Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Kfir
K
Sharabi
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
Hua
H
Lin
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Clint D J
CDJ
Tavares
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
John E
JE
Dominy
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Joao Paulo
JP
Camporez
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Rachel J
RJ
Perry
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Roger
R
Schilling
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Amy K
AK
Rines
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Jaemin
J
Lee
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Marc
M
Hickey
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Melissa
M
Bennion
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Michelle
M
Palmer
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Partha P
PP
Nag
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Joshua A
JA
Bittker
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
José
J
Perez
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Mark P
MP
Jedrychowski
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Umut
U
Ozcan
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Steve P
SP
Gygi
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
Theodore M
TM
Kamenecka
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.
Gerald I
GI
Shulman
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Stuart L
SL
Schreiber
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
Patrick R
PR
Griffin
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.
Pere
P
Puigserver
D000107:Acetylation; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D057166:High-Throughput Screening Assays; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007333:Insulin Resistance; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000037:antagonists & inhibitors*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D001786:Blood Glucose; D005947:Glucose; D051557:Hepatocyte Nuclear Factor 4; D007004:Hypoglycemic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C496593:Hnf4a protein, mouse; C485290:Ppargc1a protein, mouse
AlphaLisa; GCN5; PGC-1alpha; drug discovery; glucagon; gluconeogenesis; hepatic glucose production; insulin resistance; protein acetylation; type 2 diabetes