
The Steroid Receptor RNA Activator (SRA) enhances adipogenesis and increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. To assess the mechanism, we differentiated ST2 mesenchymal precursor cells that did or did not overexpress SRA into adipocytes using combinations of methylisobutylxanthine, dexamethasone and insulin. These studies showed that SRA overexpression promotes full adipogenesis in part by stimulation of insulin/insulin-like growth factor-1 (IGF-1) signaling. SRA overexpression inhibited phosphorylation of p38 mitogen activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) in the early differentiation of ST2 cells. Conversely, knockdown of endogenous SRA in 3T3-L1 cells increased phosphorylation of JNK. Knockdown of SRA in mature 3T3-L1 adipocytes reduced insulin receptor (IR) mRNA and protein levels, which led to decreased autophosphorylation of IRβ and decreased phosphorylation of insulin receptor substrate-1 (IRS-1) and Akt. This likely reflects a stimulatory role of SRA on IR transcription, as transfection studies showed that SRA increased expression of an IR promoter-luciferase reporter construct.
Highlights
Obesity is closely associated with a number of diseases including type 2 diabetes, cardiovascular disease, hypertension, cancer and gallstones
In agreement with a previous study [10], we found that lipid droplet formation was strongly induced with cocktails containing insulin (Figure 1C), some lipid droplets were apparent in Steroid Receptor RNA Activator (SRA)-expressing cells induced with Dex plus IBMX
We previously showed that SRA promotes adipogenesis and stimulates insulin-stimulated glucose uptake and Akt activation in adipocytes [29]
Summary
Obesity is closely associated with a number of diseases including type 2 diabetes, cardiovascular disease, hypertension, cancer and gallstones. Adipogenesis is a complex process that is highly regulated by coordinated effects of numerous transcription factors and signaling molecules, including peroxisome proliferator-activated receptor gamma (PPARc) [3,4], the CCAAT/enhancer-binding proteins (C/EBPs) [5,6], Kruppellike factors (KLFs) [7], Wingless proteins (Wnts) [8], and E2Fs [9] Both 3T3-L1 preadipocytes and bone marrow-derived ST2 adipocyte precursors can be differentiated in cell culture into mature adipocytes by standard hormone cocktails that include fetal bovine serum (FBS), 3-isobutyl-1-methylxanthine (IBMX), dexamethasone (Dex) and insulin [10,11]. The molecular mechanisms through which insulin promotes adipogenesis are not fully understood
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