PPP2R5B, a regulatory subunit of PP2A, contributes to adipocyte insulin resistance

• Published in: Molecular and cellular endocrinology 2016-12, Vol.437, p.97-107
• Main Authors: Beg, Muheeb, Srivastava, Ankita, Shankar, Kripa, Varshney, Salil, Rajan, Sujith, Gupta, Abhishek, Kumar, Durgesh, Gaikwad, Anil N.
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocyte; Adipocytes - drug effects; Adipocytes - metabolism; Adipocytes - pathology; Alkaline Phosphatase - metabolism; Animals; Biological Transport - drug effects; Diet, High-Fat; Disease Models, Animal; Down-Regulation - drug effects; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Glucose - metabolism; HEK293 Cells; High fat diet; Humans; Hyperinsulinemia; Insulin - adverse effects; Insulin Resistance; Lentivirus - metabolism; Male; Mice; Mice, Inbred C57BL; PPP2R5B; Promoter Regions, Genetic - genetics; Protein Phosphatase 2 - metabolism; Protein Subunits - metabolism; Signal Transduction - drug effects; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2016.08.016

Insulin resistance is associated with deregulation of insulin signaling owing to the chronic exposure of insulin (hyperinsulinemia) to the tissues. Phosphorylation and dephosphorylation events in insulin signaling pathway play an essential role in signal transduction and glucose uptake. Amongst all, Akt protein is considered to be central to the overall insulin signaling proteins. In glucose responsive tissues like adipose and muscles, activation of Akt is responsible for triggering GLUT4 translocation and glucose transport. Several phosphatases such as PTEN, PP2A have been reported to be involved in dephosphorylation and inactivation of Akt protein. We have identified increased PP2A activity during state of chronic hyperinsulinemia exposure along-with development of adipocyte insulin resistance. This increased phosphatase activity leads activation of cAMP/PKA axis, which in turn increased cAMP levels in insulin resistant (IR) adipocytes. Okadaic acid, an inhibitor of PP2A restored and increased insulin stimulated glucose uptake in insulin resistant (IR) and insulin sensitive (IS) adipocytes respectively. In IS adipocyte, chemical activation of PP2A through MG132 and FTY720 showed decreased insulin sensitivity corroborated with decreased Akt phosphorylation and glucose uptake. We also observed an increased expression of PP2A-B (regulatory) subunit in IR adipocytes. We found PPP2R5B, a regulatory subunit of PP2A is responsible for the dephosphorylation and inactivation of Akt protein. Increased expression of PPP2R5B was also confirmed in white adipose tissue of high fat diet induced IR mice model. Overexpression and suppression strategies confirmed the role of PPP2R5B in regulating insulin signaling. Thus, we conclude that PPP2R5B, a B subunit of PP2A is a negative regulator of Akt phosphorylation contributing partly to the chronic hyperinsulinemia induced insulin resistance in adipocytes. [Display omitted] •PP2A activity and its B subunit, PPP2R5B expression are increased in hyperinsulinemia induced insulin resistant adipocytes.•PPP2R5B negatively regulates Akt phosphorylation in both in vitro and in vivo models of insulin resistance.•Over-expression and suppression studies explain role of PP2R5B in modulating insulin signalling by Akt phosphorylation.