Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance

F. Andreozzi, C. Procopio, A. Greco, G. C. Mannino, C. Miele, G. A. Raciti, C. Iadicicco, F. Beguinot, A. E. Pontiroli, M. L. Hribal, F. Folli, G. Sesti

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis: We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling, PHLPP (also known as PHLPP1) was overexpressed in HepG2 and L6 cells. Methods: Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant PHLPP1 overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated. Results: Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (p = 0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (r = -0.48; p = 0.001), BMI (r = 0.44; p < 0.0001), insulin (r = 0.35; p < 0.0001) and HOMA (r = 0.38; p < 0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (p < 0.0001). Insulin treatment of HepG2 cells resulted in a dose- and time-dependent upregulation of PHLPP-1. Overexpression of PHLPP1 in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport. Conclusions/interpretation: Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.

Original languageEnglish (US)
Pages (from-to)1879-1887
Number of pages9
JournalDiabetologia
Volume54
Issue number7
DOIs
StatePublished - Jul 2011

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Protein Phosphatase 1
Phosphoric Monoester Hydrolases
Insulin Resistance
Phosphoprotein Phosphatases
Hep G2 Cells
Insulin
Fasting
Glucose
Skeletal Muscle
Myoblasts
Type 2 Diabetes Mellitus
leucine-rich repeat proteins
Pleckstrin Homology Domains
Glycogen Synthase Kinase 3
Subcutaneous Fat
Glycogen
Immunoblotting
Hepatocellular Carcinoma
Up-Regulation
Obesity

Keywords

  • Adipose tissue
  • Akt
  • Insulin signalling
  • Obesity
  • PHLPP

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance. / Andreozzi, F.; Procopio, C.; Greco, A.; Mannino, G. C.; Miele, C.; Raciti, G. A.; Iadicicco, C.; Beguinot, F.; Pontiroli, A. E.; Hribal, M. L.; Folli, F.; Sesti, G.

In: Diabetologia, Vol. 54, No. 7, 07.2011, p. 1879-1887.

Research output: Contribution to journalArticle

Andreozzi, F, Procopio, C, Greco, A, Mannino, GC, Miele, C, Raciti, GA, Iadicicco, C, Beguinot, F, Pontiroli, AE, Hribal, ML, Folli, F & Sesti, G 2011, 'Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance', Diabetologia, vol. 54, no. 7, pp. 1879-1887. https://doi.org/10.1007/s00125-011-2116-6
Andreozzi, F. ; Procopio, C. ; Greco, A. ; Mannino, G. C. ; Miele, C. ; Raciti, G. A. ; Iadicicco, C. ; Beguinot, F. ; Pontiroli, A. E. ; Hribal, M. L. ; Folli, F. ; Sesti, G. / Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance. In: Diabetologia. 2011 ; Vol. 54, No. 7. pp. 1879-1887.
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AU - Procopio, C.

AU - Greco, A.

AU - Mannino, G. C.

AU - Miele, C.

AU - Raciti, G. A.

AU - Iadicicco, C.

AU - Beguinot, F.

AU - Pontiroli, A. E.

AU - Hribal, M. L.

AU - Folli, F.

AU - Sesti, G.

PY - 2011/7

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N2 - Aims/hypothesis: We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling, PHLPP (also known as PHLPP1) was overexpressed in HepG2 and L6 cells. Methods: Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant PHLPP1 overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated. Results: Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (p = 0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (r = -0.48; p = 0.001), BMI (r = 0.44; p < 0.0001), insulin (r = 0.35; p < 0.0001) and HOMA (r = 0.38; p < 0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (p < 0.0001). Insulin treatment of HepG2 cells resulted in a dose- and time-dependent upregulation of PHLPP-1. Overexpression of PHLPP1 in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport. Conclusions/interpretation: Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.

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KW - Adipose tissue

KW - Akt

KW - Insulin signalling

KW - Obesity

KW - PHLPP

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