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LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice.

Thierry Touvier1, Françoise Conte-Auriol, Olivier Briand

  • 1Université Lille Nord de France, Lille, France.

The Journal of Clinical Investigation
|November 13, 2009
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Leptin receptor overlapping transcript (LEPROT) and LEPROT-like 1 (LEPROTL1) proteins regulate liver growth hormone (GH) sensitivity. Their modulation impacts GH/IGF1 axis signaling, affecting metabolism and body growth.

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Area of Science:

  • Metabolic regulation
  • Endocrinology
  • Molecular biology

Background:

  • Growth hormone (GH) is a key metabolic regulator influencing lipolysis, protein metabolism, and glucose disposal.
  • Hepatic GH sensitivity and the GH/IGF1 axis are crucial for metabolic adaptation to nutrient availability.
  • Mechanisms underlying hepatic GH resistance during nutrient scarcity are not well understood.

Purpose of the Study:

  • To investigate the role of leptin receptor overlapping transcript (LEPROT) and LEPROT-like 1 (LEPROTL1) in regulating hepatic GH sensitivity.
  • To elucidate the molecular mechanisms by which these proteins influence GH signaling and metabolism.

Main Methods:

  • Generation of transgenic mice expressing human LEPROT or LEPROTL1.
  • Assessment of GH sensitivity markers (STAT5 phosphorylation, Socs2 mRNA) in transgenic mice.
  • Gene silencing of endogenous Leprot and Leprotl1 in H4IIE hepatocytes.
  • Analysis of LEPROT and LEPROTL1 expression in response to glucose homeostasis changes.

Main Results:

  • Transgenic mice expressing LEPROT or LEPROTL1 exhibited growth retardation, reduced IGF1, and impaired hepatic GH sensitivity.
  • Co-expression of both proteins exacerbated these phenotypes.
  • Gene silencing of Leprot or Leprotl1 enhanced GH signaling and GH receptor expression in hepatocytes.
  • LEPROT and LEPROTL1 expression in the liver are regulated by glucose homeostasis.

Conclusions:

  • LEPROT and LEPROTL1 are novel regulators of liver GH signaling.
  • These proteins play a significant role in mediating GH actions on body growth and metabolism.
  • Regulation of LEPROT and LEPROTL1 genes may link nutritional status to GH signaling pathways.