Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress

Mirela Delibegovic, Derek Zimmer, Caitlin Kauffman, Kimberly Rak, Eun-Gyoung Hong, You-Ree Cho, Jason K Kim, Barbara B Kahn, Benjamin G Neel, Kendra K Bence

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B(-/-) mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B(-/-) mice are protected against high-fat diet-induced obesity and glucose intolerance, whereas muscle-specific PTP1B(-/-) mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS: We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B(-/-) and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS: Compared with normal littermates, liver-specific PTP1B(-/-) mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B(-/-) mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B(-/-) mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet-induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2alpha and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS: Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in addition to diabetes.
Original languageEnglish
Pages (from-to)590-9
Number of pages10
JournalDiabetes
Volume58
Issue number3
Early online date15 Dec 2008
DOIs
Publication statusPublished - Mar 2009

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Endoplasmic Reticulum Stress
Diet
Liver
Glucose
Adiposity
High Fat Diet
Lipid Metabolism
Insulin
Homeostasis
Insulin Resistance
Transcription Factor CHOP
Metabolic Syndrome X
Gene Expression
Protein Tyrosine Phosphatases
Glucose Intolerance
Muscle Proteins
Risk Reduction Behavior

Keywords

  • animals
  • blood glucose
  • body composition
  • dietary fats
  • endoplasmic reticulum
  • gene amplification
  • gene deletion
  • gene expression regulation
  • homeostasis
  • insulin
  • liver
  • metabolic syndrome X
  • mice
  • mice, inbred C57BL
  • mice, knockout
  • protein tyrosine phosphatase, non-receptor type 1
  • reference values
  • reverse transcriptase polymerase chain reaction
  • signal transduction

Cite this

Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress. / Delibegovic, Mirela; Zimmer, Derek; Kauffman, Caitlin; Rak, Kimberly; Hong, Eun-Gyoung; Cho, You-Ree; Kim, Jason K; Kahn, Barbara B; Neel, Benjamin G; Bence, Kendra K.

In: Diabetes, Vol. 58, No. 3, 03.2009, p. 590-9.

Research output: Contribution to journalArticle

Delibegovic, Mirela ; Zimmer, Derek ; Kauffman, Caitlin ; Rak, Kimberly ; Hong, Eun-Gyoung ; Cho, You-Ree ; Kim, Jason K ; Kahn, Barbara B ; Neel, Benjamin G ; Bence, Kendra K. / Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress. In: Diabetes. 2009 ; Vol. 58, No. 3. pp. 590-9.
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abstract = "OBJECTIVE: The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B(-/-) mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B(-/-) mice are protected against high-fat diet-induced obesity and glucose intolerance, whereas muscle-specific PTP1B(-/-) mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS: We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B(-/-) and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS: Compared with normal littermates, liver-specific PTP1B(-/-) mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B(-/-) mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B(-/-) mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet-induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2alpha and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS: Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in addition to diabetes.",
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author = "Mirela Delibegovic and Derek Zimmer and Caitlin Kauffman and Kimberly Rak and Eun-Gyoung Hong and You-Ree Cho and Kim, {Jason K} and Kahn, {Barbara B} and Neel, {Benjamin G} and Bence, {Kendra K}",
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AU - Delibegovic, Mirela

AU - Zimmer, Derek

AU - Kauffman, Caitlin

AU - Rak, Kimberly

AU - Hong, Eun-Gyoung

AU - Cho, You-Ree

AU - Kim, Jason K

AU - Kahn, Barbara B

AU - Neel, Benjamin G

AU - Bence, Kendra K

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N2 - OBJECTIVE: The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B(-/-) mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B(-/-) mice are protected against high-fat diet-induced obesity and glucose intolerance, whereas muscle-specific PTP1B(-/-) mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS: We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B(-/-) and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS: Compared with normal littermates, liver-specific PTP1B(-/-) mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B(-/-) mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B(-/-) mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet-induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2alpha and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS: Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in addition to diabetes.

AB - OBJECTIVE: The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B(-/-) mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B(-/-) mice are protected against high-fat diet-induced obesity and glucose intolerance, whereas muscle-specific PTP1B(-/-) mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS: We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B(-/-) and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS: Compared with normal littermates, liver-specific PTP1B(-/-) mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B(-/-) mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B(-/-) mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet-induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2alpha and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS: Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in addition to diabetes.

KW - animals

KW - blood glucose

KW - body composition

KW - dietary fats

KW - endoplasmic reticulum

KW - gene amplification

KW - gene deletion

KW - gene expression regulation

KW - homeostasis

KW - insulin

KW - liver

KW - metabolic syndrome X

KW - mice

KW - mice, inbred C57BL

KW - mice, knockout

KW - protein tyrosine phosphatase, non-receptor type 1

KW - reference values

KW - reverse transcriptase polymerase chain reaction

KW - signal transduction

U2 - 10.2337/db08-0913

DO - 10.2337/db08-0913

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VL - 58

SP - 590

EP - 599

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 3

ER -