TORC2 Regulates Hepatic Insulin Signaling via a Mammalian Phosphatidic Acid Phosphatase, LIPIN1

Dongryeol Ryu; Kyoung Jin Oh; Hee Yeon Jo; Susan Hedrick; Yo Na Kim; Yu Jin Hwang; Tae Sik Park; Joong Soo Han; Cheol Soo Choi; Marc Montminy; Seung Hoi Koo

doi:10.1016/j.cmet.2009.01.007

TORC2 Regulates Hepatic Insulin Signaling via a Mammalian Phosphatidic Acid Phosphatase, LIPIN1

Dongryeol Ryu, Kyoung Jin Oh, Hee Yeon Jo, Susan Hedrick, Yo Na Kim, Yu Jin Hwang, Tae Sik Park, Joong Soo Han, Cheol Soo Choi, Marc Montminy, Seung Hoi Koo

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

73 Citations (Scopus)

Abstract

TORC2 is a major transcriptional coactivator for hepatic glucose production. Insulin impedes gluconeogenesis by inhibiting TORC2 via SIK2-dependent phosphorylation at Ser171. Interruption of this process greatly perturbs hepatic glucose metabolism, thus promoting hyperglycemia in rodents. Here, we show that hyperactivation of TORC2 would exacerbate insulin resistance by enhancing expression of LIPIN1, a mammalian phosphatidic acid phosphatase for diacylglycerol (DAG) synthesis. Diet-induced or genetic obesity increases LIPIN1 expression in mouse liver, and TORC2 is responsible for its transcriptional activation. While overexpression of LIPIN1 disturbs hepatic insulin signaling, knockdown of LIPIN1 ameliorates hyperglycemia and insulin resistance by reducing DAG and PKCε activity in db/db mice. Finally, TORC2-mediated insulin resistance is partially rescued by concomitant knockdown of LIPIN1, confirming the critical role of LIPIN1 in the perturbation of hepatic insulin signaling. These data propose that dysregulation of TORC2 would further exaggerate insulin resistance and promote type 2 diabetes in a LIPIN1-dependent manner.

Original language	English
Pages (from-to)	240-251
Number of pages	12
Journal	Cell Metabolism
Volume	9
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2009.01.007
Publication status	Published - 2009 Mar 4
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank Sun Myung Park and Bo-Kyoung Kim for the technical assistance. This work was supported by a Research Program for New Drug Target Discovery (M10648000089-08N4800-08910) grant; a Korea Science and Engineering Foundation (KOSEF) grant (R01-2008-000-11935-0); a Korea Research Foundation (KRF) grant (2006-E00037) by the Ministry of Education, Science, and Technology; and a grant from the Marine Biotechnology Program funded by the Ministry of Land, Transport, and Maritime Affairs, Republic of Korea.

Keywords

HUMDISEASE
SIGNALING

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2009.01.007

Cite this

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title = "TORC2 Regulates Hepatic Insulin Signaling via a Mammalian Phosphatidic Acid Phosphatase, LIPIN1",

abstract = "TORC2 is a major transcriptional coactivator for hepatic glucose production. Insulin impedes gluconeogenesis by inhibiting TORC2 via SIK2-dependent phosphorylation at Ser171. Interruption of this process greatly perturbs hepatic glucose metabolism, thus promoting hyperglycemia in rodents. Here, we show that hyperactivation of TORC2 would exacerbate insulin resistance by enhancing expression of LIPIN1, a mammalian phosphatidic acid phosphatase for diacylglycerol (DAG) synthesis. Diet-induced or genetic obesity increases LIPIN1 expression in mouse liver, and TORC2 is responsible for its transcriptional activation. While overexpression of LIPIN1 disturbs hepatic insulin signaling, knockdown of LIPIN1 ameliorates hyperglycemia and insulin resistance by reducing DAG and PKCε activity in db/db mice. Finally, TORC2-mediated insulin resistance is partially rescued by concomitant knockdown of LIPIN1, confirming the critical role of LIPIN1 in the perturbation of hepatic insulin signaling. These data propose that dysregulation of TORC2 would further exaggerate insulin resistance and promote type 2 diabetes in a LIPIN1-dependent manner.",

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author = "Dongryeol Ryu and Oh, {Kyoung Jin} and Jo, {Hee Yeon} and Susan Hedrick and Kim, {Yo Na} and Hwang, {Yu Jin} and Park, {Tae Sik} and Han, {Joong Soo} and Choi, {Cheol Soo} and Marc Montminy and Koo, {Seung Hoi}",

note = "Funding Information: We would like to thank Sun Myung Park and Bo-Kyoung Kim for the technical assistance. This work was supported by a Research Program for New Drug Target Discovery (M10648000089-08N4800-08910) grant; a Korea Science and Engineering Foundation (KOSEF) grant (R01-2008-000-11935-0); a Korea Research Foundation (KRF) grant (2006-E00037) by the Ministry of Education, Science, and Technology; and a grant from the Marine Biotechnology Program funded by the Ministry of Land, Transport, and Maritime Affairs, Republic of Korea. ",

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AU - Hedrick, Susan

AU - Kim, Yo Na

AU - Hwang, Yu Jin

AU - Park, Tae Sik

AU - Han, Joong Soo

AU - Choi, Cheol Soo

AU - Montminy, Marc

AU - Koo, Seung Hoi

N1 - Funding Information: We would like to thank Sun Myung Park and Bo-Kyoung Kim for the technical assistance. This work was supported by a Research Program for New Drug Target Discovery (M10648000089-08N4800-08910) grant; a Korea Science and Engineering Foundation (KOSEF) grant (R01-2008-000-11935-0); a Korea Research Foundation (KRF) grant (2006-E00037) by the Ministry of Education, Science, and Technology; and a grant from the Marine Biotechnology Program funded by the Ministry of Land, Transport, and Maritime Affairs, Republic of Korea.

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N2 - TORC2 is a major transcriptional coactivator for hepatic glucose production. Insulin impedes gluconeogenesis by inhibiting TORC2 via SIK2-dependent phosphorylation at Ser171. Interruption of this process greatly perturbs hepatic glucose metabolism, thus promoting hyperglycemia in rodents. Here, we show that hyperactivation of TORC2 would exacerbate insulin resistance by enhancing expression of LIPIN1, a mammalian phosphatidic acid phosphatase for diacylglycerol (DAG) synthesis. Diet-induced or genetic obesity increases LIPIN1 expression in mouse liver, and TORC2 is responsible for its transcriptional activation. While overexpression of LIPIN1 disturbs hepatic insulin signaling, knockdown of LIPIN1 ameliorates hyperglycemia and insulin resistance by reducing DAG and PKCε activity in db/db mice. Finally, TORC2-mediated insulin resistance is partially rescued by concomitant knockdown of LIPIN1, confirming the critical role of LIPIN1 in the perturbation of hepatic insulin signaling. These data propose that dysregulation of TORC2 would further exaggerate insulin resistance and promote type 2 diabetes in a LIPIN1-dependent manner.

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ER -

TORC2 Regulates Hepatic Insulin Signaling via a Mammalian Phosphatidic Acid Phosphatase, LIPIN1

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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