Metformin inhibits growth hormone - Mediated hepatic, PDK4 gene expression through induction of orphan nuclear receptor small heterodimer partner

Yong Deuk Kim, Yong Hoon Kim, Surendar Tadi, Ji Hoon Yu, Yong Hyeon Yim, Nam Ho Jeoung, Minho Shong, Lothar Hennighausen, Robert A. Harris, In Kyu Lee, Chul Ho Lee, Hueng Sik Choi

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wildtype but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP-dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.

Original languageEnglish (US)
Pages (from-to)2484-2494
Number of pages11
JournalDiabetes
Volume61
Issue number10
DOIs
StatePublished - Oct 1 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Kim, Y. D., Kim, Y. H., Tadi, S., Yu, J. H., Yim, Y. H., Jeoung, N. H., Shong, M., Hennighausen, L., Harris, R. A., Lee, I. K., Lee, C. H., & Choi, H. S. (2012). Metformin inhibits growth hormone - Mediated hepatic, PDK4 gene expression through induction of orphan nuclear receptor small heterodimer partner. Diabetes, 61(10), 2484-2494. https://doi.org/10.2337/db11-1665