Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance

Amanda E Brandon, Bing M. Liao, Barbara Diakanastasis, Benjamin L. Parker, Katy Raddatz, Sophie A. McManus, Liam O'Reilly, Erica Kimber, A. Gabrielle van der Kraan, Dale Hancock, Darren C. Henstridge, Peter J. Meikle, Gregory J. Cooney, David E. James, Saskia Reibe, Mark A. Febbraio, Trevor J. Biden, Carsten Schmitz-Peiffer

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Protein kinase C epsilon (PKCɛ) activation in the liver is proposed to inhibit insulin action through phosphorylation of the insulin receptor. Here, however, we demonstrated that global, but not liver-specific, deletion of PKCɛ in mice protected against diet-induced glucose intolerance and insulin resistance. Furthermore, PKCɛ-dependent alterations in insulin receptor phosphorylation were not detected. Adipose-tissue-specific knockout mice did exhibit improved glucose tolerance, but phosphoproteomics revealed no PKCɛ-dependent effect on the activation of insulin signaling pathways. Altered phosphorylation of adipocyte proteins associated with cell junctions and endosomes was associated with changes in hepatic expression of several genes linked to glucose homeostasis and lipid metabolism. The primary effect of PKCɛ on glucose homeostasis is, therefore, not exerted directly in the liver as currently posited, and PKCɛ activation in this tissue should be interpreted with caution. However, PKCɛ activity in adipose tissue modulates glucose tolerance and is involved in crosstalk with the liver.

Original languageEnglish
Pages (from-to)183-191
Number of pages9
JournalCell Metabolism
Volume29
Issue number1
DOIs
Publication statusPublished - 8 Jan 2019
Externally publishedYes

Keywords

  • adipose tissue
  • glucose intolerance
  • high-fat diet
  • insulin resistance
  • liver
  • phosphoproteomics
  • PKC epsilon
  • protein kinase C
  • type 2 diabetes

Cite this

Brandon, A. E., Liao, B. M., Diakanastasis, B., Parker, B. L., Raddatz, K., McManus, S. A., ... Schmitz-Peiffer, C. (2019). Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance. Cell Metabolism, 29(1), 183-191. https://doi.org/10.1016/j.cmet.2018.09.013
Brandon, Amanda E ; Liao, Bing M. ; Diakanastasis, Barbara ; Parker, Benjamin L. ; Raddatz, Katy ; McManus, Sophie A. ; O'Reilly, Liam ; Kimber, Erica ; van der Kraan, A. Gabrielle ; Hancock, Dale ; Henstridge, Darren C. ; Meikle, Peter J. ; Cooney, Gregory J. ; James, David E. ; Reibe, Saskia ; Febbraio, Mark A. ; Biden, Trevor J. ; Schmitz-Peiffer, Carsten. / Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance. In: Cell Metabolism. 2019 ; Vol. 29, No. 1. pp. 183-191.
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title = "Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance",
abstract = "Protein kinase C epsilon (PKCɛ) activation in the liver is proposed to inhibit insulin action through phosphorylation of the insulin receptor. Here, however, we demonstrated that global, but not liver-specific, deletion of PKCɛ in mice protected against diet-induced glucose intolerance and insulin resistance. Furthermore, PKCɛ-dependent alterations in insulin receptor phosphorylation were not detected. Adipose-tissue-specific knockout mice did exhibit improved glucose tolerance, but phosphoproteomics revealed no PKCɛ-dependent effect on the activation of insulin signaling pathways. Altered phosphorylation of adipocyte proteins associated with cell junctions and endosomes was associated with changes in hepatic expression of several genes linked to glucose homeostasis and lipid metabolism. The primary effect of PKCɛ on glucose homeostasis is, therefore, not exerted directly in the liver as currently posited, and PKCɛ activation in this tissue should be interpreted with caution. However, PKCɛ activity in adipose tissue modulates glucose tolerance and is involved in crosstalk with the liver.",
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Brandon, AE, Liao, BM, Diakanastasis, B, Parker, BL, Raddatz, K, McManus, SA, O'Reilly, L, Kimber, E, van der Kraan, AG, Hancock, D, Henstridge, DC, Meikle, PJ, Cooney, GJ, James, DE, Reibe, S, Febbraio, MA, Biden, TJ & Schmitz-Peiffer, C 2019, 'Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance', Cell Metabolism, vol. 29, no. 1, pp. 183-191. https://doi.org/10.1016/j.cmet.2018.09.013

Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance. / Brandon, Amanda E; Liao, Bing M.; Diakanastasis, Barbara; Parker, Benjamin L.; Raddatz, Katy; McManus, Sophie A.; O'Reilly, Liam; Kimber, Erica; van der Kraan, A. Gabrielle; Hancock, Dale; Henstridge, Darren C.; Meikle, Peter J.; Cooney, Gregory J.; James, David E.; Reibe, Saskia; Febbraio, Mark A.; Biden, Trevor J.; Schmitz-Peiffer, Carsten.

In: Cell Metabolism, Vol. 29, No. 1, 08.01.2019, p. 183-191.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance

AU - Brandon, Amanda E

AU - Liao, Bing M.

AU - Diakanastasis, Barbara

AU - Parker, Benjamin L.

AU - Raddatz, Katy

AU - McManus, Sophie A.

AU - O'Reilly, Liam

AU - Kimber, Erica

AU - van der Kraan, A. Gabrielle

AU - Hancock, Dale

AU - Henstridge, Darren C.

AU - Meikle, Peter J.

AU - Cooney, Gregory J.

AU - James, David E.

AU - Reibe, Saskia

AU - Febbraio, Mark A.

AU - Biden, Trevor J.

AU - Schmitz-Peiffer, Carsten

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N2 - Protein kinase C epsilon (PKCɛ) activation in the liver is proposed to inhibit insulin action through phosphorylation of the insulin receptor. Here, however, we demonstrated that global, but not liver-specific, deletion of PKCɛ in mice protected against diet-induced glucose intolerance and insulin resistance. Furthermore, PKCɛ-dependent alterations in insulin receptor phosphorylation were not detected. Adipose-tissue-specific knockout mice did exhibit improved glucose tolerance, but phosphoproteomics revealed no PKCɛ-dependent effect on the activation of insulin signaling pathways. Altered phosphorylation of adipocyte proteins associated with cell junctions and endosomes was associated with changes in hepatic expression of several genes linked to glucose homeostasis and lipid metabolism. The primary effect of PKCɛ on glucose homeostasis is, therefore, not exerted directly in the liver as currently posited, and PKCɛ activation in this tissue should be interpreted with caution. However, PKCɛ activity in adipose tissue modulates glucose tolerance and is involved in crosstalk with the liver.

AB - Protein kinase C epsilon (PKCɛ) activation in the liver is proposed to inhibit insulin action through phosphorylation of the insulin receptor. Here, however, we demonstrated that global, but not liver-specific, deletion of PKCɛ in mice protected against diet-induced glucose intolerance and insulin resistance. Furthermore, PKCɛ-dependent alterations in insulin receptor phosphorylation were not detected. Adipose-tissue-specific knockout mice did exhibit improved glucose tolerance, but phosphoproteomics revealed no PKCɛ-dependent effect on the activation of insulin signaling pathways. Altered phosphorylation of adipocyte proteins associated with cell junctions and endosomes was associated with changes in hepatic expression of several genes linked to glucose homeostasis and lipid metabolism. The primary effect of PKCɛ on glucose homeostasis is, therefore, not exerted directly in the liver as currently posited, and PKCɛ activation in this tissue should be interpreted with caution. However, PKCɛ activity in adipose tissue modulates glucose tolerance and is involved in crosstalk with the liver.

KW - adipose tissue

KW - glucose intolerance

KW - high-fat diet

KW - insulin resistance

KW - liver

KW - phosphoproteomics

KW - PKC epsilon

KW - protein kinase C

KW - type 2 diabetes

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Brandon AE, Liao BM, Diakanastasis B, Parker BL, Raddatz K, McManus SA et al. Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance. Cell Metabolism. 2019 Jan 8;29(1):183-191. https://doi.org/10.1016/j.cmet.2018.09.013