Leptin is an important circulating signal for inhibiting food intake and body weight gain. In recent years, "leptin resistance" has been considered to be one of the main causes of obesity. However, the detailed mechanisms of leptin resistance are poorly understood. Increasing evidence has suggested that stress signals, which impair endoplasmic reticulum (ER) function, lead to an accumulation of unfolded proteins, which results in ER stress. In the present study, we hypothesized that ER stress is involved in leptin resistance. Tunicamycin, thapsigargin, or brefeldin A was used to induce ER stress. The activation status of leptin signals was measured by Western blotting analysis using a phospho-(Tyr705) signal transducer and activator of transcription 3 (STAT3) antibody. We observed that ER stress markedly inhibited leptin-induced STAT3 phosphorylation. In contrast, ER stress did not affect leptin-induced c-Jun NH 2 -terminal kinase activation. These results suggest that ER stress induces leptin resistance. ER stress-induced leptin resistance was mediated through protein tyrosine phosphatase 1B but not through suppressors of cytokine signaling 3. It is noteworthy that a chemical chaperone, which could improve the proteinfolding capacity, reversed ER stress-induced leptin resistance. Moreover, homocysteine, which induces ER stress, caused leptin resistance both in vitro and in vivo. Together, these findings suggest that the pathological mechanism of leptin resistance is derived from ER stress.

Increasing evidence indicates that endoplasmic reticulum stress (ER stress) is involved in the development of metabolic syndrome. However, pharmacological treatments targeting ER stress are not well understood. In the present study, we found that fluvoxamine, a selective serotonin reuptake inhibitor used for depression, can attenuate ER stress-induced “leptin resistance,” i.e., insensitivity to the anti-obesity hormone leptin. Treatment with tunicamycin, an ER stress-inducing reagent, caused cell death which was significantly inhibited by fluvoxamine. Leptin activates JAK2–STAT3 signaling. ER stress caused an impairment of leptin-induced STAT3 phosphorylation which was reversed by fluvoxamine. Fluvoxamine would be a novel leptin-sensitizing drug, which targets ER stress.

The American Society of Clinical Oncology recently published a Clinical Practice Guideline entitled "Appropriate Chemotherapy Dosing for Obesity Adult Patients with Cancer." The panel recommended that full weight (actual weight)-based cytotoxic chemotherapy doses are used to treat obese patients with cancer, particularly when the goal of treatment is cure. However, no study has examined dosage calculation methods used for obese cancer patients in Japan. Here, we retrospectively studied the relationships between chemotherapy dose intensity, the occurrence of adverse events, and treatment outcomes in obese patients undergoing chemotherapy. Patients were divided into two groups: the actual BW group (BWg) was composed of patients receiving dosage amounts calculated using their actual BW (n = 64), and the ideal BWg was composed of patients receiving dosage amounts calculated using their ideal BW (n = 41). There were significant differences in the incidence of Grade 3/4 hematological toxicity in the actual and ideal BWg in solid tumor patients, but not in patients with hematological malignancies. In solid tumor patients with ≥30 body mass index (BMI), the incidence of Grade 3/4 hematological toxicity was significantly lower in the ideal BWg than in the actual BWg. Particularly, in patients with complications, incidence of Grade 4 hematological toxicity was significantly higher in the actual BWg than in the ideal BWg. These results suggest that the tumor type, degree of obesity, complications, and choice of chemotherapy regimen should be considered when determining chemotherapy dosage for obese patients.

Obesity is a worldwide health problem that urgently needs to be solved. Leptin is an anti-obesity hormone that activates satiety signals to the brain. Evidence to suggest that leptin resistance is involved in the development of obesity is increasing; however, the molecular mechanisms involved remain unclear. We herein demonstrated that 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ) was involved in the development of leptin resistance. A treatment with 15d-PGJ 2 inhibited the leptin-induced activation of signal transducer and activator of transcription 3 (STAT3) in neuronal cells (SH-SY5Y-Ob-Rb cells). Furthermore, the intracerebroventricular administration of 15d-PGJ 2 reversed the inhibitory effects of leptin on food intake in rats. The peroxisome proliferatoractivated receptor gamma (PPAR-c) antagonist, GW9662, slightly reversed the inhibitory effects of 15d-PGJ 2 on the leptin-induced activation of STAT3 in neuronal cells. The PPAR-c agonist, rosiglitazone, also inhibited leptin-induced STAT3 phosphorylation. Therefore, the inhibitory effects of 15d-PGJ 2 may be mediated through PPAR-c. On the other hand, 15d-PGJ 2 -induced leptin resistance may not be mediated by endoplasmic reticulum stress or suppressor of cytokine signaling 3. The results of the present study suggest that 15d-PGJ 2 is a novel factor for the development of leptin resistance in obesity. Keywords: 15d-PGJ 2 , leptin, PPAR-c, STAT3. Leptin is anti-obesity hormone that was first identified in 1994 by Friedman's group (Zhang et al. 1994). Leptin is mainly secreted from adipose tissue and acts on brain hypothalamic neurons to reduce food intake (Campfield et al. 1995). Several splicing variants of the leptin receptor isoform have been identified to date. Of those, the Ob-Rb leptin receptor is the longest isoform of the leptin receptor and is considered to play an important role in regulating food intake and energy expenditure. The Ob-Rb leptin receptor is mainly expressed on the hypothalamus (Mercer et al. 1996). Leptin was previously shown to activate the Ob-Rb leptin receptor, which in turn induced JAK2-STAT3 signal transduction (Bjørbaek et al. 1997;Hosoi et al. 2002). The essential role of the Ob-Rb receptor-mediated activation of signal transducer and activator of transcription 3 (STAT3) in the anti-obesity effects of leptin have already been demonstrated (Bates et al. 2003). Thus, leptin treatments were initially expected to be useful for treating obesity. However, since most obese patients were in a state of leptin resistance, they did not adequately respond to the actions of leptin.These findings suggested that leptin resistance was involved in the development of obesity (Friedman 2003). The fact that a deeper understanding of the mechanisms underlying leptin resistance is needed represents an active area of research (Hill et al. 2003). Several studies have proposed mechanisms for the development of leptin resistance. Suppressor of cytokine signaling 3 (SOCS3) (Bjørbaek et al. 1998), protein tyrosine phosphatase 1B (Cheng et al...

Pemetrexed is a key anticancer agent for treatment of advanced non-small cell lung cancer (NSCLC). Pemetrexed is generally well tolerated, but individual-patient differences exist in severity of adverse events. Our study aimed to characterize the adverse events of pemetrexed that result in discontinuation of chemotherapy and to identify risk factors associated with those adverse events. We retrospectively studied the incidence of adverse events in 257 patients with NSCLC who received pemetrexed (P) with or without bevacizumab (B) and/or carboplatin (C): P, PB, CP, or CPB. Patients whose chemotherapy was discontinued were divided into two groups according to adverse events and disease progression. Grade 2/3 nausea, fatigue with P and PB, and rash with CP and CPB occurred more frequent in the adverse events group than in the disease progression group. Multivariate analysis indicated that grade 2/3 nausea [odds ratio (OR) 9.94; 95% confidence interval (CI) 1.46-67.37; p = 0.01] and fatigue (OR 10.62; CI 1.60-70.20; p = 0.01) with P or PB, and rash (OR 6.12; CI 1.34-27.88; p = 0.01) with CP or CPB, were independent risk factors for discontinuation of chemotherapy. Administration of dexamethasone at doses less than 4 mg after the day of pemetrexed administration was associated with nausea following P or PB (OR 11.08; 95% CI 1.02-119.95; p = 0.04). Grade 2/3 nausea and fatigue with P or PB, and rash with CP or CPB, were associated with discontinuation of chemotherapy.