title: 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.
authors.affiliation: Department of Biochemistry and Biophysics, University of California-San Francisco, San Francisco, California, USA. philipp.gut@ucsf.edu
authors.forename: Philipp
authors.initials: P
authors.lastname: Gut
authors.forename: Bernat
authors.initials: B
authors.lastname: Baeza-Raja
authors.forename: Olov
authors.initials: O
authors.lastname: Andersson
authors.forename: Laura
authors.initials: L
authors.lastname: Hasenkamp
authors.forename: Joseph
authors.initials: J
authors.lastname: Hsiao
authors.forename: Daniel
authors.initials: D
authors.lastname: Hesselson
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hirschey
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001570:Benzodiazepinones / Q000494:pharmacology; D015195:Drug Design; D005215:Fasting / Q000378:metabolism; D005508:Food Deprivation; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D021381:Protein Transport; D019076:Transgenes; D015027:Zebrafish
chemical_list: D001570:Benzodiazepinones; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D008024:Ligands; C028513:4'-chlorodiazepam; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose; C037850:PK 11195