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Cell. 2017 Mar 23;169(1):148-160.e15. doi: 10.1016/j.cell.2017.03.001.

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

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
3
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
5
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
6
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
8
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: pere_puigserver@dfci.harvard.edu.

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

PMID:
28340340
PMCID:
PMC5398763
DOI:
10.1016/j.cell.2017.03.001
[Indexed for MEDLINE]
Free PMC Article

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