Differential Insulin Receptor Substrate-1 (IRS1)-Related Modulation of Neuropeptide Y and Proopiomelanocortin Expression in Nondiabetic and Diabetic IRS2-/- Mice

被引：17

作者：

Burgos-Ramos, Emma ^{[1
,2
]}

Gonzalez-Rodriguez, Agueda ^{[3
,4
]}

Canelles, Sandra ^{[1
,2
]}

Baquedano, Eva ^{[1
,2
]}

Frago, Laura M. ^{[1
,2
]}

Revuelta-Cervantes, Jesus ^{[3
,4
]}

Gomez-Ambrosi, Javier ^{[2
,5
]}

Fruehbeck, Gema ^{[2
,5
]}

Chowen, Julie A. ^{[1
,2
]}

Argente, Jesus ^{[1
,2
]}

Valverde, Angela M. ^{[3
,4
]}

Barrios, Vicente ^{[1
,2
]}

机构：

[1] Univ Autonoma Madrid, Dept Endocrinol, Hosp Infantil Univ Nino Jesus, Inst Invest Princesa,Dept Pediat, E-28009 Madrid, Spain

[2] Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, E-28029 Madrid, Spain

[3] Univ Autonoma Madrid, Inst Invest Biomed Alberto Sols, Consejo Super Invest Cient, E-28009 Madrid, Spain

[4] Inst Salud Carlos III, Ctr Invest Biomed Red Diabet Enfermedades Metab A, E-28029 Madrid, Spain

[5] Univ Navarra Clin, Metab Res Lab, E-31008 Pamplona, Spain

来源：

ENDOCRINOLOGY | 2012年 / 153卷 / 03期

关键词：

ACTIVATES SIGNAL-TRANSDUCTION; FOOD-INTAKE; KAPPA-B; CALORIC RESTRICTION; ENERGY HOMEOSTASIS; PHOSPHATIDYLINOSITOL; 3-KINASE; SUBSTRATE-2-DEFICIENT MICE; SERINE PHOSPHORYLATION; HYPOTHALAMIC FOXO1; ARCUATE NUCLEUS;

D O I：

10.1210/en.2011-1278

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. Insulin receptor substrate-2 deficient (IRS2(-/-)) mice are an accepted model for the exploration of alterations in these signaling pathways and their relationship with diabetes; however, disturbances in hypothalamic signaling and the effect on neuropeptides controlling food intake remain unclear. Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intakeandhypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2(-/-) mice. We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2(-/-) mice. IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2(-/-). Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2(-/-) mice, with FOXO1 showing mainly nuclear localization in D IRS2(-/-) and cytoplasmic in ND IRS2(-/-) mice. D IRS2(-/-) mice exhibited higher hypothalamic inflammation markers than ND IRS2(-/-) mice. In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes. (Endocrinology 153: 1129-1140, 2012)

引用

页码：1129 / 1140

页数：12

共 65 条

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