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Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5

Yu Chen1, Difei Sun, Vidya M R Krishnamurthy

  • 1Department of Medicine, Stanford University, Stanford, USA.

American Journal of Physiology. Endocrinology and Metabolism
|March 1, 2007
PubMed

Insights

Endotoxin from Gram-negative sepsis causes cachexia by impairing growth hormone (GH) signaling. This study reveals a distal defect in STAT5b binding, further explaining reduced insulin-like growth factor-I (IGF-I) expression in sepsis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • Gram-negative sepsis and endotoxin release are common causes of cachexia.
  • Cachexia is partly due to impaired growth hormone (GH) signaling and reduced insulin-like growth factor-I (IGF-I) expression.
  • Previous studies identified a defect in the janus kinase 2 (JAK2)-signal transducer and activation of transcription (STAT) 5b pathway.

Purpose of the Study:

  • To further characterize the mechanisms of GH resistance during endotoxemia.
  • To investigate potential defects distal to the JAK2-STAT5b pathway in GH signaling.
  • To explore the impact of GH treatment in endotoxemic rats.

Main Methods:

  • Conscious rats were administered endotoxin and studied 4 hours later.
  • Liver tissue analysis included measuring mRNA expression of cytokines and GH signaling inhibitors.
  • Assessed JAK2 and STAT5 phosphorylation, nuclear phosphorylated STAT5b levels, and STAT5b DNA binding activity.

Main Results:

  • Endotoxin impaired GH-induced JAK2 and STAT5 phosphorylation in the liver.
  • Elevated hepatic tumor necrosis factor-alpha and interleukin-6 mRNA were observed, alongside increased inhibitors of GH signaling (CIS, SOCS-1, SOCS-3).
  • Nuclear phosphorylated STAT5b levels decreased significantly (61% of control), and its DNA binding was markedly reduced (17% of control), impairing IGF-I gene transcription.

Conclusions:

  • Endotoxemia causes cachexia through impaired GH signaling, involving both JAK2-STAT5b pathway defects and reduced STAT5b DNA binding.
  • GH treatment in endotoxemic rats increased pro-inflammatory cytokine gene expression, suggesting a potential adverse effect in critically ill patients.
  • These findings elucidate mechanisms of GH resistance in sepsis and highlight potential risks of GH therapy in critical illness.

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