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K Nakao

Publications and source records attributed to K Nakao.

At least 109 records · Page 6Linked to original sources
PubMed2001

[Potential molecular targets for anti-obesity drugs--after the discovery of leptin].

The discovery of the adipose-derived hormone leptin has generated interest in the interaction between peripheral signals and brain targets involved in the regulation of feedings and energy balance. Potential anti-obesity drugs can be based on any intervention between the neuropeptide and its receptor that would alter the biological responses mediated by the neuronal network, in particular, food intake, metabolism and energy expenditure. Modulation of neurons in the arcuate nucleus by leptin results in reduced expression of neuropeptide Y and agouti-related protein, and increased expression of pro-opiomelanocortin (the precursor of a-melanocyte-stimulating hormone) and cocaine- and amphetamine- regulated transcript. Whether leptin finds its way into general usage as an anti-obesity drug, the use of modern methods to identify and target the components of leptin signaling pathway will form the basis for new pharmacological approaches to the treatment of obesity.

Animals↗
PubMed2001

In vivo assessment of the regulatory mechanism of cholinergic neuronal activity associated with motility in dog small intestine.

Intestinal motor activity associated with acetylcholine (ACh) release was assessed in the small intestine of anesthetized dogs by simultaneous measurement of motor activity and local ACh concentrations within the intestinal wall with in vivo microdialysis. Basal concentration of ACh measured in the dialysate was 1.12 +/- 0.08 pmol/15 min (n = 10), a value that remained constant until 3 h after perfusion. Intra-arterial infusion of tetrodotoxin reduced dialysate ACh concentration, while the motor activity accelerated at the early phase after infusion of tetrodotoxin and then decreased, thereby suggesting that the motor activity is regulated by not only excitatory cholinergic neurons, but also inhibitory neurons. Intraarterial infusion of atropine increased dialysate ACh concentration but reduced motor activity, thereby indicating that the cholinergic neurons are tonically active and the muscarinic autoreceptors operate to inhibit the ACh release. Intraarterial infusion of norepinephrine reduced, but yohimbine increased both motor activity and dialysate ACh concentration, thereby indicating that the adrenergic neurons regulate the motor activity due to control of cholinergic neuronal activity. This in vivo microdialysis method demonstrated in the whole body of animals that the activity of cholinergic neurons was physiologically regulated by itself and adrenergic neurons.

Adrenergic alpha-Agonists↗
PubMed2001

Modification of lipases with poly(ethylene glycol) and poly(oxyethylene) detergents and their catalytic activities in organic solvents.

The alpha-chymotrypsin-poly(ethylene glycol) complex, which was prepared by lyophilizing an aqueous solution, was found to have high catalytic activity in organic media even when the molar ratio of polymer/enzyme in its preparation stage is unity. In this study, we obtained freeze-dried complexes of lipases and poly(ethylene glycol) or poly(oxyethylene) detergents including newly synthesized gemini-type detergents, and their transesterification activity in organic solvents was evaluated. The freeze-dried lipase from Pseudomonas cepacia prepared by using each modifier showed enhanced transesterification activity, exhibiting a similar dependence on the concentration of the modifier in the preparation stage to that of the alpha-chymotrypsin-poly(ethylene glycol) complex; in contrasts, the one from Candida rugosa did not do so.

Journal Article↗
PubMed2001

Simultaneous onset of type 1 diabetes mellitus and painless thyroiditis following acute pancreatitis.

A 24-year-old female suffered from acute pancreatitis, followed by simultaneous onset of painless goiter, elevation of thyroid hormones and diabetic ketoacidosis. Two months later, her insulin secreting function was severely decreased and positive for anti-GAD and anti-islet cell antibodies, whereas the serum glucagon level was normal, suggesting an autoimmune-related destruction specifically of beta cells. In addition, the initial hyperthyroid state was followed by a hypothyroid phase which later recovered to an euthyroid state, suggesting an initial destruction of thyroid cells. Because anti-thyroidal antibodies were positive, it is likely that the thyroidal destruction was also autoimmune-related. This case implies common pathogenic mechanisms in the autoimmunity related destruction of beta cells and thyroid cells.

Acute Disease↗
PubMed2001

Troglitazone not only increases GLUT4 but also induces its translocation in rat adipocytes.

Thiazolidinediones, insulin-sensitizing agents, have been reported to increase glucose uptake along with the expression of glucose transporters in adipocytes and cardiomyocytes. Recently, we have further suggested that the translocation of GLUT4 is stimulated by thiazolidinediones in L6 myocytes. However, the direct effects of thiazolidinediones on translocation of glucose transporters have not yet been determined. In this study, using hemagglutinin epitope-tagged GLUT4 (GLUT4-HA), we provide direct evidence of the effect of troglitazone on the translocation of GLUT4 in rat epididymal adipocytes. Primary cultures of rat adipocytes were transiently transfected with GLUT4-HA and overexpressed eightfold compared with endogenous GLUT4 in transfected cells. A total of 24 h of treatment with troglitazone (10(-4) mol/l) increased the cell surface level of GLUT4-HA by 1.5 +/- 0.03-fold (P < 0.01) without changing the total amount of GLUT4-HA, whereas it increased the protein level of endogenous GLUT4 (1.4-fold) without changing that of GLUT1. Thus, the direct effect on the translocation can be detected apart from the increase in endogenous GLUT4 content using GLUT4-HA. Troglitazone not only increased the translocation of GLUT4-HA on the cell surface in the basal state but also caused a leftward shift in the dose-response relations between GLUT4-HA translocation and insulin concentration in the medium (ED(50): from approximately 0.1 to 0.03 nmol/l). These effects may partly contribute to the antidiabetic activity of troglitazone in patients with obesity and type 2 diabetes.

Adipocytes↗
PubMed2001

Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway.

Ghrelin, an endogenous ligand for growth hormone secretagogue (GHS) receptor originally isolated from the stomach, occurs in the hypothalamic arcuate nucleus and may play a role in energy homeostasis. Synthetic GHSs have activated the hypothalamic arcuate neurons containing neuropeptide Y (NPY), suggesting the involvement of NPY in some of ghrelin actions. This study was designed to elucidate the role of ghrelin in the regulation of food intake. A single intracerebroventricular (ICV) injection of ghrelin (5-5,000 ng/rat) caused a significant and dose-related increase in cumulative food intake in rats. Ghrelin (500 ng/rat) was also effective in growth hormone-deficient spontaneous dwarf rats. Hypothalamic NPY mRNA expression was increased in rats that received a single ICV injection of ghrelin (500 ng/rat) (approximately 160% of that in vehicle-treated groups, P < 0.05). The ghrelin's orexigenic effect was abolished dose-dependently by ICV co-injection of NPY Y1 receptor antagonist (10-30 microg/rat). The leptin-induced inhibition of food intake was reversed by ICV co-injection of ghrelin in a dose-dependent manner (5-500 ng/rat). Leptin reduced hypothalamic NPY mRNA expression by 35% (P < 0.05), which was abolished by ICV co-injection of ghrelin (500 ng/rat). This study provides evidence that ghrelin is an orexigenic peptide that antagonizes leptin action through the activation of hypothalamic NPY/Y1 receptor pathway.

Animals↗
PubMed2001

Troglitazone induces GLUT4 translocation in L6 myotubes.

A number of studies have demonstrated that insulin resistance in the skeletal muscle plays a pivotal role in the insulin resistance associated with obesity and type 2 diabetes. A decrease in GLUT4 translocation from the intracellular pool to the plasma membranes in skeletal muscles has been implicated as a possible cause of insulin resistance. Herein, we examined the effects of an insulin-sensitizing drug, troglitazone (TGZ), on glucose uptake and the translocation of GLUT4 in L6 myotubes. The prolonged exposure (24 h) of L6 myotubes to TGZ (10(-5) mol/l) caused a substantial increase in the 2-deoxy-[3H]D-glucose (2-DG) uptake without changing the total amount of the glucose transporters GLUT4, GLUT1, and GLUT3. The TGZ-induced 2-DG uptake was completely abolished by cytochalasin-B (10 micromol/l). The ability of TGZ to translocate GLUT4 from light microsomes to the crude plasma membranes was greater than that of insulin. Both cycloheximide treatment (3.5 x 10(-6) mol/l) and the removal of TGZ by washing reversed the 2-DG uptake to the basal level. Moreover, insulin did not enhance the TGZ-induced 2-DG uptake additively. The TGZ-induced 2-DG uptake was only partially reversed by wortmannin to 80%, and TGZ did not change the expression and the phosphorylation of protein kinase B; the expression of protein kinase C (PKC)-lambda, PKC-beta2, and PKC-zeta; or 5'AMP-activated protein kinase activity. a-Tocopherol, which has a molecular structure similar to that of TGZ, did not increase 2-DG uptake. We conclude that the glucose transport in L6 myotubes exposed to TGZ for 24 h is the result of an increased translocation of GLUT4. The present results imply that the effects of troglitazone on GLUT4 translocation may include a new mechanism for improving glucose transport in skeletal muscle.

Animals↗
PubMed2001

Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes.

Lipoatrophic diabetes is caused by a deficiency of adipose tissue and is characterized by severe insulin resistance, hypoleptinemia, and hyperphagia. The A-ZIP/F-1 mouse (A-ZIPTg/+) is a model of severe lipoatrophic diabetes and is insulin resistant, hypoleptinemic, hyperphagic, and shows severe hepatic steatosis. We have also produced transgenic "skinny" mice that have hepatic overexpression of leptin (LepTg/+) and no adipocyte triglyceride stores, and are hypophagic and show increased insulin sensitivity. To explore the pathophysiological and therapeutic roles of leptin in lipoatrophic diabetes, we crossed LepTg/+ and A-ZIPTg/+ mice, producing doubly transgenic mice (LepTg/+:A-ZIPTg/+) virtually lacking adipose tissue but having greatly elevated leptin levels. The LepTg/+:A-ZIPTg/+ mice were hypophagic and showed improved hepatic steatosis. Glucose and insulin tolerance tests revealed increased insulin sensitivity, comparable to LepTg/+ mice. These effects were stable over at least 6 months of age. Pair-feeding the A-ZIPTg/+ mice to the amount of food consumed by LepTg/+:A-ZIPTg/+ mice did not improve their insulin resistance, diabetes, or hepatic steatosis, demonstrating that the beneficial effects of leptin were not due to the decreased food intake. Continuous leptin administration that elevates plasma leptin concentrations to those of LepTg/+:A-ZIPTg/+ mice also effectively improved hepatic steatosis and the disorder of glucose and lipid metabolism in A-ZIP/F-1 mice. These data demonstrate that leptin can improve the insulin resistance and diabetes of a mouse model of severe lipoatrophic diabetes, suggesting that leptin may be therapeutically useful in the long-term treatment of lipoatrophic diabetes.

Animals↗
PubMed2001

[Pathology and significance of leptin resistance in obesity].

Leptin, the protein product of the ob gene, is predominantly secreted from white adipose tissue, and acts on the brain to regulate food intake, energy expenditure, and neuroendocrine function. Obese rodent and humans are mostly associated with high circulating leptin levels. These findings have led to the conclusion that obese individuals are relatively insensitive to endogenous leptin termed 'leptin resistance'. The potential sites for leptin resistance include the blood-brain-barrier transport system and the leptin signaling mechanism in leptin-responsive neurons in the hypothalamus. In this review, we describe leptin, leptin receptor, and potential hypothesis of leptin resistance.

Animals↗
PubMed2001

[Human obesity and point mutations of leptin and leptin receptor].

Obesity-related genes were isolated and identified in these several years. Development of transgenic mice has clarified the molecular mechanisms of obesity. There have been reported point mutations of the genes correspond to leptin(ob-gene) and leptin receptor(db-gene). Thereby leptin is considered to be one of the most important regulators of energy metabolism also in human.

Animals↗
PubMed2001

[Minocycline-induced pneumonitis presenting as multiple ring-shaped opacities on chest CT, pathologically diagnosed bronchiolitis obliterans organizing pneumonia (BOOP)].

A 39-year old woman was admitted to our hospital because of cough and abnormal shadows on chest radiographs. She had been treated for 5 months for acne vulgaris with minocycline hydrochloride (MINO). Chest computed tomographic (CT) scans showed multiple ring-shaped opacities in both lungs. Bronchoalveolar lavage disclosed an increase in the total number of cells and a marked increase of lymphocytes. A lung specimen obtained by transbronchial lung biopsy (TBLB) was pathologically diagnosed as bronchiolitis obliterans organizing pneumonia (BOOP). Withdrawal of minocycline led to rapid remission without treatment. The clinical course and histological findings for TBLB suggested that this case was minocycline-induced BOOP. Several cases with minocycline-induced pneumonitis have been reported. However, there are few reported cases of minocycline-induced BOOP, the present case being only the second found in the literature.

Adult↗
PubMed2001

Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart.

In addition to cardiac myocyte hypertrophy, proliferation and increased extracellular matrix production of cardiac fibroblasts occur in response to cardiac overload. This remodeling of the cardiac interstitium is a major determinant of pathologic hypertrophy leading to ventricular dysfunction and heart failure. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones produced primarily by the atrium and ventricle, respectively. Plasma ANP and BNP concentrations are elevated in patients with hypertension, cardiac hypertrophy, and acute myocardial infarction, suggesting their pathophysiologic roles in these disorders. ANP and BNP exhibit diuretic, natriuretic, and vasodilatory activities via a guanylyl cyclase-coupled natriuretic peptide receptor subtype (guanylyl cyclase-A or GC-A). Here we report the generation of mice with targeted disruption of BNP (BNP-/- mice). We observed focal fibrotic lesions in ventricles from BNP-/- mice with a remarkable increase in ventricular mRNA expression of ANP, angiotensin converting enzyme (ACE), transforming growth factor (TGF)-beta3, and pro-alpha1(I) collagen [Col alpha1(I)], which are implicated in the generation and progression of ventricular fibrosis. Electron microscopic examination revealed supercontraction of sarcomeres and disorganized myofibrils in some ventricular myocytes from BNP-/- mice. No signs of cardiac hypertrophy and systemic hypertension were noted in BNP-/- mice. In response to acute cardiac pressure overload induced by aortic constriction, massive fibrotic lesions were found in all the BNP-/- mice examined, accompanied by further increase of mRNA expression of TGF-beta3 and Col alpha1(I). We postulate that BNP acts as a cardiocyte-derived antifibrotic factor in the ventricle.

Alleles↗
PubMed2001

[Novel actions of HMG-CoA reductase inhibitors(statins)--vascular and cerebral protection through inhibition of small GTPase Rho].

Clinical trials have demonstrated the beneficial effect of HMG-CoA reductase inhibitors(statins) for stroke prevention, independent of their lipid-lowering effects. Recent experimental progress indicated the effects of statins for brain protection on both vascular walls(endothelium, smooth muscle, inflammatory cells and platelets) and extra-vascular tissues(brain parenchyma). These pleiotropic effects of statins have been, at least in part, ascribed to inhibition of small GTPases Rho and Ras, which require isoprenoids (intermediates of the cholesterol biosynthesis pathway) for activation. Importantly, statin inhibition of Rho (1) attenuates the infarct size in a rat model of brain ischemia via the elevation of eNOS expression, and (2) suppresses vascular smooth muscle proliferation through up-regulation of CDK inhibitor p27kip1. The novel action of statin, as inhibitor of small GTPase family, should expand its potential toward integrative organ protection, beyond its conventional lipid-lowering and anti-atherogenic effects.

Animals↗
PubMed2000

The heart is a source of circulating cardiotrophin-1 in humans.

Cardiotrophin-1 (CT-1) is a new member of the interleukin (IL)-6 family of cytokines and one of the endogenous ligands for gp130 signaling pathways in the heart, which has potent hypertrophic and survival effects on cardiac myocytes. However, the clinical significance of CT-1 is poorly understood, mainly because there is no widely applicable specific and sensitive assay system for measuring plasma levels of circulating CT-1. We therefore developed a competitive radioimmunoassay (RIA) for human CT-1 with rabbit antiserum recognizing the N-terminus region of human CT-1 and using recombinant human CT-1 as a calibrator. The assay displays no cross-reactivities with any of the IL-6 family of cytokines including IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. The lower detection limit in buffer was found to be 43 fmol/ml, and the working range was 120-8300 fmol/ml (CV < 15%). This RIA directly recognizes CT-1-like immunoreactivity in human plasma with a mean value of 571 +/- 75 fmol/ml (mean +/- SD) in healthy volunteers. The RIA coupled with gel filtration chromatographic analyses showed that the major molecular form of circulating CT-1 corresponds to recombinant full-length human CT-1. Moreover, there is a significant increase in the plasma CT-1 concentration from the aorta and coronary sinus, which clearly indicates that the heart secretes CT-1 via the coronary sinus into the peripheral circulation. This RIA should serve as a powerful tool for investigating the clinical significance of CT-1.

Adult↗
PubMed2000

Kidney produces a novel acylated peptide, ghrelin.

Ghrelin is a novel growth hormone-releasing peptide with a unique acylated structure. Here we reveal that prepro-ghrelin gene is expressed in the mouse kidney and glomerulus. We also show by reverse-phase high performance liquid chromatography coupled with radioimmunoassay that the mouse kidney does produce ghrelin. The ghrelin immunoreactivity in the mouse kidney is 6.79+/-0.48 fmol/mg (n=5), which is much more abundant than that in the mouse plasma of 0.339+/-0.029 fmol/microl (n=6). Furthermore, prepro-ghrelin gene is expressed in cultured rat mesangial cells, fibroblast-like NRK-49F cells and mouse podocytes, but not in rat epithelial cell-like NRK-52E cells. Ghrelin receptor gene is also expressed in the rat kidney. These findings demonstrate that the kidney, glomerulus and renal cells express prepro-ghrelin gene and ghrelin is produced locally in the kidney, and suggest the endocrine and/or paracrine roles of ghrelin in the kidney.

Acylation↗
PubMed2000

Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor contact.

T cell differentiation in the thymus is driven by positive selection through the interaction of alphabeta T cell receptors (TCRs) with self-peptides bound to self-major histocompatibility complex molecules, yet the influence of the peptide sequence on this process remains unknown. To address this issue, we have compared CD4(+) T cell differentiation between two sets of mouse lines in which MHC class II I-A(b) molecules are occupied with either Ealpha chain-derived peptide ((p)Ealpha) or its variant, (p)60K, with one amino acid substitution from leucine to lysine at P5 residue of TCR contacts. Here, we show that despite the comparable expression of I-A(b)-peptide complex in the thymus, this substitution from leucine to lysine affects efficiency of positive selection, resulting in extremely small numbers of CD4(+) T cells to be selected to mature on I-A(b)-(p)60K complex. Furthermore, we show that, although I-A(b)-(p)Ealpha complex selects diverse T cells, T cell repertoire shaped by I-A(b)-(p)60K complex is markedly constrained. Our findings thus suggest that positive selection is both specific and degenerate, depending on the amino acid residues at TCR contacts of the selecting self-peptides.

Amino Acid Sequence↗