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Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism.

Abstract：

:Improving the control of energy homeostasis can lower cardiovascular risk in metabolically compromised individuals. To identify new regulators of whole-body energy control, we conducted a high-throughput screen in transgenic reporter zebrafish for small molecules that modulate the expression of the fasting-inducible gluconeogenic gene pck1. We show that this in vivo strategy identified several drugs that affect gluconeogenesis in humans as well as metabolically uncharacterized compounds. Most notably, we find that the translocator protein ligands PK 11195 and Ro5-4864 are glucose-lowering agents despite a strong inductive effect on pck1 expression. We show that these drugs are activators of a fasting-like energy state and, notably, that they protect high-fat diet-induced obese mice from hepatosteatosis and glucose intolerance, two pathological manifestations of metabolic dysregulation. Thus, using a whole-organism screening strategy, this study has identified new small-molecule activators of fasting metabolism.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

Gut P,Baeza-Raja B,Andersson O,Hasenkamp L,Hsiao J,Hesselson D,Akassoglou K,Verdin E,Hirschey MD,Stainier DY

doi

10.1038/nchembio.1136

subject

Has Abstract

pub_date

2013-02-01 00:00:00

pages

97-104

issue

2

eissn

1552-4450

issn

1552-4469

pii

nchembio.1136

journal_volume

9

pub_type

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