PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

Olivier Bezy; Thien T Tran; Jussi Pihlajamäki; Ryo Suzuki; Brice Emanuelli; Jonathan Winnay; Marcelo A Mori; Joel Haas; Sudha B Biddinger; Michael Leitges; Allison B Goldfine; Mary Elizabeth Patti; George L King; C Ronald Kahn

doi:10.1172/JCI46045

PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

Olivier Bezy, Thien T Tran, Jussi Pihlajamäki, Ryo Suzuki, Brice Emanuelli, Jonathan Winnay, Marcelo A Mori, Joel Haas, Sudha B Biddinger, Michael Leitges, Allison B Goldfine, Mary Elizabeth Patti, George L King, C Ronald Kahn

86 Citationer (Scopus)

Abstract

C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet- or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liver-specific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome.

Originalsprog	Engelsk
Tidsskrift	The Journal of Clinical Investigation
Vol/bind	121
Udgave nummer	6
Sider (fra-til)	2504-17
Antal sider	14
ISSN	0021-9738
DOI	https://doi.org/10.1172/JCI46045
Status	Udgivet - 1 jun. 2011

Emneord

Aging
Animals
Blood Glucose
Diabetes Mellitus, Experimental
Dietary Fats
Enzyme Induction
Fasting
Fatty Liver
Female
Gluconeogenesis
Glucose Intolerance
Humans
Insulin
Insulin Resistance
Lipogenesis
Liver
Male
Metabolic Syndrome X
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Obesity
Protein Kinase C-delta
Species Specificity
Triglycerides

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10.1172/JCI46045

Citationsformater

Bezy, O., Tran, T. T., Pihlajamäki, J., Suzuki, R., Emanuelli, B., Winnay, J., Mori, M. A., Haas, J., Biddinger, S. B., Leitges, M., Goldfine, A. B., Patti, M. E., King, G. L., & Kahn, C. R. (2011). PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. The Journal of Clinical Investigation, 121(6), 2504-17. https://doi.org/10.1172/JCI46045

@article{255878aa14cb40c6835331f024070421,

title = "PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans",

abstract = "C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet- or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liver-specific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome.",

keywords = "Aging, Animals, Blood Glucose, Diabetes Mellitus, Experimental, Dietary Fats, Enzyme Induction, Fasting, Fatty Liver, Female, Gluconeogenesis, Glucose Intolerance, Humans, Insulin, Insulin Resistance, Lipogenesis, Liver, Male, Metabolic Syndrome X, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Obesity, Protein Kinase C-delta, Species Specificity, Triglycerides",

author = "Olivier Bezy and Tran, {Thien T} and Jussi Pihlajam{\"a}ki and Ryo Suzuki and Brice Emanuelli and Jonathan Winnay and Mori, {Marcelo A} and Joel Haas and Biddinger, {Sudha B} and Michael Leitges and Goldfine, {Allison B} and Patti, {Mary Elizabeth} and King, {George L} and Kahn, {C Ronald}",

year = "2011",

month = jun,

day = "1",

doi = "10.1172/JCI46045",

language = "English",

volume = "121",

pages = "2504--17",

journal = "The Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "6",

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TY - JOUR

T1 - PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

AU - Bezy, Olivier

AU - Tran, Thien T

AU - Pihlajamäki, Jussi

AU - Suzuki, Ryo

AU - Emanuelli, Brice

AU - Winnay, Jonathan

AU - Mori, Marcelo A

AU - Haas, Joel

AU - Biddinger, Sudha B

AU - Leitges, Michael

AU - Goldfine, Allison B

AU - Patti, Mary Elizabeth

AU - King, George L

AU - Kahn, C Ronald

PY - 2011/6/1

Y1 - 2011/6/1

N2 - C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet- or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liver-specific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome.

AB - C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet- or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liver-specific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome.

KW - Aging

KW - Animals

KW - Blood Glucose

KW - Diabetes Mellitus, Experimental

KW - Dietary Fats

KW - Enzyme Induction

KW - Fasting

KW - Fatty Liver

KW - Female

KW - Gluconeogenesis

KW - Glucose Intolerance

KW - Humans

KW - Insulin

KW - Insulin Resistance

KW - Lipogenesis

KW - Liver

KW - Male

KW - Metabolic Syndrome X

KW - Mice

KW - Mice, 129 Strain

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Obesity

KW - Protein Kinase C-delta

KW - Species Specificity

KW - Triglycerides

U2 - 10.1172/JCI46045

DO - 10.1172/JCI46045

M3 - Journal article

C2 - 21576825

SN - 0021-9738

VL - 121

SP - 2504

EP - 2517

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

IS - 6

ER -

PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

Abstract

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