Abstract
Glucocorticoids play an important role in the treatment of inflammation and immune disorders, despite side effects, which include metabolic derangements such as central adiposity. These studies examine the role of protein phosphatase 5 (Ppp5) in glucocorticoid receptor (GR) complexes which mediate response to glucocorticoids. Mice homozygous for inactivated Ppp5 (Ppp5D274A/D274A) exhibit decreased adipose tissue surrounding the gonads and kidneys compared with wild-type mice. Adipocyte size is smaller, more preadipocytes/stromal cell are present in their gonadal fat tissue and differentiation of preadipocytes to adipocytes is retarded. Glucocorticoid levels are raised and the GR is hyperphosphorylated in adipose tissue of Ppp5D274A/D274A mice at Ser212 and Ser220 (orthologous to human Ser203 and Ser211) in the absence of glucocorticoids. Preadipocyte cultures from Ppp5D274A/D274A mice show decreased down regulation of Delta-like protein-1/preadipocyte factor-1, hyperphosphorylation of extra-cellular signal regulated kinase 2 (ERK2) and increased concentration of (sex determining region Y)-box 9 (SOX9), changes in a pathway essential for preadipocyte differentiation, which leads to decreased concentrations of the transcription factors CEBPβ and CEBPα necessary for the later stages of adipogenesis. The data indicate that Ppp5 plays a crucial role in modifying GR-mediated initiation of adipose tissue differentiation, suggesting that inhibition of Ppp5 may potentially be beneficial to prevent obesity during glucocorticoid treatment.
Highlights
Glucocorticoids are widely used as drugs to control both acute and chronic inflammation and, at supraphysiological concentrations, they display strong immunosuppressive actions
Our biochemical analyses, including elevated serum glucorticoids, suggest that the primary defect underlying this phenotype may be an alteration in glucocorticoid receptor (GR) function during the early stages of adipose tissue differentiation from preadipocytes
We demonstrate that preadipocytes expressing inactivated Ppp5 differentiate more slowly in culture than in wild-type preadipocytes and that more stromal cells, which include preadipocytes, are present in the gonadal fat pads of Ppp5D274A/D274A mice, data which support a block in an early step of preadipocyte differentiation
Summary
Glucocorticoids are widely used as drugs to control both acute and chronic inflammation and, at supraphysiological concentrations, they display strong immunosuppressive actions Their use, is limited by side effects, which include metabolic derangements such as central obesity, glucose intolerance and insulin resistance, which are major risk factors for Type 2 diabetes and cardiovascular disease. Protein phosphatase 5 (Ppp5/PP5), which dephosphorylates serine and threonine residues in proteins [2,3], was identified as a component of GR-Hsp complexes [4,5] and shown to interact with Hsp and Hsp via its tetratricopeptide repeat (TPR) domain [6,7]. Three TPR-containing proteins, FK506 binding protein 51 (FKBP51), FKBP52 and Ppp5/PP5 are known to separately associate with the mature GR through Hsp, to form different GR complexes [8,9]. Ppp is the only TPR protein that exhibits phosphatase activity in the GR complexes, and interaction of Ppp TPR domain with
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