Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity.
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.
Ernst
Marianne B
MB
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.
Wunderlich
Claudia M
CM
Hess
Simon
S
Paehler
Moritz
M
Mesaros
Andrea
A
Koralov
Sergei B
SB
Kleinridders
André
A
Husch
Andreas
A
Münzberg
Heike
H
Hampel
Brigitte
B
Alber
Jens
J
Kloppenburg
Peter
P
Brüning
Jens C
JC
Wunderlich
F Thomas
FT
D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001823:Body Composition / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D004195:Disease Models, Animal; D004435:Eating / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005246:Feedback / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins / Q000235:genetics; D007031:Hypothalamus / Q000473:pathology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D007328:Insulin; D020738:Leptin; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008565:Membrane Proteins; D009478:Neuropeptide Y; C502741:STT3-A protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D011333:Pro-Opiomelanocortin; D019869:Phosphatidylinositol 3-Kinases