Evidence suggesting impaired hypothalamic phosphatidylinositol-3-kinase (PI3K) pathway of leptin signaling during the development of diet-induced obesity (DIO) in mice

2006 ◽  
Vol 27 (1) ◽  
pp. 10 ◽  
Author(s):  
Anantha S. Metlakunta ◽  
Abhiram Sahu
Keyword(s):  
Pi3k Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Phosphatidylinositol 3

scholarly journals Hypothalamic Phosphatidylinositol 3-Kinase Pathway of Leptin Signaling Is Impaired during the Development of Diet-Induced Obesity in FVB/N Mice

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1121-1128 ◽  
Author(s):  
Anantha S. Metlakunta ◽  
Maitrayee Sahu ◽  
Abhiram Sahu
Keyword(s):  
Energy Homeostasis ◽  
Early Period ◽  
Pi3k Pathway ◽  
Leptin Resistance ◽  
Phosphatidylinositol 3 Kinase ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Pi3k Activity ◽  
Central Leptin Resistance ◽  
Phosphatidylinositol 3

Phosphatidylinositol 3-kinase (PI3K) pathway of leptin signaling plays an important role in transducing leptin action in the hypothalamus. Obesity is usually associated with resistance to the effect of leptin on food intake and energy homeostasis. Although central leptin resistance is thought to be involved in the development of diet-induced obesity (DIO), the mechanism behind this phenomenon is not clearly understood. To determine whether DIO impairs the effect of leptin on hypothalamic PI3K signaling, we fed 4-wk-old FVB/N mice a high-fat diet (HFD) or low-fat diet (LFD) for 19 wk. HFD-fed mice developed DIO in association with hyperleptinemia, hyperinsulinemia, and impaired glucose and insulin tolerance. Leptin (ip) significantly increased hypothalamic PI3K activity and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) levels in LFD-fed mice but not in DIO mice. Immunocytochemical study confirmed impaired p-STAT3 activation in various hypothalamic areas, including the arcuate nucleus. We next tested whether both PI3K and STAT3 pathways of leptin signaling were impaired during the early period of DIO. Leptin failed to increase PI3K activity in DIO mice that were on a HFD for 4 wk. However, leptin-induced p-STAT3 activation in the hypothalamus measured by Western blotting and immunocytochemistry remained comparable between LFD- and HFD-fed mice. These results suggest that the PI3K pathway but not the STAT3 pathway of leptin signaling is impaired during the development of DIO in FVB/N mice. Thus, a defective PI3K pathway of leptin signaling in the hypothalamus may be one of the mechanisms of central leptin resistance and DIO.

scholarly journals Role of Phosphatidylinositol-3-Kinase Pathway in Head and Neck Squamous Cell Carcinoma

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Li Du ◽  
Jingping Shen ◽  
Andrew Weems ◽  
Shi-Long Lu
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Pi3k Pathway ◽  
Neck Squamous Cell Carcinoma ◽  
Phosphatidylinositol 3 Kinase ◽  
Molecular Alterations ◽  
Future Direction ◽  
Phosphatidylinositol 3

Activation of the phosphatidylinositol-3-kinase (PI3K) pathway is one of the most frequently observed molecular alterations in many human malignancies, including head and neck squamous cell carcinoma (HNSCC). A growing body of evidence demonstrates the prime importance of the PI3K pathway at each stage of tumorigenesis, that is, tumor initiation, progression, recurrence, and metastasis. Expectedly, targeting the PI3K pathway yields some promising results in both preclinical studies and clinical trials for certain cancer patients. However, there are still many questions that need to be answered, given the complexity of this pathway and the existence of its multiple feedback loops and interactions with other signaling pathways. In this paper, we will summarize recent advances in the understanding of the PI3K pathway role in human malignancies, with an emphasis on HNSCC, and discuss the clinical applications and future direction of this field.

Phosphatidylinositol 3′-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1α and vascular endothelial growth factor expression

2011 ◽  
Vol 300 (6) ◽  
pp. H2169-H2176 ◽  
Author(s):  
Yan Xue ◽  
Nan-Lin Li ◽  
Jing-Yue Yang ◽  
Yan Chen ◽  
Lu-Lu Yang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tumor Suppressor ◽  
Active Form ◽  
Hypoxia Inducible Factor ◽  
Pi3k Pathway ◽  
Rho Proteins ◽  
Phosphatidylinositol 3 Kinase ◽  
Von Hippel Lindau ◽  
Phosphatidylinositol 3

We have previously demonstrated the roles of RhoA, Rac1, and Cdc42 in hypoxia-driven angiogenesis. However, the role of oncogenes in hypoxia signaling is poorly understood. Given the importance of Rho proteins in the hypoxic response, we hypothesized that Rho family members could act as mediators of hypoxic signal transduction. We investigated the cross-talk between hypoxia and oncogene-driven signal transduction pathways and explored the role of Rac1 on hypoxia-induced hypoxia-inducible factor (HIF)-1α and VEGF expression. Since the phosphatidylinositol 3′-kinase (PI3K) pathway is involved in signal transduction of many oncogenes, we explored the role of PI3K on Rac1-mediated expression of HIF-1α and VEGF in hypoxia. We showed that LY-294002, a PI3K inhibitor, suppressed HIF-1α and VEGF induction under hypoxic conditions by up to 50%. Activation of Rac1 resulted in an upregulation of hypoxia-induced HIF-1α expression, which was blocked by LY-294002. These data suggested that Rac1 is an intermediate in the PI3K-mediated induction of HIF-1α. Interestingly, there was a significant downregulation of the tumor suppressor genes p53 and von Hippel-Lindau tumor suppressor (VHL) in cells expressing a constitutively active form of Rac1. Rac1-mediated inhibition of p53 and VHL could therefore be implicated in the upregulation of HIF-1α expression.

scholarly journals Idelalisib in the management of lymphoma

Blood ◽  
2016 ◽  
Vol 128 (3) ◽  
pp. 331-336 ◽  
Author(s):  
Chan Yoon Cheah ◽  
Nathan H. Fowler
Keyword(s):  
Clinical Experience ◽  
Small Molecule ◽  
Therapeutic Strategy ◽  
Pi3k Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Mechanisms Of Resistance ◽  
Preclinical Data ◽  
Combination Strategies ◽  
Orally Bioavailable ◽  
Phosphatidylinositol 3

Abstract Inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway as an anticancer therapeutic strategy was realized with the approval of the orally bioavailable small molecule PI3Kδ inhibitor idelalisib. In this focused review, we highlight the rationale for targeting the pathway in lymphomas, provide a brief summary of the preclinical data, and describe the clinical experience with this agent in patients with lymphoma. We describe some of the idiosyncratic toxicities of this agent, some of the mechanisms of resistance, and some of the ongoing combination strategies.

IL-10 inhibits the starvation induced autophagy in macrophages via class I phosphatidylinositol 3-kinase (PI3K) pathway

2011 ◽  
Vol 48 (4) ◽  
pp. 720-727 ◽  
Author(s):  
Hun-Jung Park ◽  
Suk Jun Lee ◽  
Sang-Hoon Kim ◽  
Jihye Han ◽  
Joonbeom Bae ◽  
...  
Keyword(s):  
Pi3k Pathway ◽  
Class I ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3
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