RT Journal Article
SR Electronic
T1 Leptin Rapidly Improves Glucose Homeostasis in Obese Mice by Increasing Hypothalamic Insulin Sensitivity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 16180
OP 16187
DO 10.1523/JNEUROSCI.3202-10.2010
VO 30
IS 48
A1 Koch, Christiane
A1 Augustine, Rachael A.
A1 Steger, Juliane
A1 Ganjam, Goutham K.
A1 Benzler, Jonas
A1 Pracht, Corinna
A1 Lowe, Chrishanthi
A1 Schwartz, Michael W.
A1 Shepherd, Peter R.
A1 Anderson, Greg M.
A1 Grattan, David R.
A1 Tups, Alexander
YR 2010
UL http://www.jneurosci.org/content/30/48/16180.abstract
AB 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 Lepob/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.