Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity.
Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lep(ob/ob) mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes.
Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, D-35043 Marburg, Germany.
Christiane
C
Koch
Rachael A
RA
Augustine
Juliane
J
Steger
Goutham K
GK
Ganjam
Jonas
J
Benzler
Corinna
C
Pracht
Chrishanthi
C
Lowe
Michael W
MW
Schwartz
Peter R
PR
Shepherd
Greg M
GM
Anderson
David R
DR
Grattan
Alexander
A
Tups
D000273:Adipose Tissue / Q000201:enzymology / Q000503:physiopathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D007031:Hypothalamus / Q000201:enzymology / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D020738:Leptin / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001786:Blood Glucose; D007527:Isoenzymes; D020738:Leptin; D058543:Class Ia Phosphatidylinositol 3-Kinase; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005947:Glucose