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

• Published in: Cell Vol. 169; no. 1; pp. 148 - 160.e15
• Main Authors: Sharabi, Kfir, Lin, Hua, Tavares, Clint D.J., Dominy, John E., Camporez, Joao Paulo, Perry, Rachel J., Schilling, Roger, Rines, Amy K., Lee, Jaemin, Hickey, Marc, Bennion, Melissa, Palmer, Michelle, Nag, Partha P., Bittker, Joshua A., Perez, José, Jedrychowski, Mark P., Ozcan, Umut, Gygi, Steve P., Kamenecka, Theodore M., Shulman, Gerald I., Schreiber, Stuart L., Griffin, Patrick R., Puigserver, Pere
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.03.2017
• Subjects: Acetylation; AlphaLisa; animal models; Animals; bioavailability; blood glucose; Blood Glucose - metabolism; Cells, Cultured; Diabetes Mellitus, Type 2 - drug therapy; drug discovery; GCN5; gene expression; glucagon; gluconeogenesis; Gluconeogenesis - drug effects; glucose; Glucose - metabolism; hepatic glucose production; Hepatocyte Nuclear Factor 4 - metabolism; hepatocytes; Hepatocytes - metabolism; High-Throughput Screening Assays; homeostasis; Hypoglycemic Agents - administration & dosage; Insulin Resistance; liver; Mice; noninsulin-dependent diabetes mellitus; p300-CBP Transcription Factors - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - antagonists & inhibitors; PGC-1alpha; protein acetylation; type 2 diabetes; hepatic glucose production; PGC-1alpha; GCN5; type 2 diabetes; drug discovery; AlphaLisa; protein acetylation; glucagon; insulin resistance; gluconeogenesis
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2017.03.001

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. [Display omitted] •High-throughput screen identifies small molecules that increase PGC-1α acetylation•Small molecules inhibit PGC-1α-dependent gluconeogenic activity•SR-18292 suppresses HNF4α/PGC-1α gluconeogenic transcriptional function•SR-18292 improves insulin sensitivity and reduces blood glucose in T2D mice A small molecule targeting gluconeogenesis improves glucose homeostasis in animals with type 2 diabetes, suggesting a new therapeutic approach for this metabolic disease.