Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes

Kfir Sharabi; Hua Lin; Clint D.J. Tavares; John E. Dominy; Joao Paulo Camporez; Rachel J. Perry; Roger Schilling; Amy K. Rines; Jaemin Lee; Marc Hickey; Melissa Bennion; Michelle Palmer; Partha P. Nag; Joshua A. Bittker; José Perez; Mark P. Jedrychowski; Umut Ozcan; Steve P. Gygi; Theodore M. Kamenecka; Gerald I. Shulman; Stuart L. Schreiber; Patrick R. Griffin; Pere Puigserver

doi:10.1016/j.cell.2017.03.001

Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes

Kfir Sharabi, Hua Lin, Clint D.J. Tavares, John E. Dominy, Joao Paulo Camporez, Rachel J. Perry, Roger Schilling, Amy K. Rines, Jaemin Lee, Marc Hickey, Melissa Bennion, Michelle Palmer, Partha P. Nag, Joshua A. Bittker, José Perez, Mark P. Jedrychowski, Umut Ozcan, Steve P. Gygi, Theodore M. Kamenecka, Gerald I. ShulmanStuart L. Schreiber, Patrick R. Griffin, Pere Puigserver^*

^*Corresponding author for this work

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

131 Scopus citations

Abstract

Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.

Original language	American English
Pages (from-to)	148-160.e15
Journal	Cell
Volume	169
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2017.03.001
State	Published - 23 Mar 2017
Externally published	Yes

Bibliographical note

Funding Information:
K.S. was partially funded by a post-doctoral fellowship from the AHA (15POST22880002). C.D.J.T. was partially funded by a post-doctoral fellowship from the ADA (1-16-PDF-111). A.K.R. received a post-doctoral fellowship from NIH/NIDDK (F32 DK102293-01). The HTS was funded by a grant from NIH to the Broad Institute as a MLPCN Center (S.L.S.) (U54HG005032). P.P. and P.R.G. were funded by the NIH/NIDDK (R24DK080261). G.I.S. was funded by NIH/NIDDK (R01DK-40936 9 and 2U2CDK059635). P.P. was funded by R03DA032468, R01 DK069966, and the ADA (7-12-MN-68).

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

AlphaLisa
GCN5
PGC-1alpha
drug discovery
glucagon
gluconeogenesis
hepatic glucose production
insulin resistance
protein acetylation
type 2 diabetes

UN SDGs

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

Access to Document

10.1016/j.cell.2017.03.001

Cite this

Sharabi, K., Lin, H., Tavares, C. D. J., Dominy, J. E., Camporez, J. P., Perry, R. J., Schilling, R., Rines, A. K., Lee, J., Hickey, M., Bennion, M., Palmer, M., Nag, P. P., Bittker, J. A., Perez, J., Jedrychowski, M. P., Ozcan, U., Gygi, S. P., Kamenecka, T. M., ... Puigserver, P. (2017). Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes. Cell, 169(1), 148-160.e15. https://doi.org/10.1016/j.cell.2017.03.001

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title = "Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes",

abstract = "Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.",

keywords = "AlphaLisa, GCN5, PGC-1alpha, drug discovery, glucagon, gluconeogenesis, hepatic glucose production, insulin resistance, protein acetylation, type 2 diabetes",

author = "Kfir Sharabi and Hua Lin and Tavares, {Clint D.J.} and Dominy, {John E.} and Camporez, {Joao Paulo} and Perry, {Rachel J.} and Roger Schilling and Rines, {Amy K.} and Jaemin Lee and Marc Hickey and Melissa Bennion and Michelle Palmer and Nag, {Partha P.} and Bittker, {Joshua A.} and Jos{\'e} Perez and Jedrychowski, {Mark P.} and Umut Ozcan and Gygi, {Steve P.} and Kamenecka, {Theodore M.} and Shulman, {Gerald I.} and Schreiber, {Stuart L.} and Griffin, {Patrick R.} and Pere Puigserver",

note = "Funding Information: K.S. was partially funded by a post-doctoral fellowship from the AHA (15POST22880002). C.D.J.T. was partially funded by a post-doctoral fellowship from the ADA (1-16-PDF-111). A.K.R. received a post-doctoral fellowship from NIH/NIDDK (F32 DK102293-01). The HTS was funded by a grant from NIH to the Broad Institute as a MLPCN Center (S.L.S.) (U54HG005032). P.P. and P.R.G. were funded by the NIH/NIDDK (R24DK080261). G.I.S. was funded by NIH/NIDDK (R01DK-40936 9 and 2U2CDK059635). P.P. was funded by R03DA032468, R01 DK069966, and the ADA (7-12-MN-68). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

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doi = "10.1016/j.cell.2017.03.001",

language = "American English",

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Sharabi, K, Lin, H, Tavares, CDJ, Dominy, JE, Camporez, JP, Perry, RJ, Schilling, R, Rines, AK, Lee, J, Hickey, M, Bennion, M, Palmer, M, Nag, PP, Bittker, JA, Perez, J, Jedrychowski, MP, Ozcan, U, Gygi, SP, Kamenecka, TM, Shulman, GI, Schreiber, SL, Griffin, PR & Puigserver, P 2017, 'Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes', Cell, vol. 169, no. 1, pp. 148-160.e15. https://doi.org/10.1016/j.cell.2017.03.001

TY - JOUR

T1 - Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes

AU - Sharabi, Kfir

AU - Lin, Hua

AU - Tavares, Clint D.J.

AU - Dominy, John E.

AU - Camporez, Joao Paulo

AU - Perry, Rachel J.

AU - Schilling, Roger

AU - Rines, Amy K.

AU - Lee, Jaemin

AU - Hickey, Marc

AU - Bennion, Melissa

AU - Palmer, Michelle

AU - Nag, Partha P.

AU - Bittker, Joshua A.

AU - Perez, José

AU - Jedrychowski, Mark P.

AU - Ozcan, Umut

AU - Gygi, Steve P.

AU - Kamenecka, Theodore M.

AU - Shulman, Gerald I.

AU - Schreiber, Stuart L.

AU - Griffin, Patrick R.

AU - Puigserver, Pere

N1 - Funding Information: K.S. was partially funded by a post-doctoral fellowship from the AHA (15POST22880002). C.D.J.T. was partially funded by a post-doctoral fellowship from the ADA (1-16-PDF-111). A.K.R. received a post-doctoral fellowship from NIH/NIDDK (F32 DK102293-01). The HTS was funded by a grant from NIH to the Broad Institute as a MLPCN Center (S.L.S.) (U54HG005032). P.P. and P.R.G. were funded by the NIH/NIDDK (R24DK080261). G.I.S. was funded by NIH/NIDDK (R01DK-40936 9 and 2U2CDK059635). P.P. was funded by R03DA032468, R01 DK069966, and the ADA (7-12-MN-68). Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/3/23

Y1 - 2017/3/23

N2 - Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.

AB - Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.

KW - AlphaLisa

KW - GCN5

KW - PGC-1alpha

KW - drug discovery

KW - glucagon

KW - gluconeogenesis

KW - hepatic glucose production

KW - insulin resistance

KW - protein acetylation

KW - type 2 diabetes

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U2 - 10.1016/j.cell.2017.03.001

DO - 10.1016/j.cell.2017.03.001

M3 - Article

C2 - 28340340

AN - SCOPUS:85015986323

SN - 0092-8674

VL - 169

SP - 148-160.e15

JO - Cell

JF - Cell

IS - 1

ER -

Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes

Abstract

Bibliographical note

Keywords

UN SDGs

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