Leptin Promotes cPLA2 Gene Expression through Activation of the MAPK/NF-κB/p300 Cascade

Abstract

Hyperplasia or hypertrophy of adipose tissues plays a crucial role in obesity, which is accompanied by the release of leptin. Recently, obesity was determined to be associated with various pulmonary diseases including asthma, acute lung injury, and chronic obstructive pulmonary disease. However, how obesity contributes to pulmonary diseases and whether leptin directly regulates lung inflammation remains unclear. We used cell and animal models to study the mechanisms of leptin mediation of pulmonary inflammation. We found that leptin activated de novo synthesis of cytosolic phospholipase A2-α (cPLA2-α) in vitro in the lung alveolar type II cells, A549, and in vivo in ICR mice. Upregulated cPLA2-α protein was attenuated by pretreatment with an OB-R blocking antibody, U0126, SB202190, SP600125, Bay11-7086, garcinol, and p300 siRNA, suggesting roles of p42/p44 MAPK, p38 MAPK, JNK1/2, NF-κB, and p300 in leptin effects. Leptin enhanced the activities of p42/p44 MAPK, p38 MAPK, JNK1/2, and p65 NF-κB in a time-dependent manner. Additional studies have suggested the participation of OB-R, p42/p44 MAPK, and JNK1/2 in leptin-increased p65 phosphorylation. Furthermore, p300 phosphorylation and histone H4 acetylation were reduced by blockage of OB-R, p42/p44 MAPK, p38 MAPK, JNK1/2, and NF-κB in leptin-stimulated cells. Similarly, blockage of the MAPKs/NF-κB/p300 cascade significantly inhibited leptin-mediated cPLA2-α mRNA expression. Our data as a whole showed that leptin contributed to lung cPLA2-α expression through OB-R-dependent activation of the MAPKs/NF-κB/p300 cascade.

PCNA and JNK1‐Stat3 pathways respectively promotes and inhibits diabetes‐associated centrosome amplification by targeting at the ROCK1/14‐3‐3σ complex in human colon cancer HCT116 cells

“…Adipose tissue is composed of adipocytes and a vascular‐stromal fraction, which contains macrophages, fibroblasts, endothelial cells, and pre‐adipocytes. In addition to the regulation of whole‐body fatty acid homeostasis, adipose tissue functions as a complex endocrine organ, secreting adipokines, such as leptin, adiponectin, visfatin, tumor necrosis factor‐α, interleukin‐6, monocyte chemotactic protein‐1, and adipocyte fatty acid‐binding protein (Hsu, Wu, Chang, & Lin, ). Leptin induces matrix metalloproteinase 7 expression to promote ovarian cancer cell invasion by activating ERK and JNK pathways (Ghasemi, Hashemy, Aghaei, & Panjehpour, ).…”

Acute Strenuous Exercise Induces an Imbalance on Histone H4 Acetylation/Histone Deacetylase 2 and Increases the Proinflammatory Profile of PBMC of Obese Individuals

“…Thus, the impaired cortisol action on PBMC of obese individuals may contribute to the enhancement in proinflammatory cytokine production and histone H4 hyperacetylation in obesity. On the other hand, in vitro data revealed that leptin increased the activation of MAPKs/NF- κ B pathway through acetylation of histone H4 [ 42 ]. As the expansion of adipose tissue in obesity is accompanied by the augmentation of leptin, we hypothesized that leptin may play a key role in H4ac status in PBMC of the obese.…”

Chemical and Biological Aspects of Garcinol and Isogarcinol: Recent Developments

“…Garcinol blocked the formation of high fat diet (HFD)‐induced obesity and suppressed glutamate pyruvate transaminase, cholesterol and triacylglycerol in the plasma of animals fed with garcinol . Pretreatment of leptin‐stimulated cells with garcinol (1 μM) also inhibited leptin‐associated cPLA 2 expression via inhibition of p300 HAT . In addition, garcinol displayed beneficial effects on diabetic Wistar rats and oral application of garcinol (10 mg/kg and 20 mg/kg) normalized diabetic parameters in the rats similar to the antidiabetic drug glibenclamide .…”

“…[75] Pretreatment of leptinstimulated cells with garcinol (1 μM) also inhibited leptin-associated cPLA 2 expression via inhibition of p300 HAT. [76] In addition, garcinol displayed beneficial effects on diabetic Wistar rats and oral application of garcinol (10 mg/kg and 20 mg/kg) normalized diabetic parameters in the rats similar to the antidiabetic drug glibenclamide. [77] Osteolysis is often based on activated osteoclasts which are bone-resorbing osteoimmune cells.…”