title: Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling.
abstract: Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1)-associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food-restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30-120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1-associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3-overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity.
authors.affiliation: Dept. of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Anantha S
authors.initials: AS
authors.lastname: Metlakunta
authors.forename: Maitrayee
authors.initials: M
authors.lastname: Sahu
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dhillon
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Abhiram
authors.initials: A
authors.lastname: Sahu
mesh_terms: D050154:Adiposity; D000818:Animals; D031204:Caloric Restriction; D002460:Cell Line; D004435:Eating; D005838:Genotype; D007031:Hypothalamus / Q000201:enzymology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology* / Q000235:genetics; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D015431:Weight Loss
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D020738:Leptin; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011333:Pro-Opiomelanocortin; D058539:Phosphatidylinositol 3-Kinase; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2