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Biomedical subjects

H Masuzaki

Publications and source records attributed to H Masuzaki.

At least 55 records · Page 3Linked to original sources
PubMed1999

Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action.

To understand the role of agouti-related protein (AGRP), an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action, we produced a full-length recombinant AGRP and examined its effect on the satiety effect of leptin. We also studied leptin's regulation of hypothalamic AGRP mRNA expression. A single intracerebroventricular (i.c.v.) injection of AGRP significantly increased cumulative food intake and body weight in a dose-dependent manner in rats. The leptin-induced inhibition of food intake and body weight was reversed by co-injection of AGRP in a dose-dependent manner. Hypothalamic AGRP mRNA expression was upregulated in leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice and downregulated in lethal yellow agouti mice (KKAy mice) with hyperleptinemia. A single i.c.v. injection of leptin reversed the increased AGRP mRNA levels in ob/ob mice but not in db/db mice. In control mice and KKAy mice, AGRP mRNA expression was upregulated during fasting, when plasma leptin concentrations were decreased. No significant increase in AGRP mRNA expression was noted during fasting in control mice and KKAy mice treated with leptin. This study provides the first direct evidence that AGRP is a negative regulator of leptin action, and leptin downregulates hypothalamic AGRP production. Because leptin is shown to increase hypothalamic alpha-melanocyte stimulating hormone (alpha-MSH) production, our data suggest that its action via the hypothalamic melanocortin system is determined by the balance between the levels of its agonist and antagonist, alpha-MSH and AGRP.

Agouti-Related Protein↗
PubMed1999

Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes.

Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKAy mice (Ay/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the Ay allele (Tg/+:Ay/+) were significantly higher than those in Ay/+ mice. Although no significant differences in body weight were noted among Tg/+:Ay/+ mice, Ay/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:Ay/+ compared with Ay/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in Ay/+ mice were comparable to those in Tg/+:Ay/+ mice, Tg/+:Ay/+ mice developed obesity-diabetes syndrome similar to that of Ay/+ mice. Body weights of 12-week-old Tg/+:Ay/+ and Ay/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:Ay/+ mice but were markedly reduced in Ay/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:Ay/+ mice were markedly improved as compared with Ay/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:Ay/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes.

Aging↗
PubMed1999

Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion.

Leptin is an adipocyte-derived blood-borne satiety factor that acts directly on the hypothalamus, thereby regulating food intake and energy expenditure. We have demonstrated that the hypothalamic arcuate nucleus (Arc) is a primary site of the satiety effect of leptin (Neurosci Lett 224:149-152, 1997). To explore the hypothalamic pathway of sympathetic activation of leptin, we examined the effects of a single intravenous or intracerebroventricular injection of recombinant human leptin on catecholamine secretion in rats. We also examined the effects of direct microinjection of leptin into the ventromedial hypothalamus (VMH), Arc, paraventricular nucleus (PVN), and dorsomedial hypothalamus (DMH) in rats. To further assess whether sympathetic activation of leptin is mediated via the VMH, we also examined the effects of a single intravenous injection of leptin in VMH-lesioned rats. A single injection of leptin (0.25-1.0 mg i.v./rat or 0.5-2.0 pg i.c.v./rat) increased plasma norepinephrine (NE) and epinephrine (EPI) concentrations in a dose-dependent manner. Plasma NE and EPI concentrations were increased significantly when leptin was injected directly into the VMH but were unchanged when injected into the Arc, PVN, and DMH. Plasma NE and EPI concentrations were unchanged in VMH-lesioned rats that received a single intravenous injection of leptin. The present study provides evidence that a leptin-induced increase in catecholamine secretion is mediated primarily via the VMH and suggests the presence of distinct hypothalamic pathways mediating the satiety effect and sympathetic activation of leptin.

Animals↗
PubMed1999

Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin.

Excess of body fat, or obesity, is a major health problem and confers a higher risk of cardiovascular and metabolic disorders such as diabetes, hypertension, and coronary heart disease. Leptin is an adipocyte-derived satiety factor that plays an important role in the regulation of energy homeostasis, and its synthesis and secretion are markedly increased in obese subjects. To explore the metabolic consequences of an increased amount of leptin on a long-term basis in vivo, we generated transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. Overexpression of leptin in the liver has resulted in complete disappearance of white and brown adipose tissue for a long period of time in mice. Transgenic skinny mice exhibit increased glucose metabolism accompanied by the activation of insulin signaling in the skeletal muscle and liver. They also show small-sized livers with a marked decrease in glycogen and lipid storage. The phenotypes are in striking contrast to those of recently reported animal models of lipoatrophic diabetes and patients with lipoatrophic diabetes with reduced amount of leptin. The present study provides evidence that leptin is an adipocyte-derived antidiabetic hormone in vivo and suggests its pathophysiologic and therapeutic implications in diabetes.

Animals↗
PubMed1998

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.

Adipose Tissue, Brown↗
PubMed1998

A HhaI/BstUI polymorphism in a novel gene at human chromosome 11p15.5.

We found a HhaI/BstUI polymorphism in the 3' untranslated region of a novel gene which was localized to 11p15.5. This region is one of prominent imprinting domains and contains multiple imprinted genes, such as H19, IGF2, KVLQT1, and p57KIP2, which suggests that regional factors might contribute to the imprinting. This polymorphism will be useful in the allelic analysis of expression and methylation of the novel gene.

Alleles↗
PubMed1998

A positive umbilical venous-arterial difference of leptin level and its rapid decline after birth.

OBJECTIVE: We investigated the site of leptin production in the fetoplacental circulation. STUDY DESIGN: We simultaneously determined plasma leptin levels in cord vessels and maternal peripheral veins of 38 healthy pregnant women. We also compared plasma leptin levels in 20 neonates at birth and on the fifth day after birth. RESULTS: Leptin levels in cord vessels were significantly (p < 0.001) lower than those in maternal veins (mean 29.5 ng/ml). Leptin levels in umbilical arteries (mean 9.8 ng/ml) were significantly (p < 0.01) lower than those in umbilical veins (mean 12.9 ng/ml). Leptin levels in neonatal veins on the fifth day (mean 3.0 ng/ml) were markedly (p < 0.001) lower than those in umbilical arteries of the same neonates (mean 10.9 ng/ml). CONCLUSION: The higher leptin levels in umbilical veins than in umbilical arteries and the marked decrease during the neonatal period suggest that the placenta is one of the major sources of leptin in the fetal circulation.

Adult↗
PubMed1998

Fetal blood flow redistribution in term intrauterine growth retardation (IUGR) and post-natal growth.

OBJECTIVE: The purpose of the present study was to evaluate the relationship between intrauterine growth retardation, represented by fetal blood flow redistribution and infantile growth. METHODS: The blood flow velocity waveform of umbilical and middle cerebral arteries was recorded by Doppler ultrasonography in 77 growth-retarded fetuses. We recorded the pulsatility index (PI) of the umbilical artery and middle cerebral and calculated the PI ratio of the middle cerebral to umbilical artery (C/U ratio). We selected a cutoff value of 1.0 to distinguish between normal and abnormal C/U ratios. To evaluate the development of infants, height, body weight and head circumference were measured serially at 3, 6 and 12 months of age. RESULTS: Birth weight was significantly lower in newborns who had abnormal C/U ratios (2021+/-295 g vs. 2294+/-236 g). The number of cases admitted to NICU was higher and the duration of admission was longer in abnormal C/U ratio group (15/29 and 33.7+/-13.5 days) than normal C/U ratio group (7/48 and 26.6+/-5.6 days). Body weight was lower in infants of abnormal C/U ratio group at 3 months, but was not different at 6 and 12 months. The height was shorter in abnormal C/U ratio group at birth, there were no significant differences at 3, 6 and 12 months. The number of newborn infants with growth retardation was slightly higher in abnormal C/U ratio group, but the difference was not significant at 6 and 12 months. There was no relationship between C/U and growth variables recorded at birth and follow-up in infants. CONCLUSION: Intrauterine growth-retardation, represented by abnormal fetal blood redistribution was associated with adverse perinatal outcome, but the influence was not found at the first year of life.

Adult↗
PubMed1998

The significance of the Trp 64 Arg mutation of the beta3-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.

Adult↗
PubMed1998

Detection and assessment of pyelectasis in the fetus: relationship to postnatal renal function.

OBJECTIVE: To assess the relationship between fetal pyelectasis determined by ultrasonography and postnatal renal function. METHODS: We first established normal values for anteroposterior, transverse, and longitudinal diameters of the renal pelvis sonographically in 68 normal fetuses at 30-40 weeks' gestation. We also evaluated prospectively the relationship between the severity of pyelectasis (diameter at least two standard deviations above the normal mean) in 36 fetuses at 30-40 weeks' gestation and postnatal renal function. Fetal renal function also was evaluated through measurement of the hourly urine production rate, whereas postnatal renal function was assessed by technetium 99m-diethylenetriamine penta-acetic acid renography and excretory urography. RESULTS: Fetal pyelectasis was diagnosed when renal pelvic diameters were at least 8 mm (anteroposterior), 11 mm (transverse), and 14 mm (longitudinal), all upper limits of normal diameters of 68 normal fetuses as determined in the first part of the study. Pyelectasis was associated with a normal urine production rate in all fetuses, but in six fetuses it was associated with a normal urine production rate in all fetuses, but in six fetuses it was associated with a progressive deterioration of renal function within the 1st month of life, requiring neonatal surgery. In the other 30 fetuses with pyelectasis, who did not require neonatal surgery, pyelectasis decreased gradually or totally disappeared within 2 years. Renal pelvic anteroposterior, transverse, and longitudinal pelvic diameters were at least 20, 25, and 26 mm, respectively, during late fetal life in those neonates at the time of corrective surgery. The mean anteroposterior diameter in those fetuses who did not require surgery at infancy (11 +/- 6 mm) was significantly less than in those requiring surgery (33 +/- 14 mm, P < .01). Likewise, the transverse diameters were 17 +/- 10 mm and 38 +/- 16 mm (P < .01) and the longitudinal diameters were 20 +/- 10 mm and 48 +/- 22 mm (P < .01). CONCLUSION: Neonatal surgery is recommended when the anteroposterior, transverse, and longitudinal renal pelvic diameters during the prenatal period are at least 20, 25, and 26 mm, respectively. Surgery is not necessary when the diameters are less than 20 mm.

Dilatation, Pathologic↗
PubMed1998

Effect of experimentally induced urethral obstruction and surgical decompression in utero on renal development and function in rabbits.

To investigate the effect of urethral obstruction during late fetal life on renal development and function, we developed a rabbit fetal model of obstructive nephropathy to examine the pathological and biochemical consequences of urethral obstruction and beneficial effects of early surgical decompression. Animals were divided into four groups, i.e., obstructed, early decompressed, late decompressed, and control. Fetal renal development was evaluated by histological examination and counting the number of glomeruli in the four groups. The number of renal glomeruli correlated with gestational age in the normal fetus (r = 0.90, P < 0.0001). Urethral ligation on gestational day 25 (full-term, 31 days) resulted in thinning of the renal cortex and significantly decreased the number of renal glomeruli. The concentration of urinary microalbumin was higher when urethral obstruction was maintained for 3 days than 1 day after urethral obstruction, although urinary beta2- microglobulin, Na, Cl, and osmotic pressure did not change during this period. Decompression of urethral obstruction 1 day after induction of urethral obstruction resulted in improvement in the severity glomerular hypoplasia compared with late decompression (P < 0.01). Our results suggest that the rabbit fetal model simulates fetal urethral obstruction in humans, and indicates that early surgical decompression may be effective in restoration of normal renal function.

Albuminuria↗
PubMed1998

Augmentation of leptin synthesis and secretion through activation of protein kinases A and C in cultured human trophoblastic cells.

Leptin is a fat cell-derived hormone that regulates food intake and energy expenditure. We previously demonstrated that leptin is produced by nonadipose cells, i.e. by placental trophoblasts. We also reported that a human trophoblastic cell line, BeWo cells, expresses leptin gene and secretes leptin into culture media. To elucidate the regulatory mechanisms of leptin production by human trophoblasts, we investigated synthesis and secretion of leptin in BeWo cells and in explant cultures of human placental tissue. Leptin production and gene expression in BeWo cells were increased by treatment with forskolin. The forskolin-induced increase in leptin production was completely suppressed by H89, an inhibitor of protein kinase A. Leptin production and gene expression in BeWo cells were increased by treatment with phorbol myristate acetate (PMA). The PMA-induced increase in leptin production was completely suppressed by H7 and staurosporine, both of which are inhibitors of protein kinase C. Leptin secretion from first trimester chorionic tissue was approximately 50-fold greater than that from term placental tissue. Leptin production and gene expression in explant cultures of placental tissue at both stages of pregnancy were augmented markedly by treatment with forskolin or PMA. The present study demonstrated augmentation of leptin production by protein kinase A and protein kinase C in cultured human trophoblasts, thereby leading to a better understanding of the regulatory mechanisms of leptin production in human trophoblasts in vivo.

Cell Line↗
PubMed1998

Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia.

Preeclampsia (PE) is a hypertensive disorder, which develops in late pregnancy and is usually associated with placental hypoxia and dysfunction. We have recently demonstrated that leptin is a novel placenta-derived hormone in humans and suggested its significance in human pregnancy (see Ref. 19). To explore the changes in the leptin production in placenta in PE, we measured the plasma leptin level and placental leptin messenger RNA expression in pregnant women with PE. Plasma leptin levels in preeclamptic women were elevated significantly, compared with gestational age- and body mass index-matched normal pregnant women (P < 0.0001). Plasma leptin levels in the severe PE group were significantly higher than those in the mild PE group (P < 0.0001). Plasma leptin levels in preeclamptic women were reduced, soon after the placental delivery, to those expected for their body mass indices. Northern blot analysis revealed that leptin messenger RNA levels are increased in the placentas from preeclamptic women, compared with normal pregnant women. Leptin secretion was increased significantly in a human trophoblastic cell line (BeWo cells) cultured under hypoxic conditions (5% O2), compared with those cultured under standard conditions (20% O2; P < 0.01). The present study demonstrated that placental production of leptin is augmented in severe PE, probably because of placental hypoxia, thereby suggesting the possible significance of leptin as a marker of placental hypoxia in severe PE.

Adult↗
PubMed1998

[Leptin Receptor].

Leptin is a fat cell-derived satiety factor that regulates food intake and energy expenditure. Its effects are mediated by interactions with the leptin receptor (Ob-R) that is alternatively spliced to encode at least five isoforms(a-e), which are distributed in a wide range of tissues including the hypothalamus. Ob-R is a member of cytokine receptors and involves the JAK-STAT signal transduction system. We found Ob-R mutations in Zucker fatty rats and obese Koletsky rats and demonstrated that Ob-R dysfunction brings around hyperphagia and obesity. However we and others have not found any Ob-R mutation in human obese subjects.

Animals↗
PubMed1998

Development of a sensitive ELISA for human leptin, using monoclonal antibodies.

A new, sensitive ELISA for human leptin in plasma and cerebrospinal fluid (CSF) was developed, using monoclonal antibodies. The lower limit of detection of this ELISA was 0.78 pg/assay. Both intra- and interassay imprecision values were <7%. The dilution curves of plasma and CSF showed good linearity, and the recovery was 83.2-95.6%. There was good correlation between plasma leptin concentrations by the ELISA and a commercially available RIA (r = 0.99). Our ELISA is advantageous because it does not require radioisotopes, it produces results in hours rather than days, and more importantly, it improves on the detection limit and plasma interference of the RIA kit. The new ELISA enables measurement of low concentrations of leptin, as are seen in CSF and in plasma of patients with anorexia nervosa.

Adipose Tissue↗
PubMed1997

Identification of the human leptin 5'-flanking sequences involved in the trophoblast-specific transcription.

Leptin is an adipocyte-derived blood-borne satiety factor that is involved in the regulation of energy homeostasis. We have recently demonstrated nonadipose tissue production of leptin; leptin is synthesized in and secreted from placental trophoblasts (Nature Med. 3: 1029-1033, 1997). To understand the transcriptional regulation of the human leptin gene in placental trophoblasts, we examined the promoter activity of various lengths of the human leptin 5'-flanking sequences in BeWo cells, a human trophoblastic cell line. The 2080-bp human leptin gene promoter region (-2080 to +108) showed a high-level transcription activity in BeWo cells. When DNA sequences between -1885 and -1830 were deleted, the promoter activity was reduced dramatically in BeWo cells. No significant changes in the promoter activity were noted when tested in primary cultures of rat mature adipocytes. Electrophoretic mobility shift assays revealed the presence of nuclear protein(s) binding to the sequences in BeWo cells but not in isolated rat mature adipocytes. The present study provides new insight into the trophoblast-specific transcription of the human leptin gene.

Adipocytes↗