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Sohei Tsukita,
Tetsuya Yamada, Kenji Uno,
Kei Takahashi,
Keizo Kaneko,
Yasushi Ishigaki,
Junta Imai,
Yutaka Hasegawa,
Shojiro Sawada,
Hisamitsu Ishihara,
Yoshitomo Oka,
Hideki Katagiri
[show abstract]
[hide abstract]
ABSTRACT: Considering the explosive increase in obesity worldwide, there must be an unknown mechanism(s) promoting energy accumulation under conditions of overnutrition. We identified a feed-forward mechanism favoring energy storage, originating in hepatic glucokinase (GK) upregulation. High-fat feeding induced hepatic GK upregulation, and hepatic GK overexpression dose-dependently decreased adaptive thermogenesis by downregulating thermogenesis-related genes in brown adipose tissue (BAT). This intertissue (liver-to-BAT) system consists of the afferent vagus from the liver and sympathetic efferents from the medulla and antagonizes anti-obesity effects of leptin on thermogenesis. Furthermore, upregulation of endogenous GK in the liver by high-fat feeding was more marked in obesity-prone than in obesity-resistant strains and was inversely associated with BAT thermogenesis. Hepatic GK overexpression in obesity-resistant mice promoted weight gain, while hepatic GK knockdown in obesity-prone mice attenuated weight gain with increased adaptive thermogenesis. Thus, this intertissue energy-saving system may contribute to determining obesity predisposition.
Cell metabolism 12/2012; 16(6):825-32. · 17.35 Impact Factor
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Kei Takahashi,
Tetsuya Yamada,
Sohei Tsukita,
Keizo Kaneko,
Yuta Shirai,
Yuichiro Munakata,
Yasushi Ishigaki,
Junta Imai, Kenji Uno,
Yutaka Hasegawa,
Shojiro Sawada,
Yoshitomo Oka,
Hideki Katagiri
[show abstract]
[hide abstract]
ABSTRACT: Chronic stress is well known to affect metabolic regulation. However, molecular mechanisms interconnecting stress response systems and metabolic regulations have yet to be elucidated. Various physiological processes, including glucose/lipid metabolism, are regulated by the circadian clock, and core clock gene dysregulation reportedly leads to metabolic disorders. Glucocorticoids, acting as end-effectors of the hypothalamus-pituitary-adrenal (HPA) axis, entrain the circadian rhythms of peripheral organs, including the liver, by phase-shifting core clock gene expressions. Therefore, we examined whether chronic stress affects circadian expressions of core clock genes and metabolism-related genes in the liver using the chronic mild stress (CMS) procedure. In BALB/c mice, CMS elevated and phase-shifted serum corticosterone levels, indicating overactivation of the HPA axis. The rhythmic expressions of core clock genes, e.g. Clock, Npas2, Bmal1, Per1 and Cry1, were altered in the liver, while being completely preserved in the hypothalamic suprachiasmatic nuculeus (SCN), suggesting that the SCN is not involved in alterations in hepatic core clock gene expressions. In addition, circadian patterns of glucose and lipid metabolism-related genes, e.g. peroxisome proliferator activated receptor α(Pparα), Pparγ-1, Pparγ-coactivator-1α and phosphoenolepyruvate carboxykinase, were also disturbed by CMS. In contrast, in C57BL/6 mice, the same CMS procedure altered neither serum corticosterone levels nor rhythmic expressions of hepatic core clock genes and metabolism-related genes. Thus, chronic stress can interfere with the circadian expressions of both core clock genes and metabolism-related genes in the liver possibly involving HPA axis overactivation. This mechanism might contribute to metabolic disorders in stressful modern societies.
AJP Endocrinology and Metabolism 12/2012; · 4.75 Impact Factor
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Tokuo Saito,
Yutaka Hasegawa,
Yasushi Ishigaki,
Tetsuya Yamada,
Junhong Gao,
Junta Imai, Kenji Uno,
Keizo Kaneko,
Takehide Ogihara,
Tatsuo Shimosawa,
Tomoichiro Asano,
Toshiro Fujita,
Yoshitomo Oka,
Hideki Katagiri
[show abstract]
[hide abstract]
ABSTRACT: AIMS: Vascular remodelling and aortic aneurysm formation are induced mainly by inflammatory responses in the adventitia and media. However, relatively little is known about the mechanistic significance of endothelium in the pathogenesis of these vascular disorders. The transcription factor nuclear factor-kappa B (NF-κB) regulates the expressions of numerous genes, including those related to pro-inflammatory responses. Therefore, to investigate the roles of endothelial pro-inflammatory responses, we examined the impact of blocking endothelial NF-κB signalling on intimal hyperplasia and aneurysm formation. METHODS AND RESULTS: To block endothelial NF-κB signalling, we used transgenic mice expressing dominant-negative IκBα selectively in endothelial cells (E-DNIκB mice). E-DNIκB mice were protected from the development of cuff injury-induced neointimal formation, in association with suppressed arterial expressions of cellular adhesion molecules, a macrophage marker, and inflammatory factors. In addition, the blockade of endothelial NF-κB signalling prevented abdominal aortic aneurysm formation in an experimental model, hypercholesterolaemic apolipoprotein E-deficient mice with angiotensin II infusion. In this aneurysm model as well, aortic expressions of an adhesion molecule, a macrophage marker, and inflammatory factors were suppressed with the inhibited expression and activity of matrix metalloproteinases in the aorta. CONCLUSION: Endothelial NF-κB activation up-regulates adhesion molecule expression, which may trigger macrophage infiltration and inflammation in the adventitia and media. Thus, the endothelium plays important roles in vascular remodelling and aneurysm formation through its intracellular NF-κB signalling.
Cardiovascular research 09/2012; · 5.80 Impact Factor
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Yutaka Hasegawa,
Tokuo Saito,
Takehide Ogihara,
Yasushi Ishigaki,
Tetsuya Yamada,
Junta Imai, Kenji Uno,
Junhong Gao,
Keizo Kaneko,
Tatsuo Shimosawa,
Tomoichiro Asano,
Toshiro Fujita,
Yoshitomo Oka,
Hideki Katagiri
[show abstract]
[hide abstract]
ABSTRACT: Nuclear factor-κB (NF-κB) signaling plays critical roles in physiological and pathological processes such as responses to inflammation and oxidative stress.
To examine the role of endothelial NF-κB signaling in vivo, we generated transgenic mice expressing dominant-negative IκB under the Tie2 promoter/enhancer (E-DNIκB mice). These mice exhibited functional inhibition of NF-κB signaling specifically in endothelial cells. Although E-DNIκB mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet- or genetics-induced. Obesity-induced macrophage infiltration into adipose tissue and plasma oxidative stress markers were decreased and blood flow and mitochondrial content in muscle and active-phase locomotor activity were increased in E-DNIκB mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-κB signaling prevented age-related insulin resistance and vascular senescence and, notably, prolonged life span. These antiaging phenotypes were also associated with decreased oxidative stress markers, increased muscle blood flow, enhanced active-phase locomotor activity, and aortic upregulation of mitochondrial sirtuin-related proteins.
The endothelium plays important roles in obesity- and age-related disorders through intracellular NF-κB signaling, thereby ultimately affecting life span. Endothelial NF-κB signaling is a potential target for treating the metabolic syndrome and for antiaging strategies.
Circulation 03/2012; 125(9):1122-33. · 14.74 Impact Factor
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Junhong Gao,
Yasushi Ishigaki,
Tetsuya Yamada,
Keiichi Kondo,
Suguru Yamaguchi,
Junta Imai, Kenji Uno,
Yutaka Hasegawa,
Shojiro Sawada,
Hisamitsu Ishihara,
Seiichi Oyadomari,
Masataka Mori,
Yoshitomo Oka,
Hideki Katagiri
[show abstract]
[hide abstract]
ABSTRACT: The processes of arteriosclerosis, including atherosclerosis and vascular remodeling, are affected by interactions among numerous biological pathways such as responses to inflammation, oxidative stress, and endoplasmic reticulum stress. C/EBP homologous protein (CHOP), which is well known to induce cellular apoptosis in response to severe endoplasmic reticulum stress, is reportedly upregulated in plaque lesions.
We examined the effects of CHOP deficiency on 2 types of arteriosclerosis: cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerosis. Cuff injury-induced neointimal formation was markedly inhibited in CHOP(-/-) mice with suppressed aortic expression of inflammatory factors and smooth muscle cell proliferation-related proteins. A CHOP deficiency also inhibited aortic plaque formation in hypercholesterolemic apolipoprotein E(-/-) mice with suppressed aortic expression of inflammatory factors and oxidative stress markers. Bone marrow transplantation experiments revealed that recipient CHOP deficiency significantly suppressed both cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerotic plaque formation to a greater extent than donor CHOP deficiency, suggesting the importance of CHOP in vascular cells for arteriosclerosis progression. Furthermore, in our in vitro experiments, in not only macrophages but also endothelial and smooth muscle cell lines, endoplasmic reticulum stress inducers upregulated inflammation-, adhesion-, or smooth muscle cell proliferation-related proteins, whereas decreased CHOP expression remarkably suppressed endoplasmic reticulum stress-induced upregulation of these proteins.
In addition to the well-known signaling for apoptosis induction, CHOP may play important roles in augmenting potentially pathological biological stress responses. This noncanonical role of CHOP, especially that expressed in vascular cells, may contribute to the progression of vascular remodeling and atherosclerosis.
Circulation 08/2011; 124(7):830-9. · 14.74 Impact Factor
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Kenji Uno,
Tetsuya Yamada,
Yasushi Ishigaki,
Junta Imai,
Yutaka Hasegawa,
Junhong Gao,
Keizo Kaneko,
Kimihiko Matsusue,
Tomomi Yamazaki,
Yoshitomo Oka,
Hideki Katagiri
[show abstract]
[hide abstract]
ABSTRACT: Obesity is commonly associated with hypertension. Increased sympathetic tonus in obese subjects contributes to the underlying mechanism. However, the precise mechanisms whereby obesity induces this sympathetic activation remain unclear. Hepatic peroxisome proliferator-activated receptor (PPAR)-γ2 expression, which is reportedly upregulated during obesity development, affects sympathetic activation via hepatic vagal afferents. Herein, we report involvement of this neuronal relay in obesity-related hypertension.
Peroxisome proliferator-activated receptor-γ and a direct PPARγ target, fat-specific protein 27 (Fsp27), were adenovirally overexpressed or knocked down in the liver, in combination with surgical dissection or pharmacological deafferentation of the hepatic vagus. Adenoviral PPARγ2 expression in the liver raised blood pressure (BP) in wild-type but not in β1/β2/β3 adrenergic receptor-deficient mice. In addition, knockdown of endogenous PPARγ in the liver lowered BP in murine obesity models. Either surgical dissection or pharmacological deafferentation of the hepatic vagus markedly blunted BP elevation in mice with diet-induced and genetically-induced obesity. In contrast, BP was not elevated in other models of hepatic steatosis, DGAT1 and DGAT2 overexpressions, in which PPARγ is not upregulated in the liver. Thus, hepatic PPARγ upregulation associated with obesity is involved in BP elevation during obesity development. Furthermore, hepatic expression of Fsp27 raised BP and the effect was blocked by hepatic vagotomy. Hepatic Fsp27 is actually upregulated in murine obesity models and its knockdown reversed BP elevation.
The hepatic PPARγ-Fsp27 pathway plays important roles in the development of obesity-related hypertension via afferent vagal signals from the liver.
European Heart Journal 08/2011; 33(10):1279-89. · 10.48 Impact Factor
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[show abstract]
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ABSTRACT: Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic β-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic β-cell functions both in vivo and in vitro.
First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine β-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells.
Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-β(1), but not with a protein kinase A inhibitor, H-89, inhibited IL-6-induced enhancement of GSIS. An inositol triphosphate (IP(3)) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6.
The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic β-cells and enhances GSIS. The PLC-IP(3)-dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS.
Diabetes 02/2011; 60(2):537-47. · 8.29 Impact Factor
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Trina A Knotts,
Hyun Woo Lee,
Jae Bum Kim,
Pieter J Oort,
Ruth McPherson,
Robert Dent,
Keisuke Tachibana,
Takefumi Doi,
Songtao Yu,
Janardan K Reddy, Kenji Uno,
Hideki Katagiri,
Magdalena Pasarica,
Steven R Smith,
Dorothy D Sears,
Michel Grino,
Sean H Adams
[show abstract]
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ABSTRACT: Tumor suppressor candidate 5 (TUSC5) is a gene expressed abundantly in white adipose tissue (WAT), brown adipose tissue (BAT), and peripheral afferent neurons. Strong adipocyte expression and increased expression following peroxisome proliferator activated receptor gamma (PPARgamma) agonist treatment of 3T3-L1 adipocytes suggested a role for Tusc5 in fat cell proliferation and/or metabolism. However, the regulation of Tusc5 in WAT and its potential association with obesity phenotypes remain unclear. We tested the hypothesis that the TUSC5 gene is a bona fide PPARgamma target and evaluated whether its WAT expression or single-nucleotide polymorphisms (SNPs) in the TUSC5 coding region are associated with human obesity. Induction of Tusc5 mRNA levels in 3T3-L1 adipocytes by troglitazone and GW1929 followed a dose-response consistent with these agents' binding affinities for PPARgamma. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPARgamma protein binds a approximately -1.1 kb promotor sequence of murine TUSC5 transiently during 3T3-L1 adipogenesis, concurrent with histone H3 acetylation. No change in Tusc5 mRNA or protein levels was evident in type 2 diabetic patients treated with pioglitazone. Tusc5 expression was not induced appreciably in liver preparations overexpressing PPARs, suggesting that tissue-specific factors regulate PPARgamma responsiveness of the TUSC5 gene. Finally, we observed no differences in Tusc5 WAT expression or prevalence of coding region SNPs in lean versus obese human subjects. These studies firmly establish the murine TUSC5 gene locus as a PPARgamma target, but the significance of Tusc5 in obesity phenotypes or in the pharmacologic actions of PPARgamma agonists in humans remains equivocal.
PPAR Research 01/2009; 2009:867678. · 2.73 Impact Factor
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Junta Imai,
Hideki Katagiri,
Tetsuya Yamada,
Yasushi Ishigaki,
Toshinobu Suzuki,
Hirohito Kudo, Kenji Uno,
Yutaka Hasegawa,
Junhong Gao,
Keizo Kaneko,
Hisamitsu Ishihara,
Akira Niijima,
Masamitsu Nakazato,
Tomoichiro Asano,
Yasuhiko Minokoshi,
Yoshitomo Oka
[show abstract]
[hide abstract]
ABSTRACT: Metabolic regulation in mammals requires communication between multiple organs and tissues. The rise in the incidence of obesity and associated metabolic disorders, including type 2 diabetes, has renewed interest in interorgan communication. We used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiological compensation for insulin resistance. We found that hepatic activation of extracellular regulated kinase (ERK) signaling induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.
Science 12/2008; 322(5905):1250-4. · 31.20 Impact Factor
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Yasushi Ishigaki,
Hideki Katagiri,
Junhong Gao,
Tetsuya Yamada,
Junta Imai, Kenji Uno,
Yutaka Hasegawa,
Keizo Kaneko,
Takehide Ogihara,
Hisamitsu Ishihara,
Yuko Sato,
Kenji Takikawa,
Norihisa Nishimichi,
Haruo Matsuda,
Tatsuya Sawamura,
Yoshitomo Oka
[show abstract]
[hide abstract]
ABSTRACT: Several clinical studies of statin therapy have demonstrated that lowering low-density lipoprotein (LDL) cholesterol prevents atherosclerotic progression and decreases cardiovascular mortality. In addition, oxidized LDL (oxLDL) is suggested to play roles in the formation and progression of atherosclerosis. However, whether lowering oxLDL alone, rather than total LDL, affects atherogenesis remains unclear.
To clarify the atherogenic impact of oxLDL, lectin-like oxLDL receptor 1 (LOX-1), an oxLDL receptor, was expressed ectopically in the liver with adenovirus administration in apolipoprotein E-deficient mice at 46 weeks of age. Hepatic LOX-1 expression enhanced hepatic oxLDL uptake, indicating functional expression of LOX-1 in the liver. Although plasma total cholesterol, triglyceride, and LDL cholesterol levels were unaffected, plasma oxLDL was markedly and transiently decreased in LOX-1 mice. In controls, atherosclerotic lesions, detected by Oil Red O staining, were markedly increased (by 38%) during the 4-week period after adenoviral administration. In contrast, atherosclerotic progression was almost completely inhibited by hepatic LOX-1 expression. In addition, plasma monocyte chemotactic protein-1 and lipid peroxide levels were decreased, whereas adiponectin was increased, suggesting decreased systemic oxidative stress. Thus, LOX1 expressed in the livers of apolipoprotein E-deficient mice transiently removes oxLDL from circulating blood and possibly decreases systemic oxidative stress, resulting in complete prevention of atherosclerotic progression despite the persistence of severe LDL hypercholesterolemia and hypertriglyceridemia.
OxLDL has a major atherogenic impact, and oxLDL removal is a promising therapeutic strategy against atherosclerosis.
Circulation 08/2008; 118(1):75-83. · 14.74 Impact Factor
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Yutaka Hasegawa,
Takehide Ogihara,
Tetsuya Yamada,
Yasushi Ishigaki,
Junta Imai, Kenji Uno,
Junhong Gao,
Keizo Kaneko,
Hisamitsu Ishihara,
Hironobu Sasano,
Hiromitsu Nakauchi,
Yoshitomo Oka,
Hideki Katagiri
[show abstract]
[hide abstract]
ABSTRACT: There is controversy regarding the roles of bone marrow (BM)-derived cells in pancreatic beta-cell regeneration. To examine these roles in vivo, mice were treated with streptozotocin (STZ), followed by bone marrow transplantation (BMT; lethal irradiation and subsequent BM cell infusion) from green fluorescence protein transgenic mice. BMT improved STZ-induced hyperglycemia, nearly normalizing glucose levels, with partially restored pancreatic islet number and size, whereas simple BM cell infusion without preirradiation had no effects. In post-BMT mice, most islets were located near pancreatic ducts and substantial numbers of bromodeoxyuridine-positive cells were detected in islets and ducts. Importantly, green fluorescence protein-positive, i.e. BM-derived, cells were detected around islets and were CD45 positive but not insulin positive. Then to examine whether BM-derived cell mobilization contributes to this process, we used Nos3(-/-) mice as a model of impaired BM-derived cell mobilization. In streptozotocin-treated Nos3(-/-) mice, the effects of BMT on blood glucose, islet number, bromodeoxyuridine-positive cells in islets, and CD45-positive cells around islets were much smaller than those in streptozotocin-treated Nos3(+/+) controls. A series of BMT experiments using Nos3(+/+) and Nos3(-/-) mice showed hyperglycemia-improving effects of BMT to correlate inversely with the severity of myelosuppression and delay of peripheral white blood cell recovery. Thus, mobilization of BM-derived cells is critical for BMT-induced beta-cell regeneration after injury. The present results suggest that homing of donor BM-derived cells in BM and subsequent mobilization into the injured periphery are required for BMT-induced regeneration of recipient pancreatic beta-cells.
Endocrinology 06/2007; 148(5):2006-15. · 4.46 Impact Factor
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Junhong Gao,
Hideki Katagiri,
Yasushi Ishigaki,
Tetsuya Yamada,
Takehide Ogihara,
Junta Imai, Kenji Uno,
Yutaka Hasegawa,
Makoto Kanzaki,
Tokuo T Yamamoto,
Shun Ishibashi,
Yoshitomo Oka
[show abstract]
[hide abstract]
ABSTRACT: Although apolipoprotein E (apoE) is well known to play a major role in lipid metabolism, its role in glucose and energy homeostasis remains unclear. Herein, we established apoE-deficient genetically obese Ay (apoE(-/-);Ay/+) mice. ApoE deficiency in Ay mice prevented the development of obesity, with decreased fat accumulation in the liver and adipose tissues. ApoE(-/-);Ay/+ mice exhibited better glucose tolerance than apoE(+/+);Ay/+ mice. Insulin tolerance testing and hyperinsulinemic-euglycemic clamp study revealed marked improvement of insulin sensitivity, despite increased plasma free fatty acid levels. These metabolic phenotypes were reversed by adenoviral replenishment of apoE protein, indicating circulating apoE to be involved in increased adiposity and obesity-related metabolic disorders. Uptake of apoE-lacking VLDL into the liver and adipocytes was markedly inhibited, but adipocytes in apoE(-/-);Ay/+ mice exhibited normal differentiation, suggesting that apoE-dependent VLDL transport is involved in the development of obesity, i.e., surplus fat accumulation. Interestingly, apoE(-/-);Ay/+ mice exhibited decreased food intake and increased energy expenditure. Pair-feeding experiments indicate these phenomena to both contribute to the obesity-resistant phenotypes associated with apoE deficiency. Thus, apoE is involved in maintaining energy homeostasis. ApoE-dependent excess fat accumulation is a promising therapeutic target for the metabolic syndrome.
Diabetes 02/2007; 56(1):24-33. · 8.29 Impact Factor
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Junta Imai,
Hideki Katagiri,
Tetsuya Yamada,
Yasushi Ishigaki,
Takehide Ogihara, Kenji Uno,
Yutaka Hasegawa,
Junhong Gao,
Hisamitsu Ishihara,
Hironobu Sasano,
Yoshitomo Oka
[show abstract]
[hide abstract]
ABSTRACT: Several lines of evidence suggest important roles for adiponectin in glucose and lipid metabolism and atherosclerosis. However, the mechanisms regulating serum adiponectin levels and adiponectin production are still not completely understood. Our aim was to determine whether adiponectin synthesis is physiologically regulated by the sympathetic nervous system (SNS).
Mice were exposed to cold (4 degrees C) for 12 hours and for 24 hours with or without inhibition of noradrenaline synthesis or pan-beta adrenergic function, followed by measurement of serum adiponectin concentrations and levels of adiponectin and uncoupling protein (UCP) 1 expressions in various white adipose tissues (WATs).
Cold exposure significantly reduced serum adiponectin concentrations without changing body weights or WAT sizes in either subcutaneous or intra-abdominal fat tissues. The serum adiponectin reduction was associated with a decrease in adiponectin mRNA expression in subcutaneous, epididymal, and mesenteric fat tissues. In these adipose tissues, UCP1 expression was markedly enhanced, suggesting SNS activation in these tissues. Administration of alpha-methyl-p-tyrosine or a combination of SR59230A and propranolol reversed the cold-exposure-induced decreases in serum adiponectin concentrations and adiponectin mRNA expression in these tissues. In contrast, in retroperitoneal fat, the effects of cold exposure on adiponectin and UCP1 expressions were strikingly weak but were not reversed by SNS inhibitors.
SNS physiologically regulates serum adiponectin levels and adiponectin synthesis in WATs in vivo, although responsiveness to SNS stimulation differs markedly among WATs. Sympathetic activation might be involved in development of the metabolic syndrome by modulation of serum adiponectin concentrations.
Obesity 08/2006; 14(7):1132-41. · 4.28 Impact Factor
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Kenji Uno,
Hideki Katagiri,
Tetsuya Yamada,
Yasushi Ishigaki,
Takehide Ogihara,
Junta Imai,
Yutaka Hasegawa,
Junhong Gao,
Keizo Kaneko,
Hiroko Iwasaki,
Hisamitsu Ishihara,
Hironobu Sasano,
Kouichi Inukai,
Hiroyuki Mizuguchi,
Tomoichiro Asano,
Masakazu Shiota,
Masamitsu Nakazato,
Yoshitomo Oka
[show abstract]
[hide abstract]
ABSTRACT: Coordinated control of energy metabolism and glucose homeostasis requires communication between organs and tissues. We identified a neuronal pathway that participates in the cross talk between the liver and adipose tissue. By studying a mouse model, we showed that adenovirus-mediated expression of peroxisome proliferator-activated receptor (PPAR)-g2 in the liver induces acute hepatic steatosis while markedly decreasing peripheral adiposity. These changes were accompanied by increased energy expenditure and improved systemic insulin sensitivity. Hepatic vagotomy and selective afferent blockage of the hepatic vagus revealed that the effects on peripheral tissues involve the afferent vagal nerve. Furthermore, an antidiabetic thiazolidinedione, a PPARg agonist, enhanced this pathway. This neuronal pathway from the liver may function to protect against metabolic perturbation induced by excessive energy storage.
Science 07/2006; 312(5780):1656-9. · 31.20 Impact Factor
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Tetsuya Yamada,
Hideki Katagiri,
Yasushi Ishigaki,
Takehide Ogihara,
Junta Imai, Kenji Uno,
Yutaka Hasegawa,
Junhong Gao,
Hisamitsu Ishihara,
Akira Niijima,
Hiroyuki Mano,
Hiroyuki Aburatani,
Tomoichiro Asano,
Yoshitomo Oka
[show abstract]
[hide abstract]
ABSTRACT: Intra-abdominal fat accumulation is involved in development of the metabolic syndrome, which is associated with insulin and leptin resistance. We show here that ectopic expression of very low levels of uncoupling protein 1 (UCP1) in epididymal fat (Epi) reverses both insulin and leptin resistance. UCP1 expression in Epi improved glucose tolerance and decreased food intake in both diet-induced and genetically obese mouse models. In contrast, UCP1 expression in Epi of leptin-receptor mutant mice did not alter food intake, though it significantly decreased blood glucose and insulin levels. Thus, hypophagia induction requires a leptin signal, while the improved insulin sensitivity appears to be leptin independent. In wild-type mice, local-nerve dissection in the epididymis or pharmacological afferent blockade blunted the decrease in food intake, suggesting that afferent-nerve signals from intra-abdominal fat tissue regulate food intake by modulating hypothalamic leptin sensitivity. These novel signals are potential therapeutic targets for the metabolic syndrome.
Cell Metabolism 04/2006; 3(3):223-9. · 13.67 Impact Factor
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Yasushi Ishigaki,
Hideki Katagiri,
Tetsuya Yamada,
Takehide Ogihara,
Junta Imai, Kenji Uno,
Yutaka Hasegawa,
Junhong Gao,
Hisamitsu Ishihara,
Tooru Shimosegawa,
Hideyuki Sakoda,
Tomoichiro Asano,
Yoshitomo Oka
[show abstract]
[hide abstract]
ABSTRACT: For examining whether dissipating excess energy in the liver is a possible therapeutic approach to high-fat diet-induced metabolic disorders, uncoupling protein-1 (UCP1) was expressed in murine liver using adenoviral vectors in mice with high-fat diet-induced diabetes and obesity, and in standard diet-fed lean mice. Once diabetes with obesity developed, hepatic UCP1 expression increased energy expenditure, decreased body weight, and reduced fat in the liver and adipose tissues, resulting in markedly improved insulin resistance and, thus, diabetes and dyslipidemia. Decreased expressions of enzymes for lipid synthesis and glucose production and activation of AMP-activated kinase in the liver seem to contribute to these improvements. Hepatic UCP1 expression also reversed high-fat diet-induced hyperphagia and hypothalamic leptin resistance, as well as insulin resistance in muscle. In contrast, intriguingly, in standard diet-fed lean mice, hepatic UCP1 expression did not significantly affect energy expenditure or hepatic ATP contents. Furthermore, no alterations in blood glucose levels, body weight, or adiposity were observed. These findings suggest that ectopic UCP1 in the liver dissipates surplus energy without affecting required energy and exerts minimal metabolic effects in lean mice. Thus, enhanced UCP expression in the liver is a new potential therapeutic target for the metabolic syndrome.
Diabetes 03/2005; 54(2):322-32. · 8.29 Impact Factor
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Junta Imai,
Hideki Katagiri,
Tetsuya Yamada,
Yasushi Ishigaki,
Takehide Ogihara, Kenji Uno,
Yutaka Hasegawa,
Junhong Gao,
Hisamitsu Ishihara,
Hironobu Sasano,
Hiroyuki Mizuguchi,
Tomoichiro Asano,
Yoshitomo Oka
[show abstract]
[hide abstract]
ABSTRACT: To generate insulin-producing cells in the liver, recombinant adenovirus containing a constitutively active mutant of PDX1 (PDX1-VP16), designed to activate target genes without the need for protein partners, was prepared and administered intravenously to streptozotocin (STZ)-treated diabetic mice. The effects were compared with those of administering wild-type PDX1 (wt-PDX1) adenovirus. Administration of these adenoviruses at 2x10(8)pfu induced similar levels of PDX1 protein expression in the liver. While wt-PDX1 expression exerted small effects on blood glucose levels, treatment with PDX1-VP16 adenovirus efficiently induced insulin production in hepatocytes, resulting in reversal of STZ-induced hyperglycemia. The effects were sustained through day 40 when exogenous PDX1-VP16 protein expression was undetectable in the liver. Endogenous PDX1 protein came to be expressed in the liver, which is likely to be the mechanism underlying the sustained effects. On the other hand, albumin and transferrin expressions were observed in insulin-producing cells in the liver, suggesting preservation of hepatocytic functions. Thus, transient expression of an active mutant of PDX1 in the liver induced sustained PDX1 and insulin expressions without loss of hepatocytic function.
Biochemical and Biophysical Research Communications 02/2005; 326(2):402-9. · 2.48 Impact Factor
