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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.

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Figure 1: Rapid pharmacological profiling of gluconeogenesis.
Figure 2: A small-molecule screen identifies functionally conserved as well as unknown modulators of gluconeogenesis.
Figure 3: TSPO ligands enhance a gluconeogenic fasting response.
Figure 4: TSPO ligands induce a fasting-like energy state in the liver.
Figure 5: PK 11195 improves hepatosteatosis and glucose tolerance in diet-induced obese mice.

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Acknowledgements

The authors thank A. Schlegel, O. Stone and K. Ashrafi for critical reading of the manuscript; the members of the Stainier lab for technical advice throughout the project; and A. Ayala, M. Alva, P. Lopez Pazmino and M. Sklar for zebrafish care. We are grateful to C. Miller from the Gladstone Histology Core for histological processing of mouse livers. We also thank R. Peterson for sharing knowledge on in vivo bioluminescence measurements in zebrafish. This study was supported in part by a postdoctoral fellowship DFG GU 1082/101 from the German Research Foundation to P.G., grant DK59637 to the Mouse Metabolic Phenotypic Centers lipid lab, Pilot/Feasibility grants from the University of California–San Francisco Liver Center (P30 DK026743) and Diabetes and Endocrinology Center (P30 DK063720), US National Institutes of Health (NIH) grant NS051470 to K.A., funds from the Gladstone Institutes and the Glenn Foundation for Medical Research to E.V., the American Heart Association grant 12SDG8840004 to M.D.H., NIH grant RO1 DK60322, a pilot and feasibility award from the University of California–San Fransisco diabetes center funded by NIH U01 DK089541 and the Packard Foundation to D.Y.R.S.

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P.G. conceived the study, designed and performed experiments, analyzed data and wrote the paper. D.Y.R.S. designed experiments, analyzed data, supervised the work and wrote the paper. M.D.H. designed and performed experiments and analyzed data. O.A., B.B.-R., D.H., L.H. and J.H. performed experiments. K.A. and E.V. contributed material and supervised the work. All authors commented on the paper.

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Correspondence to Philipp Gut or Didier Y R Stainier.

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The authors declare no competing financial interests.

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Gut, P., Baeza-Raja, B., Andersson, O. et al. Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nat Chem Biol 9, 97–104 (2013). https://doi.org/10.1038/nchembio.1136

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