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.
OBJECTIVE
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
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.
Department of Cellular and Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
J
J
Levi
F K
FK
Huynh
H C
HC
Denroche
U H
UH
Neumann
M M
MM
Glavas
S D
SD
Covey
T J
TJ
Kieffer
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003433:Crosses, Genetic; D005260:Female; D007328:Insulin / Q000097:blood; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood* / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000294:innervation* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009765:Obesity / Q000097:blood* / Q000378:metabolism* / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D015167:Vagotomy, Truncal; D014630:Vagus Nerve / Q000503:physiopathology / Q000601:surgery
D001786:Blood Glucose; D007328:Insulin; D018971:Insulin-Like Growth Factor Binding Protein 2; D020738:Leptin; D020033:Protein Isoforms; D054411:Receptors, Leptin; C515447:leptin receptor, mouse