leptin and Eye-Diseases

TOR (target of rapamycin) is a serine-threonine protein kinase that is conserved across a diverse range of species from fungi to mammals. The signaling pathway that is anchored by TOR is also conserved across species. In mammals, mTOR integrates growth factor, amino acid, nutrient and energy sensing signals, and thus plays a major role in cell growth and proliferation, protein synthesis and autophagy. As a result of the pivotal role of mTOR in signaling, the aberrant regulation of mTOR has been implicated in several disease processes, including cancer, diabetes, ocular diseases and neurodegenerative disorders, as well as in lifespan extension. More recently, rapamycin (sirolimus) analogs that antagonize the mTOR signaling pathway have been approved for the treatment of several cancers. This review describes some recent advances in the understanding of mTOR signaling, with an emphasis on the functional consequences of mTOR inhibition and therapeutic intervention strategies.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Enzyme Inhibitors; Eye Diseases; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Longevity; Neoplasms; Neurodegenerative Diseases; Protein Serine-Threonine Kinases; Signal Transduction; TOR Serine-Threonine Kinases

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. Recently, leptin was found to be an angiogenic factor, and its vitreous levels are associated with angiogenic eye diseases such as proliferative diabetic retinopathy. However, the molecular mechanism for leptin-elicited angiogenesis remains to be elucidated. Pigment epithelium-derived factor (PEDF) has been shown to be the most potent natural inhibitor of angiogenesis in the mammalian eye, and its levels in the vitreous were decreased in angiogenic eye diseases. In this study, we investigated whether and how PEDF could inhibit the leptin-induced DNA synthesis in microvascular endothelial cells (EC), a key step of angiogenesis. Leptin significantly increased intracellular reactive oxygen species (ROS) generation in microvascular EC. PEDF was found to inhibit the leptin-induced ROS generation in EC. An anti-oxidant, N-acetylcysteine, or PEDF completely prevented the leptin-induced upregulation of vascular endothelial growth factor (VEGF) mRNA levels as well as any increase in DNA synthesis in microvascular EC. Polyclonal antibodies against human VEGF were also found to completely inhibit DNA synthesis in leptin-exposed EC. The present study suggests that leptin could elicit angiogenesis through autocrine VEGF production via intracellular ROS generation. PEDF may block the angiogenic effects of leptin through its anti-oxidative properties.

Topics: Acetylcysteine; Animals; Antioxidants; Brain; Cattle; DNA; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Eye Diseases; Eye Proteins; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Microcirculation; Neovascularization, Pathologic; Nerve Growth Factors; Proteins; Reactive Oxygen Species; Receptors, Leptin; Receptors, Vascular Endothelial Growth Factor; Retinal Neovascularization; Retinal Vessels; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serpins; Thymidine; Time Factors; Vascular Endothelial Growth Factor A

Whether leptin, a product of the ob gene, can be stimulated by glucocorticoid administration has been an issue of controversy. We investigated the effect of intravenous administration of methylprednisolone (500 mg/day x 3 days) on plasma levels of leptin in 16 patients (female/male = 11/5) with Graves' hyperthyroidism and active ophthalmopathy who received pulse therapy. Significant elevation of plasma leptin levels started at the eighth hour (13.9+/-1.8 ng/mL, p=0.042) and lasted until the 72nd hour (21.2+/-5.0 ng/mL, p=0.009), as compared with basal levels (8.8+/-1.2 ng/mL). When methylprednisolone was replaced with oral prednisolone (10 mg three times per day x 2 weeks), no difference in plasma leptin levels was noted compared with basal measurement. Under methylprednisolone administration, a significant suppression of tumor necrosis factor-alpha began at the 24th hour (8.1+/-1.3 pg/mL, p=0.004) and lasted until the 48th hour (8.1+/-1.0 pg/mL, p=0.008), as compared with basal measurement (12.5+/-1.5 pg/mL). Compared with basal levels (93+/-2 mg/dL), significant elevation in the plasma glucose level started at the third hour (135+/-10 mg/dL, p=0.000) and lasted until the 72nd hour (110+/-4 mg/dL, p=0.019). The timing of serum insulin elevation approximated that of plasma glucose (3 hours: 14+/-3 microU/mL, p=0.006) and lasted until the end of prednisolone administration (2 weeks: 12+/-2 microU/mL, p=0.044), when compared with basal levels (14+/-3 microU/mL). We concluded that the parental administration of pharmacological doses of methylprednisolone to patients with Graves' hyperthyroidism could acutely raise their plasma level of leptin.

Topics: Adult; Aged; Blood Glucose; Eye Diseases; Fatty Acids, Nonesterified; Female; Graves Disease; Humans; Injections, Intravenous; Insulin; Kinetics; Leptin; Lipids; Male; Methylprednisolone; Middle Aged; Prednisolone; Tumor Necrosis Factor-alpha