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Biomedical subjects

Yasuo Terauchi

Publications and source records attributed to Yasuo Terauchi.

At least 37 records · Page 2Linked to original sources
PubMed2005

Serum ferritin is associated with visceral fat area and subcutaneous fat area.

OBJECTIVE: Until now, few clinical studies have reported on the association between the indexes of body fat distribution and serum ferritin, an indicator of body iron stores and a putative risk factor for insulin resistance. We investigated the association between serum ferritin concentrations and the indexes of distribution of adipose tissues in the body, such as the visceral fat area (VFA), the subcutaneous fat area (SFA), and the hepatic fat content in Japanese subjects. RESEARCH DESIGN AND METHODS: A total of 248 Japanese subjects (127 men and 121 postmenopausal women aged 57.8 +/- 13.9 years, BMI 25.7 +/- 4.6 kg/m2; 140 subjects with type 2 diabetes and 108 nondiabetic subjects) were evaluated. Subjects with a history of alcohol intake were excluded from the study. We measured body height, body weight, and serum ferritin, as well as fasting plasma glucose and plasma insulin concentrations. We estimated insulin resistance by homeostasis model assessment. The fat distribution was evaluated by measuring the VFA and SFA by abdominal computed tomography at the umbilical level. To assess the hepatic fat content, the ratio of the computed tomography attenuation value of the liver to that of the spleen was calculated. RESULTS: Serum ferritin was significantly correlated with the various indexes of adiposity examined, such as the hepatic fat content (r = -0.280, P < 0.0001), VFA (r = 0.254, P < 0.0001), SFA (r = 0.231, P = 0.0005), and homeostasis model assessment (r = 0.286, P = 0.0008). CONCLUSIONS: This is the first report to directly demonstrate an association between serum ferritin and VFA and SFA. The results of this study suggest that the serum ferritin concentration may be a useful indicator of systemic fat content and degree of insulin resistance.

Adult↗
PubMed2005

[PPAR and diabetes].

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play crucial roles in metabolic diseases such as hyperlipidemia, insulin resistance, and diabetes. The three PPAR subtypes, alpha, gamma, and delta, have distinct expression patterns and regulate glucose homeostasis based on the need of a specific tissue. While PPARalpha potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-lowering fibrates, PPARgamma is essential for adipocyte differentiation and hypertrophy, and mediates the activity of the insulin sensitizing thiazolidinediones. PPARdelta may be important in regulating body weight and lipid metabolism in fat tissues. Thus, uncovering the regulatory mechanisms and transcriptional targets of these PPARs will provide insights into the pathogenesis of metabolic diseases and offer valuable information for rational drug design.

Animals↗
PubMed2005

The role of phosphoinositide-3-kinase in mast cell homing to the gastrointestinal tract.

Phosphoinositide-3-kinases (PI3Ks) are a family of lipid kinases essential in a variety of physiological reactions. A series of gene-targeted mice lacking different PI3Ks and related molecules has enabled us to understand their in vivo roles, particularly those of class IA members. Studies on knockout mice lacking class IA PI3Ks and knock-in mice expressing mutant forms of enzymes have revealed the importance of this class of PI3Ks in mast cell development in the gastrointestinal tract. Here we studied the role of the p85a regulatory subunit, the most abundantly expressed regulatory subunit of class IA PI3Ks, using p85a knockout mice. Development of mast cells in the gastrointestinal tract but not in the skin was severely impaired in mice lacking the p85a regulatory subunit. Stem cell factor (SCF)-mediated signalling functions including proliferative response and chemotactic activities were both impaired in p85a knockout mast cells, likely due to the mast cell deficiency. Mastocytosis upon Strongyloides veneZuelensis infection was also impaired in p85alpha knockout mice. Reconstitution with Th2-conditioned but not untreated bone marrow-derived mast cells (BMMCs) restored anti-bacterial immunity, indicating the importance of Th2 response in addition to the recruitment of mast cells in the control of nematode infection.

Animals↗
PubMed2004

Expression of DGAT2 in white adipose tissue is regulated by central leptin action.

Acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes catalyze the final step in mammalian triglyceride synthesis, and their functions are considered to be involved in the mechanisms of obesity, insulin resistance, and leptin resistance. Insulin receptor substrate-2 (IRS-2)-deficient mice exhibit obesity-associated with hypertrophic adipocytes and leptin resistance. Screening for transcripts of genes involved in fatty acid and triglyceride synthesis to investigate the mechanism of the hypertrophic change in the adipocytes showed that expression of DGAT2 mRNA was up-regulated in the white adipose tissue (WAT) of Irs2-/- mice, whereas that of DGAT1 was down-regulated. This reciprocal expression of DGAT1 and DGAT2 was also observed in WAT of leptin-deficient ob/ob mice. A high fat diet also resulted in increased DGAT2 and reduced DGAT1 in the WAT of C57BL/6 mice. Induction of adipocyte hypertrophy in vitro up-regulated both DGAT1 and DGAT2 expression in 3T3-L1 cells, suggesting that adipocyte non-autonomous mechanism in vivo is required for the reciprocal changes in expression of DGAT1 and DGAT2. In fact, intracerebroventricular infusion of leptin reduced DGAT2 expression in WAT of Irs2-/- mice and ob/ob mice, independently of DGAT1 expression. We propose the hypothesis that leptin regulates adipocyte size by altering expression patterns of DGAT via central nervous system to determine the levels of triglyceride synthesis.

3T3-L1 Cells↗
PubMed2004

Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity.

Adiponectin/Acrp30 is a hormone secreted by adipocytes, which acts as an antidiabetic and antiatherogenic adipokine. We reported previously that AdipoR1 and -R2 serve as receptors for adiponectin and mediate increased fatty acid oxidation and glucose uptake by adiponectin. In the present study, we examined the expression levels and roles of AdipoR1/R2 in several physiological and pathophysiological states such as fasting/refeeding, obesity, and insulin resistance. Here we show that the expression of AdipoR1/R2 in insulin target organs, such as skeletal muscle and liver, is significantly increased in fasted mice and decreased in refed mice. Insulin deficiency induced by streptozotocin increased and insulin replenishment reduced the expression of AdipoR1/R2 in vivo. Thus, the expression of AdipoR1/R2 appears to be inversely correlated with plasma insulin levels in vivo. Interestingly, the incubation of hepatocytes or myocytes with insulin reduced the expression of AdipoR1/R2 via the phosphoinositide 3-kinase/Foxo1-dependent pathway in vitro. Moreover, the expressions of AdipoR1/R2 in ob/ob mice were significantly decreased in skeletal muscle and adipose tissue, which was correlated with decreased adiponectin binding to membrane fractions of skeletal muscle and decreased AMP kinase activation by adiponectin. This adiponectin resistance in turn may play a role in worsening insulin resistance in ob/ob mice. In conclusion, the expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyper-insulinemia models via the insulin/phosphoinositide 3-kinase/Foxo1 pathway and is correlated with adiponectin sensitivity.

Adenoviridae↗
PubMed2004

A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program.

Mutant mouse models are indispensable tools for clarifying the functions of genes and for elucidating the underlying pathogenic mechanisms of human diseases. Currently, several large-scale mutagenesis projects that employ the chemical mutagen N-ethyl-N-nitrosourea (ENU) are underway worldwide. One specific aim of our ENU mutagenesis project is to generate diabetic mouse models. We screened 9375 animals for dominant traits using a clinical biochemical test and thereby identified 11 mutations in the glucokinase (Gk) gene that were associated with hyperglycemia. GK is a key regulator of insulin secretion in the pancreatic beta-cell. Approximately 190 heterozygous mutations in the human GK gene have been reported to cause maturity onset diabetes of the young, type 2 (MODY2). In addition, five mutations have been reported to cause permanent neonatal diabetes mellitus (PNDM) when present on both alleles. The mutations in our 11 hyperglycemic mutants are located at different positions in Gk. Four have also been found in human MODY2 patients, and another mutant bears its mutation at the same location that is mutated in a PNDM patient. Thus, ENU mutagenesis is effective for developing mouse models for various human genetic diseases, including diabetes mellitus. Some of our Gk mutant lines displayed impaired glucose-responsive insulin secretion and the mutations had different effects on Gk mRNA levels and/or the stability of the GK protein. This collection of Gk mutants will be valuable for understanding GK gene function, for dissecting the function of the enzyme and as models of human MODY2 and PNDM.

Amino Acid Sequence↗
PubMed2004

Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2(-/-) mice.

We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice develop diabetes as a result of insulin resistance in the liver and failure of beta-cell hyperplasia. In this study we introduced the IRS-2 gene specifically into the liver of Irs2(-/-) mice with adenovirus vectors. Glucose tolerance tests revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia, but the improvement in hyperinsulinemia was only partial. Endogenous glucose production (EGP) and the rate of glucose disappearance (Rd) were measured during hyperinsulinemic-euglycemic clamp studies: EGP was increased 2-fold in the Irs2(-/-) mice, while Rd decreased by 50%. Restoration of IRS-2 in the liver suppressed EGP to a level similar to that in wild-type mice, but Rd remained decreased in the Adeno-IRS-2-infected Irs2(-/-) mice. Irs2(-/-) mice also exhibit obesity and hyperleptinemia associated with impairment of hypothalamic phosphatidylinositol 3-kinase activation. Continuous intracerebroventricular leptin infusion or caloric restriction yielded Irs2(-/-) mice whose adiposity was comparable to that of Irs2(+/+) mice, and both the hyperglycemia and the hyperinsulinemia of these mice improved with increased Rd albeit partially. Finally combination treatment consisting of adenovirus-mediated gene transfer of IRS-2 and continuous intracerebroventricular leptin infusion completely reversed the hyperglycemia and hyperinsulinemia in Irs2(-/-) mice. EGP and Rd also became normal in these mice as well as in mice treated by caloric restriction plus adenoviral gene transfer. We therefore concluded that a combination of increased EGP due to insulin signaling defects in the liver and reduced Rd due to obesity accounts for the systemic insulin resistance in Irs2(-/-) mice.

Adenoviridae↗
PubMed2004

Impairment of bone healing by insulin receptor substrate-1 deficiency.

Insulin receptor substrate-1 (IRS-1) is an essential molecule for intracellular signaling of insulin-like growth factor (IGF)-I and insulin, both of which are potent anabolic regulators of bone and cartilage metabolism. To investigate the role of IRS-1 in bone regeneration, fracture was introduced in the tibia, and its healing was compared between wild-type (WT) mice and mice lacking the IRS-1 gene (IRS-1(-/-) mice). Among 15 IRS-1(-/-) mice, 12 remained in a non-union state even at 10 weeks after the operation, whereas all 15 WT mice showed a rigid bone union at 3 weeks. This impairment was because of the suppression of callus formation with a decrease in chondrocyte proliferation and increases in hypertrophic differentiation and apoptosis. Reintroduction of IRS-1 to the IRS-1(-/-) fractured site using an adenovirus vector significantly restored the callus formation. In the culture of chondrocytes isolated from the mouse growth plate, IRS-1(-/-) chondrocytes showed less mitogenic ability and Akt phosphorylation than WT chondrocytes. An Akt inhibitor decreased the IGF-I-stimulated DNA synthesis of chondrocytes more potently in the WT culture than in the IRS-1(-/-) culture. We therefore conclude that IRS-1 deficiency impairs bone healing at least partly by inhibiting chondrocyte proliferation through the phosphatidylinositol 3-kinase/Akt pathway, and we propose that IRS-1 can be a target molecule for bone regenerative medicine.

Adenoviridae↗
PubMed2004

Protective effect of endogenous PPARgamma against acute gastric mucosal lesions associated with ischemia-reperfusion.

Acute gastric mucosal lesions (AGMLs) are an important cause of gastrointestinal bleeding. Herein, we demonstrate that peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of a nuclear receptor family, functions as an endogenous anti-inflammatory pathway in a murine model of AGML induced by ischemia-reperfusion (I/R). Treatment with specific PPARgamma ligands such as BRL-49653, pioglitazone, or troglitazone was examined in a model of AGML induced by I/R. PPARgamma-deficient and wild-type mice were also examined for their response to I/R in stomach. Specific PPARgamma ligands exhibited dramatic and rapid protection against AGML formation associated with I/R in mice in a dose-dependent manner. In contrast, the AGML induced by I/R in PPARgamma-deficient mice was more severe than that observed in wild-type mice. Administration of the PPARgamma ligand significantly inhibited the upregulation of TNF-alpha, ICAM-1, inducible nitric oxide synthase, apoptosis, and nitrotyrosine formation induced by I/R in the stomach. These data indicate that an endogenous pathway associated with PPARgamma plays an important role in the pathogenesis of I/R-associated injury in the stomach.

Animals↗
PubMed2004

PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors.

Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARgamma, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARgamma-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARgamma gene. Heterozygous PPARgamma-deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARgamma haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARgamma haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARgamma-dependent regulation of bone metabolism in vivo, in that PPARgamma insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.

Animals↗
PubMed2004

Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus.

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity.

Animals↗
PubMed2004

Deficiency of insulin receptor substrate-1 impairs skeletal growth through early closure of epiphyseal cartilage.

UNLABELLED: Morphological analyses in and around the epiphyseal cartilage of mice deficient in insulin receptor substrate-1 (IRS-1) showed IRS-1 signaling to be important for skeletal growth by preventing early closure of the epiphyseal cartilage and maintaining the subsequent bone turnover at the primary spongiosa. INTRODUCTION: IRS-1 is an essential molecule for intracellular signaling by IGF-I and insulin, both of which are potent anabolic regulators of cartilage and bone metabolism. To clarify the role of IRS-1 signaling in the skeletal growth, morphological analyses were performed in and around the epiphyseal cartilage of mice deficient in IRS-1 (IRS-1(-/-)), whose limbs and trunk were 20-30% shorter than wildtype (WT) mice. MATERIALS AND METHODS: The epiphyseal cartilage and the primary spongiosa at proximal tibias of homozygous IRS-1(-/-) and WT male littermates were compared using histological, immunohistochemical, enzyme cytohistochemical, ultrastructural, and bone histomorphometrical analyses. RESULTS: In and around the WT epiphyseal cartilage, IRS-1 and insulin-like growth factor (IGF)-1 receptors were widely expressed, whereas IRS-2 was weakly localized in bone cells. Chronological observation revealed that height of the proliferative zone and the size of hypertrophic chondrocytes were decreased in WT mice as a function of age, and these decreases were accelerated in the IRS-1 (-/-) cartilage, whose findings at 12 weeks were similar to those of WT at 24 weeks. In the IRS-1(-/-) cartilage, proliferating chondrocytes with positive proliferating cell nuclear antigen (PCNA) or parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor immunostaining had almost disappeared by 12 weeks. Contrarily, TUNEL+ apoptotic cells were increased in the hypertrophic zone, at the bottom of which most of the chondrocytes were surrounded by the calcified matrix, suggesting the closure of the cartilage. In the primary spongiosa, bone volume, alkaline phosphatase (ALP)+ osteoblasts, TRACP+ osteoclasts, and the osteopontin-positive cement line were markedly decreased. Bone histomorphometrical parameters for both bone formation and resorption were significantly lower in IRS-1(-/-) mice, indicating the suppression of bone turnover. CONCLUSION: The IRS-1(-/-) epiphyseal cartilage exhibited insufficient proliferation of chondrocytes, calcification of hypertrophic chondrocytes, acceleration of apoptosis, and early closure of the growth plate. Thus, the data strongly suggest that IRS-1 signaling is important for the skeletal growth by preventing early closure of the epiphyseal cartilage and by maintaining the subsequent bone turnover at the primary spongiosa.

Animals↗
PubMed2004

Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-gamma-deficient mice on a high-fat diet.

Heterozygous peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient (PPARgamma(+/-)) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction of PPAR-gamma activity on beta-cell function, we investigated insulin secretion in PPARgamma(+/-) mice on a high-fat diet. Glucose-induced insulin secretion in PPARgamma(+/-) mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARgamma(+/-) mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-gamma agonist, pioglitazone, reduced the islet TG content in PPARgamma(+/-) mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-gamma protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-gamma agonist can restore impaired insulin secretion under conditions of islet fat accumulation.

Animals↗
PubMed2004

Increased serum leptin protects from adiposity despite the increased glucose uptake in white adipose tissue in mice lacking p85alpha phosphoinositide 3-kinase.

Mice lacking the p85alpha regulatory subunit of phosphoinositide (PI) 3-kinase (Pik3r1(-/-)) showed increased glucose uptake in white adipose tissue (WAT) and skeletal muscle due to increased phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] production and on a normal diet had a body weight and fat mass similar to wild-type mice. After 3 months on a high-fat diet, Pik3r1(-/-) mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice. On the normal diet, serum leptin levels of Pik3r1(-/-) mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes. Leptin (5 microg/g body wt per day) caused a reduction in food intake and decrease in body weight by the wild-type mice as well as Pik3r1(-/-) mice, suggesting Pik3r1(-/-) mice having leptin sensitivity similar to wild-type mice. The slightly increased serum leptin compensated for the increased glucose uptake by adipocytes in Pik3r1(-/-) mice, thereby preventing adiposity on the normal diet. On the high-fat diet, leptin (5 microg/g body wt per day) failed to decrease food intake or body weight in either genotype, indicating that both genotypes had indeed become severely leptin resistant. Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r1(-/-) mice. Our findings suggest that primary increase in serum leptin on the normal diet play a role in the protection from adiposity in Pik3r1(-/-) mice.

Adipocytes↗
PubMed2003

ATP-sensitive K+ channel-mediated glucose uptake is independent of IRS-1/phosphatidylinositol 3-kinase signaling.

We previously found that disruption of Kir6.2-containing ATP-sensitive K+ (KATP) channels increases glucose uptake in skeletal muscle, but the mechanism is not clear. In the present study, we generated knockout mice lacking both Kir6.2 and insulin receptor substrate-1 (IRS-1). Because IRS-1 is the major substrate of insulin receptor kinase, we expected disruption of the IRS-1 gene to reduce glucose uptake in Kir6.2 knockout mice. However, the double-knockout mice do not develop insulin resistance or glucose intolerance. An insulin tolerance test reveals the glucose-lowering effect of exogenous insulin in double-knockout mice and in Kir6.2 knockout mice to be similarly enhanced compared with wild-type mice. The basal 2-deoxyglucose uptake rate in skeletal muscle of double-knockout mice is increased similarly to the rate in Kir6.2 knockout mice. Accordingly, disruption of the IRS-1 gene affects neither systemic insulin sensitivity nor glucose uptake in skeletal muscles of Kir6.2-deficient mice. In addition, no significant changes were observed in phosphatidylinositol 3-kinase (PI3K) activity and its downstream signal in skeletal muscle due to lack of the Kir6.2 gene. Disruption of Kir6.2-containing Katp channels clearly protects against IRS-1-associated insulin resistance by increasing glucose uptake in skeletal muscles by a mechanism separate from the IRS-1/PI3K pathway.

Adenosine Triphosphate↗