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

Author:
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
Source:
Cell 2017 v.169 no.1 pp. 148-160.e15
ISSN:
0092-8674
Subject:
acetylation, animal models, bioavailability, blood glucose, gene expression, gluconeogenesis, glucose, hepatocytes, homeostasis, insulin resistance, liver, noninsulin-dependent diabetes mellitus
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.
Agid:
5657330