TY - JOUR T1 - Leptin Rapidly Improves Glucose Homeostasis in Obese Mice by Increasing Hypothalamic Insulin Sensitivity JF - The Journal of Neuroscience JO - J. Neurosci. SP - 16180 LP - 16187 DO - 10.1523/JNEUROSCI.3202-10.2010 VL - 30 IS - 48 AU - Christiane Koch AU - Rachael A. Augustine AU - Juliane Steger AU - Goutham K. Ganjam AU - Jonas Benzler AU - Corinna Pracht AU - Chrishanthi Lowe AU - Michael W. Schwartz AU - Peter R. Shepherd AU - Greg M. Anderson AU - David R. Grattan AU - Alexander Tups Y1 - 2010/12/01 UR - http://www.jneurosci.org/content/30/48/16180.abstract N2 - 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. ER -