Leptin Induces Mitogen-activated Protein Kinase- dependent Proliferation of C3H10T1/2 Cells

Abstract

Leptin, secreted by adipocytes, regulates satiety and energy expenditure. Several forms of leptin receptors produced by alternative mRNA splicing are found in many tissues, including the hypothalamus, liver, lung, kidney, hematopoietic cells, and gonads, suggesting that leptin exerts effects in these tissues. In accordance with the distribution of leptin receptors, there is accumulating evidence that leptin plays various roles in reproduction, hematopoiesis, and the immune systems in addition to the regulation of food intake and energy expenditure. In the present study, we examined the in vitro effects of leptin on proliferation of a mouse embryonic cell line, C3H10T1/2, and its mechanism of action. Leptin caused a dose-and time-dependent increase in mitogen-activated protein kinase (MAPK) activity that was accompanied by an increase in C3H10T1/2 cell number. The MAPK kinase-1-specific inhibitor PD98059 completely blocked the increases in both MAPK activity and cell proliferation caused by leptin. These findings indicate that leptin stimulates the proliferation of C3H10T1/2 cells via the MAPK cascade.The ob gene has been cloned as a genetic factor responsible for obesity in genetically obese rodents, ob/ob mice (1). The ob gene product (leptin), mutated in ob/ob mice, serves as a satiety factor secreted from adipose tissue and plays an important role in regulating body weight through its receptor in the hypothalamus (1-4). In addition to regulating body weight, leptin also influences reproductive, hematopoietic, and immune systems in which its receptors are expressed (5-10), suggesting that leptin also has extrahypothalamic actions. Furthermore, leptin receptors are expressed in various tissues including lung, kidney, testis, and adipose tissue (11,12). These findings suggest that leptin plays diverse roles in many systems. However, the mechanism of its signal transduction in these organs remains unclear.Recently, STATs 1 have been suggested to be involved in the signal transduction mechanism of leptin. It was reported that leptin activated STAT-1, -3, and -5 (13) and in artificial reconstruction systems using Cos cells transfected with leptin receptors and STATs. Furthermore, activation of STAT-3 by leptin was observed in the hypothalamus in vivo (15). We recently found that leptin induced tyrosine phosphorylation of several cellular proteins including STAT-1 in ACHN cells (cloned human renal carcinoma cells) and suggested that ACHN cells were useful for analyzing the signal transduction mechanism of leptin (16).On the other hand, pathways other than STATs may be involved in leptin signal transduction system. Because leptin is considered to be a member of the cytokine family from the results of structural analysis (17), its signal transduction system may be similar to those of other cytokines. Many cytokines stimulate a molecular cascade coupled with Ras activation (18 -20). p21 ras plays a key role in the phosphorylation and activation of mitogen-activated protein kinases (MAPKs) (21, 22), which in turn phosp...

Aromatase activity of human mesenchymal stem cells is stimulated by early differentiation, vitamin D and leptin

“…Several in vitro studies indicate that stromal cells are responsive to leptin, which increases proliferation, differentiation to osteoblastic lineage and the number of mineralized nodules (Takahashi et al 1997, Thomas et al 1999, Reseland et al 2001, but inhibits differentiation to adipocytes (Thomas et al 1999, Hess et al 2005. These observations suggest that leptin may participate in the regulation of bone mass, but the mechanism remains unclear.…”

Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells

“…The effect of ERK1/2 signaling on TIMP-1 promoter activity was specific, because it was blocked by the ERK1/2 inhibitor PD098059, but not by SB203580 or overexpressing dominant negative p38 mutants. ERK1/2 activation by leptin or its receptors has been reported in a number of cell systems (32)(33)(34)(35)64). In COS and Chinese hamster ovary cells transfected with the leptin receptors, ERK1/2 can be activated via two pathways.…”

“…But leptin can also use other signaling cascades via JAK activation. Among these are p38 (31), extracellular signal-regulated kinase (ERK1/2) (2,(31)(32)(33)(34)(35)(36), and c-Jun terminal/stressactivated protein kinases (37) of the mitogen-activated protein kinase (MAPK) family members. Furthermore, leptin was found to generate increased amounts of H 2 O 2 in isolated vascular endothelial cells in association with atherogenic processes (37,38).…”

Leptin: its role in obesity and beyond

“…This finding, in combination with the previously mentioned observation that insulin stimulates leptin secretion, suggests the existence of a negative feedback loop between leptin and insulin. Second, one study suggested a decrease in insulin receptor substrate-1 (IRS-1) phosphorylation as well as modulation of downstream effectors of insulin action and up-regulation of gluconeogenesis in hepatocytes exposed to leptin in vitro [88], although other studies have produced conflicting results [89,90]. Finally, leptin has been recently shown to stimulate haematopoiesis in vitro [91,92] and has also been found in human fetuses, where it may be involved in the regulation of fetal haematopoiesis [57, 93,94].…”