Hepatic leptin signalling and subdiaphragmatic vagal efferents are not required for leptin-induced increases of plasma IGF binding protein-2 (IGFBP-2) in ob/ob mice

Diabetologia. 2012 Mar;55(3):752-62. doi: 10.1007/s00125-011-2426-8. Epub 2011 Dec 28.


Aims/hypothesis: The fat-derived hormone leptin plays a crucial role in the maintenance of normal body weight and energy expenditure as well as in glucose homeostasis. Recently, it was reported that the liver-derived protein, insulin-like growth factor binding protein-2 (IGFBP-2), is responsible for at least some of the glucose-normalising effects of leptin. However, the exact mechanism by which leptin upregulates IGFBP-2 production is unknown. Since it is believed that circulating IGFBP-2 is predominantly derived from the liver and leptin has been shown to have both direct and indirect actions on the liver, we hypothesised that leptin signalling in hepatocytes or via brain-liver vagal efferents may mediate leptin control of IGFBP-2 production.

Methods: To address our hypothesis, we assessed leptin action on glucose homeostasis and plasma IGFBP-2 levels in both leptin-deficient ob/ob mice with a liver-specific loss of leptin signalling and ob/ob mice with a subdiaphragmatic vagotomy. We also examined whether restoring hepatic leptin signalling in leptin receptor-deficient db/db mice could increase plasma IGFBP-2 levels.

Results: Continuous leptin administration increased plasma IGFBP-2 levels in a dose-dependent manner, in association with reduced plasma glucose and insulin levels. Interestingly, leptin was still able to increase plasma IGFBP-2 levels and improve glucose homeostasis in both ob/ob mouse models to the same extent as their littermate controls. Further, restoration of hepatic leptin signalling in db/db mice did not increase either hepatic or plasma IGFBP-2 levels.

Conclusions/interpretation: Taken together, these data indicate that hepatic leptin signalling and subdiaphragmatic vagal inputs are not required for leptin upregulation of plasma IGFBP-2 nor blood glucose lowering in ob/ob mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Crosses, Genetic
  • Female
  • Insulin / blood
  • Insulin-Like Growth Factor Binding Protein 2 / blood*
  • Insulin-Like Growth Factor Binding Protein 2 / metabolism
  • Leptin / administration & dosage
  • Leptin / genetics
  • Leptin / metabolism*
  • Liver / innervation*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Obesity / blood*
  • Obesity / metabolism*
  • Obesity / physiopathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism
  • Signal Transduction*
  • Up-Regulation
  • Vagotomy, Truncal
  • Vagus Nerve / physiopathology
  • Vagus Nerve / surgery


  • Blood Glucose
  • Insulin
  • Insulin-Like Growth Factor Binding Protein 2
  • Leptin
  • Protein Isoforms
  • Receptors, Leptin
  • leptin receptor, mouse