Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism

Ruth C. Meex; Andrew J. Hoy; Alexander Morris; Russell D. Brown; Jennifer C Y Lo; Melissa Burke; Robert J A Goode; Bronwyn A. Kingwell; Michael J. Kraakman; Mark A. Febbraio; Jan Willem Greve; Sander S. Rensen; Mark P. Molloy; Graeme I. Lancaster; Clinton R. Bruce; Matthew J. Watt

doi:10.1016/j.cmet.2015.09.023

Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism

Ruth C. Meex, Andrew J. Hoy, Alexander Morris, Russell D. Brown, Jennifer C Y Lo, Melissa Burke, Robert J A Goode, Bronwyn A. Kingwell, Michael J. Kraakman, Mark A. Febbraio, Jan Willem Greve, Sander S. Rensen, Mark P. Molloy, Graeme I. Lancaster, Clinton R. Bruce, Matthew J. Watt^*

^*Corresponding author for this work

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142 Citations (Scopus)

Abstract

Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition.

Original language	English
Pages (from-to)	1078-1089
Number of pages	12
Journal	Cell Metabolism
Volume	22
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2015.09.023
Publication status	Published - 1 Dec 2015

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Meex, R. C., Hoy, A. J., Morris, A., Brown, R. D., Lo, J. C. Y., Burke, M., Goode, R. J. A., Kingwell, B. A., Kraakman, M. J., Febbraio, M. A., Greve, J. W., Rensen, S. S., Molloy, M. P., Lancaster, G. I., Bruce, C. R., & Watt, M. J. (2015). Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism. Cell Metabolism, 22(6), 1078-1089. https://doi.org/10.1016/j.cmet.2015.09.023

Meex, Ruth C. ; Hoy, Andrew J. ; Morris, Alexander ; Brown, Russell D. ; Lo, Jennifer C Y ; Burke, Melissa ; Goode, Robert J A ; Kingwell, Bronwyn A. ; Kraakman, Michael J. ; Febbraio, Mark A. ; Greve, Jan Willem ; Rensen, Sander S. ; Molloy, Mark P. ; Lancaster, Graeme I. ; Bruce, Clinton R. ; Watt, Matthew J. / Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism. In: Cell Metabolism. 2015 ; Vol. 22, No. 6. pp. 1078-1089.

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title = "Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism",

abstract = "Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition.",

author = "Meex, {Ruth C.} and Hoy, {Andrew J.} and Alexander Morris and Brown, {Russell D.} and Lo, {Jennifer C Y} and Melissa Burke and Goode, {Robert J A} and Kingwell, {Bronwyn A.} and Kraakman, {Michael J.} and Febbraio, {Mark A.} and Greve, {Jan Willem} and Rensen, {Sander S.} and Molloy, {Mark P.} and Lancaster, {Graeme I.} and Bruce, {Clinton R.} and Watt, {Matthew J.}",

year = "2015",

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doi = "10.1016/j.cmet.2015.09.023",

language = "English",

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Meex, RC, Hoy, AJ, Morris, A, Brown, RD, Lo, JCY, Burke, M, Goode, RJA, Kingwell, BA, Kraakman, MJ, Febbraio, MA, Greve, JW, Rensen, SS, Molloy, MP, Lancaster, GI, Bruce, CR & Watt, MJ 2015, 'Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism', Cell Metabolism, vol. 22, no. 6, pp. 1078-1089. https://doi.org/10.1016/j.cmet.2015.09.023

Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism. / Meex, Ruth C.; Hoy, Andrew J.; Morris, Alexander; Brown, Russell D.; Lo, Jennifer C Y; Burke, Melissa; Goode, Robert J A; Kingwell, Bronwyn A.; Kraakman, Michael J.; Febbraio, Mark A.; Greve, Jan Willem; Rensen, Sander S.; Molloy, Mark P.; Lancaster, Graeme I.; Bruce, Clinton R.; Watt, Matthew J.

In: Cell Metabolism, Vol. 22, No. 6, 01.12.2015, p. 1078-1089.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism

AU - Meex, Ruth C.

AU - Hoy, Andrew J.

AU - Morris, Alexander

AU - Brown, Russell D.

AU - Lo, Jennifer C Y

AU - Burke, Melissa

AU - Goode, Robert J A

AU - Kingwell, Bronwyn A.

AU - Kraakman, Michael J.

AU - Febbraio, Mark A.

AU - Greve, Jan Willem

AU - Rensen, Sander S.

AU - Molloy, Mark P.

AU - Lancaster, Graeme I.

AU - Bruce, Clinton R.

AU - Watt, Matthew J.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition.

AB - Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition.

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AN - SCOPUS:84951104864

VL - 22

SP - 1078

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JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 6

ER -

Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism

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