RT Journal Article
SR Electronic
T1 Enhanced Stat3 Activation in POMC Neurons Provokes Negative Feedback Inhibition of Leptin and InsulinSignaling in Obesity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 11582
OP 11593
DO 10.1523/JNEUROSCI.5712-08.2009
VO 29
IS 37
A1 Marianne B. Ernst
A1 Claudia M. Wunderlich
A1 Simon Hess
A1 Moritz Paehler
A1 Andrea Mesaros
A1 Sergei B. Koralov
A1 André Kleinridders
A1 Andreas Husch
A1 Heike Münzberg
A1 Brigitte Hampel
A1 Jens Alber
A1 Peter Kloppenburg
A1 Jens C. Brüning
A1 F. Thomas Wunderlich
YR 2009
UL http://www.jneurosci.org/content/29/37/11582.abstract
AB Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in maintenance of energy homeostasis. While Stat3 activation in POMC neurons is required for POMC expression, the role of elevated basal Stat3 activation as present in the development of obesity has not been directly addressed. Here, we have generated and characterized mice expressing a constitutively active version of Stat3 (Stat3-C) in POMC neurons (Stat3-CPOMC mice). On normal chow diet, these animals develop obesity as a result of hyperphagia and decreased POMC expression accompanied by central leptin and insulin resistance. This unexpected finding coincides with POMC-cell-specific, Stat3-mediated upregulation of SOCS3 expression inhibiting both leptin and insulin signaling as insulin-stimulated PIP3 (phosphatidylinositol-3,4,5 triphosphate) formation and protein kinase B (AKT) activation in POMC neurons as well as with the fact that insulin's ability to hyperpolarize POMC neurons is largely reduced in POMC cells of Stat3-CPOMC mice. These data indicate that constitutive Stat3 activation is not sufficient to promote POMC expression but requires simultaneous PI3K (phosphoinositide 3-kinase)-dependent release of FOXO1 repression. In contrast, upon exposure to a high-fat diet, food intake and body weight were unaltered in Stat3-CPOMC mice compared with control mice. Taken together, these experiments directly demonstrate that enhanced basal Stat3 activation in POMC neurons as present in control mice upon high-fat feeding contributes to the development of hypothalamic leptin and insulin resistance.