[Download] "Protein Phosphatase 5 and Glucocorticoid Receptor Beta in Glucocorticoid Resistance and Lipogenesis" by Terry D. Hinds * eBook PDF Kindle ePub Free
eBook details
- Title: Protein Phosphatase 5 and Glucocorticoid Receptor Beta in Glucocorticoid Resistance and Lipogenesis
- Author : Terry D. Hinds
- Release Date : January 18, 2013
- Genre: Medical,Books,Professional & Technical,
- Pages : * pages
- Size : 14366 KB
Description
Glucocorticoid (GR) and peroxisome proliferator-activated receptor γ (PPARγ) play important roles in adipocyte differentiation by controlling the balance between lipolysis and lipogenesis. In this work, we show that the nuclear receptor co-chaperone, protein phosphatase 5 (PP5), and GR isoform, GRβ, are key regulators of adipogenesis. Glucocorticoids (GC) are well-known antagonists of insulin and long-term GC treatment results in insulin resistance and obesity, however, acute treatment results in lipolysis and weight loss. These GC effects are mediated by the GR, specifically the GRα isoform. In this dissertation, we show that PP5 and GRβ are inhibitory to the actions of the hormone-binding isoform, GRα. Loss of PP5 elevated dexamethasone (Dex)-induced GRα activity at reporter and pro-lipolytic endogenous genes, such as PDK4 that correlated with increased phosphorylation of GR. GRβ exhibits a degenerate amino acid sequence in helix 12 that abrogates ligand-binding and acts as a dominant-negative inhibitor of hGRα.We also demonstrate hormonal and dietary control of mGRβ expression. In vitro, upregulation of mGRβ was observed in response to dexamethasone, inflammatory cytokine TNFα and insulin. In vivo studies to confirm the involvement of mGRβ in metabolism showed significantly elevated levels of mGRβ in the livers of mice subjected to fasting-refeeding. Mice on a long-term high-fat diet developed insulin resistance with a significant increase in hepatic and visceral adipose GRβ and TNFα. Interestingly, PP5 only increased in the visceral adipose of these mice, which suggest a possible role of regulation on lipogenesis. Rosiglitazone-induced PPARγ activity in PP5KO MEF cells was greatly reduced at lipogenic genes, such as aP2 and CD36. These data suggest that PP5 serves as a reciprocal modulator by exerting negative control over the lipolytic actions of GRα, while promoting the lipogenic properties of PPARγ.In mouse 3T3-L1 preadipocyte cells, levels of three proteins known to inhibit GRα activity, GRβ, PP5 and FKBP51, were highly elevated in the differentiated state, while expression of FKBP52 - a positive GR regulator - was unchanged. Importantly, PP5 KO cells were highly resistant to differentiation, showing almost no intracellular lipid accumulation and higher levels of free fatty acids (FFA) in the media. These phenotypes were completely reversed in PP5KO cells following reintroduction of PP5. We propose that obesity is a result of GC-resistance, and that mGRβ or PP5 may work to increase lipid storage by inhibiting the actions of GRα.