Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] Journal article | | Title | Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. | | Author(s) | Ernst MB, Wunderlich CM, Hess S, Paehler M, Mesaros A, Koralov SB, Kleinridders A, Husch A, Münzberg H, Hampel B, Alber J, Kloppenburg P, Brüning JC, Wunderlich FT | | Institution | Institute for Genetics, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center of Molecular Medicine Cologne, D-50674 Cologne, Germany. | | Source | J Neurosci 2009 Sep 16; 29(37):11582-93. | | MeSH | 1-Phosphatidylinositol 3-Kinase
Agouti-Related Protein
Animals
Body Composition
Body Weight
Disease Models, Animal
Eating
Electrophoretic Mobility Shift Assay
Enzyme-Linked Immunosorbent Assay
Feedback
Gene Expression Regulation
Glucose Tolerance Test
Green Fluorescent Proteins
Hypothalamus
Insulin
Insulin Resistance
Leptin
Leukemia Inhibitory Factor
Membrane Proteins
Mice
Mice, Transgenic
Neural Inhibition
Neurons
Neuropeptide Y
Obesity
Patch-Clamp Techniques
Pro-Opiomelanocortin
Signal Transduction
Suppressor of Cytokine Signaling Proteins
Transfection
| | Abstract | 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-C(POMC) 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 PIP(3) (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-C(POMC) 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-C(POMC) 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. | | Language | eng | | Pub Type(s) | In Vitro
Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19759305 |
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