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 journalArticlepeer-review

148 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 languageAmerican English
Pages (from-to)148-160.e15
JournalCell
Volume169
Issue number1
DOIs
StatePublished - 23 Mar 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

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

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