As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at ∼58% compared with a peak at ∼42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at ∼42%, relatively low compared with that of protein-coding cDNAs.
IntroductionObesity is defined as increased mass of adipose tissue and confers a higher risk of arterial blood pressure (BP) elevation or hypertension (1-4). On the other hand, weight reduction lowers BP in obese hypertensive subjects (5-8), suggesting an important association between energy homeostasis and BP. However, the mechanism for that association is poorly understood. Obesity-related hypertension may be secondary to insulin resistance and/or hyperinsulinemia (2,3,8). Several lines of evidence have also suggested that increased sympathetic nerve activity may contribute to the development of obesity-related hypertension (2, 6, 7).The adipose tissue participates in the regulation of a variety of homeostatic processes as an endocrine organ that secretes many biologically active molecules such as FFA, adipsin, angiotensinogen,. Leptin is such an adipocyte-derived hormone that is involved in the regulation of food intake and body weight (10). It also increases the overall sympathetic nerve activity, which leads to a significant increase in energy expenditure (11-15). The biologic actions of leptin are thought to be mediated through the activation of leptin receptor that is expressed in the hypothalamus (16)(17)(18)(19). We and others demonstrated that the hypothalamic arcuate nucleus is a primary site of the satiety effect of leptin (20,21) and that its satiety effect is mediated at least partly by hypothalamic melanocortin system (22,23).Numerous studies have demonstrated that plasma leptin concentrations are elevated significantly in several models of rodent obesity and in human obesity in proportion to the degree of adiposity (24-26), suggesting the state of "leptin resistance" in obesity. Nevertheless, because of the potent pleiotropic actions of leptin, it is conceivable, though paradoxically, that hyperleptinemia may be involved in the pathogenesis of obesity and its related disorders. In this regard, a recent study reported a significant correlation between BP and plasma leptin concentrations in patients with essential hypertension (27), suggesting that leptin may play roles in the pathogenesis of obesity-related hypertension.We have recently produced transgenic skinny mice overexpressing leptin under the control of the liver-specific promoter and demonstrated that chronic hyperleptinemia results in complete disappearance of adipose tissue for a long period (28). These mice also exhibit increased glucose metabolism and insulin sensitivity, accompanied by an activation of insulin signaling in the skeletal muscle and liver (28,29). Accordingly, transgenic skinny mice will serve as the unique experimental model system with which to assess the long-term effects of leptin in vivo. To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA y mice with hyperleptinemia, in which hypothalamic melano...
Objectives-Fish oil rich in n-3 polyunsaturated fatty acids (PUFAs) or n-3 PUFAs have been shown to reduce the incidence of coronary heart disease. Here we investigated the effect of highly purified eicosapentaenoic acid (EPA) on production of adiponectin, the only established antiatherogenic and antiinflammatory adipocytokine, in rodent models of obesity and human obese subjects. Methods and Results-We demonstrated that EPA increases adiponectin secretion in genetically obese ob/ob mice and high-fat diet-induced obese mice. In the in vitro coculture of adipocytes and macrophages, EPA reversed the coculture-induced decrease in adiponectin secretion at least in part through downregulation of tumor necrosis factor-␣ in macrophages. We also showed significant increase in plasma adiponectin concentrations in human obese subjects after a 3-month treatment with EPA (1.8 g daily). Multivariate regression analysis revealed that EPA treatment is the only independent determinant of plasma adiponectin concentrations. Conclusion-This study demonstrates that EPA increases adiponectin secretion in rodent models of obesity and human obese subjects, possibly through the improvement of the inflammatory changes in obese adipose tissue. Because EPA has reduced the risk of major coronary events in a large-scale, prospective, randomized clinical trial, this study provides important insight into its therapeutic implication in obesity-related metabolic sequelae. (Arterioscler Thromb Vasc Biol. 2007;27:1918-1925.)Key Words: adipocytes Ⅲ adiponectin Ⅲ EPA Ⅲ macrophages Ⅲ obesity T he adipose tissue has a high capacity to secrete many biologically active substances (or adipocytokines) such as leptin and tumor necrosis factor-␣ (TNF␣). 1 Dysregulation of pro-and antiinflammatory adipocytokine production is associated with the metabolic syndrome, suggesting that inflammatory changes within obese adipose tissue may critically contribute to the development of many aspects of the metabolic syndrome and results in diabetes and atherosclerosis. Among numerous adipocytokines, adiponectin is unique in that it is the only established adipocytokine with antiatherogenic and antiinflammatory properties. 2,3 It also increases tissue fat oxidation, leading to reduced levels of fatty acids (FAs) and tissue triglyceride content, thus enhancing insulin sensitivity in the liver and skeletal muscle. 2,4,5 Because plasma adiponectin concentrations are decreased in obese subjects, 1,2 extensive researches have been aimed at the upregulation of adiponectin and its cognate receptors (AdipoR1 and AdipoR2) for the treatment of obesityrelated metabolic sequelae. 2 Previous studies showed that the adipose tissue is markedly infiltrated by macrophages in several models of rodent obesities and human obese subjects, 6,7 suggesting that macrophages participate in the inflammatory pathways that are activated in obese adipose tissue. Using an in vitro coculture system composed of adipocytes and macrophages, we have demonstrated that a paracrine loop involving saturate...
Urinary neutrophil gelatinase-associated lipocalin (Ngal or lipocalin 2) is a very early and sensitive biomarker of kidney injury. Here we determined the origin and time course of Ngal appearance in several experimental and clinically relevant renal diseases. Urinary Ngal levels were found to be markedly increased in lipoatrophic- and streptozotocin-induced mouse models of diabetic nephropathy. In the latter mice, the angiotensin receptor blocker candesartan dramatically decreased urinary Ngal excretion. The reabsorption of Ngal by the proximal tubule was severely reduced in streptozotocin-induced diabetic mice, but upregulation of its mRNA and protein in the kidney was negligible, compared to those of control mice, suggesting that increased urinary Ngal was mainly due to impaired renal reabsorption. In the mouse model of unilateral ureteral obstruction, Ngal protein synthesis was dramatically increased in the dilated thick ascending limb of Henle and N was found in the urine present in the swollen pelvis of the ligated kidney. Five patients with nephrotic syndrome or interstitial nephritis had markedly elevated urinary Ngal levels at presentation, but these decreased in response to treatment. Our study shows that the urinary Ngal level may be useful for monitoring the status and treatment of diverse renal diseases reflecting defects in glomerular filtration barrier, proximal tubule reabsorption, and distal nephrons.
OBJECTIVE -Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS -A total of 136Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) (n ϭ 70) and the untreated control group (n ϭ 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone.RESULTS -The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA 1c levels and increased plasma adiponectin concentrations relative to the control group (P Ͻ 0.01). It also significantly decreased CRP and PWV (P Ͻ 0.01). The antiatherogenic effect was observed in both the nonresponders showing Ͻ1% of reduction in HbA 1c (n ϭ 30) and responders showing Ͼ1% of reduction (n ϭ 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism.CONCLUSIONS -This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect. Diabetes Care 26:2493-2499, 2003T ype 2 diabetes contributes to the risk of developing atherosclerotic diseases such as coronary heart disease and stroke and coronary restenosis after angioplasty or stenting (1-4). Therefore, it is of clinical importance to evaluate and treat cardiovascular complications in type 2 diabetic patients beyond glycemic control.Peroxisome proliferator-activated receptor-␥ (PPAR-␥) is a member of the nuclear receptor superfamily that, when activated by insulin sensitizers of the thiazolidinedione (TZD) class, including troglitazone, pioglitazone, and rosiglitazone, regulates a host of target genes (5,6). In humans with and animal models of insulin resistance and type 2 diabetes, TZDs can improve hyperglycemia and hyperinsulinemia and are currently used to manage type 2 diabetes (7). PPAR-␥ occurs abundantly in adipocytes where it regulates adipocyte differentiation (8), but it is also expressed in all major cell types participating in vascular injury, namely, endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages (9,10). PPAR-␥ regulates the recruitment of monocytes to endothelial cells (11), modulates the inflammatory response in monocytes/macrophages and VSMCs (12-14), and inhibits macrophage foam cell formation and VSMCs proliferation and migration (13)(14)(15). In experimental models of atherosclerosis, ligandactivated PPAR-␥ prevents t...
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