title: Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ).
abstract: Glucocorticoid receptor-α (GRα) and peroxisome proliferator-activated receptor-γ (PPARγ) regulate adipogenesis by controlling the balance between lipolysis and lipogenesis. Here, we show that protein phosphatase 5 (PP5), a nuclear receptor co-chaperone, reciprocally modulates the lipometabolic activities of GRα and PPARγ. Wild-type and PP5-deficient (KO) mouse embryonic fibroblast cells were used to show binding of PP5 to both GRα and PPARγ. In response to adipogenic stimuli, PP5-KO mouse embryonic fibroblast cells showed almost no lipid accumulation with reduced expression of adipogenic markers (aP2, CD36, and perilipin) and low fatty-acid synthase enzymatic activity. This was completely reversed following reintroduction of PP5. Loss of PP5 increased phosphorylation of GRα at serines 212 and 234 and elevated dexamethasone-induced activity at prolipolytic genes. In contrast, PPARγ in PP5-KO cells was hyperphosphorylated at serine 112 but had reduced rosiglitazone-induced activity at lipogenic genes. Expression of the S112A mutant rescued PPARγ transcriptional activity and lipid accumulation in PP5-KO cells pointing to Ser-112 as an important residue of PP5 action. This work identifies PP5 as a fulcrum point in nuclear receptor control of the lipolysis/lipogenesis equilibrium and as a potential target in the treatment of obesity.
authors: Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, Ohio 43614, USA.
authors: Terry D
authors: TD
authors: Hinds
authors: Lance A
authors: LA
authors: Stechschulte
authors: Harrison A
authors: HA
authors: Cash
authors: Donald
authors: D
authors: Whisler
authors: Ananya
authors: A
authors: Banerjee
authors: Weidong
authors: W
authors: Yong
authors: Saja S
authors: SS
authors: Khuder
authors: Meenakshi K
authors: MK
authors: Kaw
authors: Weinian
authors: W
authors: Shou
authors: Sonia M
authors: SM
authors: Najjar
authors: Edwin R
authors: ER
authors: Sanchez
mesh_terms: D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004586:Electrophoresis; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D047495:PPAR gamma; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5