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

Publication ,  Journal Article
Gut, P; Baeza-Raja, B; Andersson, O; Hasenkamp, L; Hsiao, J; Hesselson, D; Akassoglou, K; Verdin, E; Hirschey, MD; Stainier, DYR
Published in: Nat Chem Biol
February 2013

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.

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Published In

Nat Chem Biol

DOI

EISSN

1552-4469

Publication Date

February 2013

Volume

9

Issue

2

Start / End Page

97 / 104

Location

United States

Related Subject Headings

  • Zebrafish
  • Transgenes
  • Protein Transport
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Mice, Obese
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Ligands
  • Isoquinolines
 

Citation

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Gut, P., Baeza-Raja, B., Andersson, O., Hasenkamp, L., Hsiao, J., Hesselson, D., … Stainier, D. Y. R. (2013). Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nat Chem Biol, 9(2), 97–104. https://doi.org/10.1038/nchembio.1136
Gut, Philipp, Bernat Baeza-Raja, Olov Andersson, Laura Hasenkamp, Joseph Hsiao, Daniel Hesselson, Katerina Akassoglou, Eric Verdin, Matthew D. Hirschey, and Didier Y. R. Stainier. “Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism.Nat Chem Biol 9, no. 2 (February 2013): 97–104. https://doi.org/10.1038/nchembio.1136.
Gut P, Baeza-Raja B, Andersson O, Hasenkamp L, Hsiao J, Hesselson D, et al. Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nat Chem Biol. 2013 Feb;9(2):97–104.
Gut, Philipp, et al. “Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism.Nat Chem Biol, vol. 9, no. 2, Feb. 2013, pp. 97–104. Pubmed, doi:10.1038/nchembio.1136.
Gut P, Baeza-Raja B, Andersson O, Hasenkamp L, Hsiao J, Hesselson D, Akassoglou K, Verdin E, Hirschey MD, Stainier DYR. Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nat Chem Biol. 2013 Feb;9(2):97–104.

Published In

Nat Chem Biol

DOI

EISSN

1552-4469

Publication Date

February 2013

Volume

9

Issue

2

Start / End Page

97 / 104

Location

United States

Related Subject Headings

  • Zebrafish
  • Transgenes
  • Protein Transport
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Mice, Obese
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Ligands
  • Isoquinolines