Noriko Satoh

Satiety effect and sympathetic activation of leptin are mediated by hypothalamic melanocortin system

Leptin is an adipocyte-derived blood-borne satiety factor that decreases food intake and increases energy expenditure, thereby leading to a substantial decrease in body weight. To explore the possible roles of the hypothalamic melanocortin system in leptin action, we examined the effects of intracerebroventricular (i.c.v.) injection of leptin with or without SHU9119, a potent antagonist of alpha-melanocyte stimulating hormone, on food intake, body weight, and mitochondrial uncoupling protein-1 (UCP-1) mRNA expression in the brown adipose tissue (BAT) in rats. A single i.c.v. injection of leptin decreased cumulative food intake and body weight gain, and increased UCP-1 mRNA expression during 3 h at the onset of the dark phase. Inhibition of food intake and body weight change with leptin was reversed by co-injection of SHU9119 in a dose-dependent manner. Co-injection of SHU9119 also inhibited completely the leptin-induced increase in UCP-1 mRNA expression in the BAT. Treatment with SHU9119 alone did not affect food intake, body weight, and UCP-1 mRNA expression in rats. The present study provides evidence that the hypothalamic melanocortin system plays a central role in both satiety effect and sympathetic activation of leptin.

The arcuate nucleus as a primary site of satiety effect of leptin in rats

The obese (ob) gene encodes a fat cell-derived circulating satiety factor (leptin) that is involved in the regulation of energy homeostasis. In the present study, we examined effects of i.c.v. injection of recombinant human leptin on food intake and body weight gain in rats. We also studied effects of direct microinjections of leptin into the arcuate nucleus (Arc), ventromedial hypothalamus (VMH), and lateral hypothalamus (LH). A single i.c.v. injection of recombinant human leptin (0.25-2.0 micrograms/rat) reduced significantly and dose-dependently food intake and body weight gain in rats. Microinjections (0.125-0.5 microgram/site) into the bilateral Arc, VMH, and LH caused dose-related decreases in food intake and body weight gain as compared with vehicle-treated groups with a rank order of potency; Arc > VMH = LH. The present study provides the first direct evidence that the Arc is a primary site of satiety effect of leptin.

Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes

Sickness evokes various neural responses, one of which is activation of the hypothalamo–pituitary–adrenal (HPA) axis. This response can be induced experimentally by injection of bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1. Although prostaglandins (PGs) long have been implicated in LPS-induced HPA axis activation, the mechanism downstream of PGs remained unsettled. By using mice lacking each of the four PGE receptors (EP1–EP4) and an EP1-selective antagonist, ONO-8713, we showed that both EP1 and EP3 are required for adrenocorticotropic hormone release in response to LPS. Analysis of c-Fos expression as a marker for neuronal activity indicated that both EP1 and EP3 contribute to activation of neurons in the paraventricular nucleus of the hypothalamus (PVN). This analysis also revealed that EP1, but not EP3, is involved in LPS-induced activation of the central nucleus of the amygdala. EP1 immunostaining in the PVN revealed its localization at synapses on corticotropin-releasing hormone-containing neurons. These findings suggest that EP1- and EP3-mediated neuronal pathways converge at corticotropin-releasing hormone-containing neurons in the PVN to induce HPA axis activation upon sickness.

Unbalanced M1/M2 Phenotype of Peripheral Blood Monocytes in Obese Diabetic Patients: Effect of pioglitazone

The monocyte-macrophage system exists in at least two distinct phenotypes of differentiation: proinflammatory (M1) and anti-inflammatory (M2) (1,2). Macrophages, when infiltrated into obese adipose tissue, exhibit a phenotypic switch from M2 to M1 polarization, thereby contributing to obesity-induced adipose tissue inflammation and insulin resistance (1). Expression of both M1 and M2 markers is detected in circulating peripheral blood mononuclear cells as well as in atherosclerotic plaques (3). However, there have been no detailed studies on the M1/M2 phenotype of monocytes and their association with cardiovascular risks in obese subjects with type 2 diabetes. On the other hand, we demonstrated that pioglitazone, a thiazolidinedione class of insulin sensitizer, exerts an antiatherogenic effect independent of its antidiabetic effect …

A novel oxidized low-density lipoprotein marker, serum amyloid A-LDL, is associated with obesity and the metabolic syndrome

BACKGROUNDnThe putative association between the novel oxidized low-density lipoprotein markers, serum amyloid A-LDL (SAA-LDL) and alpha1-antitrypsin-LDL (AT-LDL), and obesity and the metabolic syndrome (MetS) has not been previously studied. In the present report, we investigated the levels of SAA-LDL and AT-LDL in relation to the components of the MetS. We also assessed the effect of weight reduction therapy on serum SAA-LDL and AT-LDL levels among obese subjects.nnnMETHODSnThe study population included 421 obese Japanese outpatients (185 men and 236 women, mean age: 51.1 years) enrolled in the multicenter Japan Obesity and Metabolic Syndrome Study (JOMS). The novel oxidized low-density lipoprotein markers, serum SAA-LDL and AT-LDL, were measured in all participants.nnnRESULTSnCirculating SAA-LDL levels were independently associated with the presence and the number of components of the MetS. SAA-LDL levels were also significantly and independently correlated with high-sensitivity C-reactive protein. Notably, successful weight reduction resulted in a significant decrease in circulating SAA-LDL concentrations. Levels of AT-LDL were not associated with the MetS.nnnCONCLUSIONSnWe documented, for the first time, that serum SAA-LDL levels correlate positively with the number of components of the MetS and weight reduction. Whether SAA-LDL may be involved in the pathophysiology of MetS and atherosclerosis deserves further investigation.

Soluble VEGF receptor-2 is increased in sera of subjects with metabolic syndrome in association with insulin resistance

OBJECTIVEnMetabolic syndrome (MetS) is associated with impaired angiogenesis. Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis through binding to its specific receptor, VEGF receptor-2 (VEGFR-2), whereas the expression of VEGF and VEGFR-2 in the myocardium of insulin-resistant rats is down-regulated. Soluble VEGF receptor-1 (sVEGFR-1) and -2 (sVEGFR-2) have been reported to inhibit angiogenesis both in vitro and in vivo. However, the balance between circulating levels of VEGF and its soluble receptors, which may reflect and/or affect cardiovascular VEGF signaling, in subjects with MetS is unknown.nnnMETHODS AND RESULTSnWe carried out a cross-sectional study including 272 consecutive, apparently healthy subjects who were not receiving any drugs. Plasma levels of VEGF and serum levels of its soluble receptors were determined using enzyme-linked immunosorbent assays. VEGF and sVEGFR-1 levels did not differ between subjects with and those without MetS. However, sVEGFR-2 levels were significantly increased in MetS compared with non-MetS subjects. Stepwise regression analysis revealed that HOMA-IR was the strongest independent determinant of the sVEGFR-2 level. Accordingly, the mean sVEGFR-2 levels increased in proportion to both the accumulation of components of MetS and quartile of HOMA-IR. Interestingly, multiple regression analyses revealed that independent determinants of VEGF were the body mass index and blood pressure, whereas, in contrast, those of sVEGFR-2 were HOMA-IR and high-sensitivity C-reactive protein.nnnCONCLUSIONSnThe correlation of sVEGFR-2 with insulin resistance supports the need for further investigations to define the clinical utility and predictive value of serum sVEGFR-2 levels in cardiovascular dysfunction in MetS.

Augmented expression of obese (ob) gene during the process of obesity in genetically obese-hyperglycemic Wistar fatty (falfa) rats

Expression of the obese (ob) gene is up‐regulated in the adipose tissue in several obese rodent models. To study the regulation of the ob gene expression during the development of obesity, we examined the ob gene expression in genetically obese‐hyperglycemic Wistar fatty (falfa) rats at several stages of obesity. The ob mRNA levels in the adipose tissue from Wistar fatty rats was unequivocally augmented and continued to rise in the process of obesity. Furthermore, the ob gene expression in this obese model was much more rapidly enhanced in the mesenteric fat than in the subcutaneous fat. Moreover, the ob gene expression was more greatly augmented in the mesenteric fat than the lipoprotein lipase gene expression. These results suggest the presence of obesity‐linked and region‐specific regulation of the ob gene expression.

The significance of the Trp 64 Arg mutation of the β3-adrenergic receptor gene in impaired glucose tolerance, non—insulin-dependent diabetes mellitus, and insulin resistance in Japanese subjects☆

It has been reported that the Trp 64 Arg mutation of the human beta3-adrenergic receptor (beta3-AR) gene is related to an earlier age of onset of non-insulin-dependent diabetes mellitus (NIDDM) and features of insulin resistance and weight gain in morbidly obese patients. However, such findings have not been consistent in varying ethnic populations. In the present study, we investigated the frequency of the Trp 64 Arg mutation of the human beta3-AR gene in Japanese control subjects (n = 253) and in NIDDM (n = 314) and impaired glucose tolerance (IGT) patients (n = 100). We compared the frequency of the mutation with the body-mass index (BMI) in these groups and with the metabolic clearance rate (MCR) of glucose in the NIDDM patients. A Trp 64 Arg mutation was observed in 36.7%, 31.6%, and 37.0% of the control, NIDDM, and IGT subjects, respectively. The frequency of the homozygotes for the mutation was 4.3%, 4.8%, and 3.0%, respectively. Neither the genotype frequency (Trp/Arg, Arg/Arg) nor the frequency of the mutated allele was significantly different among the three groups. The BMI of the subjects with the mutation was not significantly higher than that of the subjects without the mutation in each group. Furthermore, the allele frequency (A) was not different among the subjects with different BMIs (BMI < 22.0, 22.0 < or = BMI < or = 26.4, BMI > 26.4) in each group. In a separate group of NIDDM patients, the MCR of the subjects with intermediate BMIs (22.0 < or = BMI < or = 26.4) with the mutation tended to be lower than that of those without the mutation. In addition, the MCR of the subjects with the mutation in this group was significantly lower compared with that of those with a BMI less than 22. These results indicate that the Trp 64 Arg mutation of the beta3-AR gene may not contribute to the development of NIDDM or be a determinant of obesity in the Japanese population. However, the mutation may contribute to insulin resistance in NIDDM patients with an intermediate BMI.

Effects of risedronate or alfacalcidol on bone mineral density, bone turnover, back pain, and fractures in Japanese men with primary osteoporosis: results of a two-year strict observational study

Although osteoporosis in men is already a major public health problem, there is still a dearth of data about the effects of risedronate in male osteoporosis, especially in Japanese with primary osteoporosis. Therefore, the objective of our study was to investigate the effects of risedronate on bone mineral density (BMD), bone turnover, back pain, and fractures in these patients prospectively for two years (at baseline, threexa0months, six months, twelvexa0months, and twenty-fourxa0months) both longitudinally and compared with those of alfacalcidol. The subjects enrolled for this study were 66 Japanese male patients with untreated primary osteoporosis (mean age 63.52xa0±xa08.7xa0years), who were divided into two groups (44 with risedronate and 22 with alfacalcidol). We measured BMD by dual energy X-ray absorptiometry at three sites—the lumbar spine, femoral neck, and distal radius. Risedronate treatment significantly increased BMD at the lumbar spine and at the femoral neck, reduced bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx), and reduced back pain, both longitudinally and compared with alfacalcidol treatment. We observed a lower rate of incident fracture in risedronate users. However, multiple logistic regression analysis revealed that this trend was not statistically significant, possibly because of the small number of patients enrolled. These potentially beneficial effects of risedronate on bone in male patients with primary osteoporosis suggest the possibility that osteoporosis should be treated with risedronate regardless of gender in order to effectively prevent subsequent osteoporotic fractures.

Transmitral E/A ratio decreases in association with abdominal fat accumulation in patients with impaired glucose tolerance or mild diabetes without left ventricular hypertrophy

An abnormal left ventricular (LV) diastolic function is an early sign of diabetic cardiomyopathy, which is characterized by an impaired diastolic and/or systolic function of the left ventricle in the absence of ischemic, valvular, or hypertensive heart disease, and serves as a marker of cardiovascular risk. However, it is unclear whether LV diastolic abnormalities can be detected in patients with impaired glucose tolerance (IGT) or mild diabetes without LV hypertrophy (LVH). We examined echocardiographic data from 92 consecutive Japanese patients aged 45–79 years with or without IGT or mild diabetes in the absence of LVH. Impaired glucose tolerance or mild diabetes was defined as the presence of one or more of the following criteria: fasting plasma glucose >110 mg/dl, hemoglobin A1c >5.6%, homeostasis model assessment ratio >1.73, or the taking of oral antihyperglycemic drugs. Left ventricular hypertrophy was defined as an LV mass index (LVMI) >116 g/m2 in men and >104 g/m2 in women. Patients with ischemic, valvular, or hypertensive heart disease were excluded. The age, blood pressure, heart rate, and LVMI were similar between patients with (IGT/DM group, n = 43) and without IGT or mild diabetes (non-IGT/DM group, n = 49), whereas the body mass index and waist circumference (WC) were greater in the IGT/DM compared to the non-IGT/DM group (P < 0.05 and P < 0.001, respectively). The transmitral E/A ratio was lower and the deceleration time longer in the IGT/DM than in the non-IGT/DM group (both P < 0.05). Stepwise regression analysis revealed that age and WC were independent determinants of the E/A ratio. In conclusion, diastolic abnormalities without LVH can be detected in Japanese patients with IGT or mild diabetes. The E/A ratio decreases in association with abdominal fat accumulation.