Ghrelin Augments the Expressions and Secretions of Proinflammatory Adipokines, VEGF₁₂₀ and MCP‐1, in Differentiated 3T3‐L1 Adipocytes

Abstract

Ghrelin is a physiological-active peptide with growth hormone-releasing activity, orexigenic activity, etc. In addition, the recent study has also suggested that ghrelin possesses the pathophysiological abilities related to type 2 diabetes. However, the ghrelin-direct-effects implicated in type 2 diabetes on peripheral tissues have been still unclear, whereas its actions on the central nervous system (CNS) appear to induce the development of diabetes. Thus, to assess its peripheral effects correlated with diabetes, we investigated the regulatory mechanisms about adipokines, which play a central role in inducing peripheral insulin resistance, secreted from mature 3T3-L1 adipocytes stimulated with ghrelin in vitro. The stimulation with 50 nmol/L ghrelin for 24 h resulted in the significant 1.9-fold increase on vascular endothelial growth factor-120 (VEGF 120 ) releases (P < 0.01) and the 1.7-fold on monocyte chemoattractant protein-1 (MCP-1) (P < 0.01) from 3T3-L1 adipocytes, respectively, while ghrelin failed to enhance tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), IL-6, IL-10 and adiponectin secretions. In addition, Akt phosphorylation on Ser473 and c-Jun NH 2 -terminal protein kinase (JNK) phosphorylation on Thr183/Tyr185 were markedly enhanced 1.4-fold (P < 0.01) and 1.6-fold (P < 0.01) in the ghrelin-stimulated adipocytes, respectively. Furthermore, the treatment with LY294002 (50 mmol/L) and Wortmannin (10nmol/L), inhibitors of phosphatidylinositol 3-kinase (PI3K), significantly decreased the amplified VEGF 120 secretion by 29% (P < 0.01) and 28% (P < 0.01) relative to the cells stimulated by ghrelin alone, respectively, whereas these inhibitors had no effects on increased MCP-1 release. On the other hand, JNK inhibitor SP600125 (10 mmol/L) clearly reduced the increased MCP-1, but not VEGF 120 , release by 35% relative to the only ghrelin-stimulated cells (P < 0.01). In conclusion, ghrelin can enhance the secretions of proinflammatory adipokines, VEGF 120 and MCP-1, but fails to affect IL-10 and adiponectin which are considered to be anti-inflammatory adipokines. Moreover, this augmented VEGF 120 release is invited through the activation of PI3K pathways and the MCP-1 is through JNK pathways. Consequently, our results strongly suggest that ghrelin can induce the development of diabetes via its direct-action in peripheral tissues, as well as, via CNS.

MAPKs/AP-1, not NF-κB, is responsible for MCP-1 production in TNF-α-activated adipocytes

“…MCP-1 is one of key chemokines that initiate obesity-induced inflammation and monocyte chemoattractant activities [ 24 ]. In agreement with previous findings from other researchers [ 25 , 26 ], we also found that resting adipocytes could release a certain amount of MCP-1 ( Figure 1 ) which may recruit monocytes to adipose tissue where they differentiate into macrophages [ 17 ]. TNF-α released from these macrophages can further increase MCP-1 production of adipocytes [ 27 ].…”

The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 β-Cells

“…In addition, we verified the involvement of the JNK and PI3K/Akt pathways, which are intracellular signal transduction pathways acting downstream of oxidative stress [26,27]. The increase of MCP-1 secretion in response to stimulation with palmitate was significantly reduced by the treatment with SP600125, a JNK-specific inhibitor, but there were no effects of the treatment with LY294002, an inhibitor of PI3K/Akt, on the palmitate-induced MCP-1 release.…”

The association of semaphorin 5A with lymph node metastasis and adverse prognosis in cervical cancer

“…To block phosphoinositide 3-kinase (PI3K)/AKT signaling, the PI3K inhibitor LY294002 (Cell Signaling Technology, Danvers, MA) was used. Cells were treated with 50 μmol/L LY294002 for 24 h. Cells were treated with 50 μmol/L LY294002 for 24 h. The concentration of LY294002 was set at 50 μmol/L in accordance with previous study [ 16 ].…”