Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently reported that PPAR alpha deficiency leads to hypoglycaemia and hypoinsulinemia in mice (Yessoufou et al. Endocrinology 147:4410-4418, 2006). Besides, these mice exhibited high adiposity with an inflammatory state. We, therefore, assessed, in this study, the effects of PPAR alpha deficiency on the expression of mRNA encoding for the insulin gene transcription factors in pancreatic beta-cells along with those implicated in inflammation in adipose tissues. On fasting, the adult PPAR alpha-null mice were hypoglycemic. Serum insulin concentrations and its pancreatic mRNA transcripts were downregulated in PPAR alpha-null mice, suggesting that PPAR alpha gene deletion contributes to low insulin gene transcription. The PPAR alpha gene deletion downregulates the mRNA expression of insulin gene transcription factors, i.e., Pdx-1, Nkx6.1, and MafA. Besides, the pancreatic function was diminished by PPAR alpha deficiency as PPAR alpha-null mice expressed low pancreatic Glut2 and glucokinase mRNA. PPAR alpha-null mice also expressed high adiponectin and leptin mRNA levels compared to wild type animals. Adipose tissues of PPAR alpha-null mice exhibited upregulation of CD14 and CD68 mRNA, generally expressed by macrophages. PPAR alpha gene deletion downregulates the adipocyte mRNA of certain pro-inflammatory agents, like MCP-1, TNF-alpha, IL-1 beta, IL-6, and RANTES, though pro-inflammatory TLR-2 and TLR-4 mRNAs were upregulated in the adipose tissues. Our results suggest that PPAR alpha deficiency, in mice, is implicated in the modulation of insulin gene transcription and inflammatory status in adipose tissues.
Mol Cell Biochem 2009 Mar
PMID:Peroxisome proliferator-activated receptor-alpha modulates insulin gene transcription factors and inflammation in adipose tissues in mice. 1903 51

In view of the central role of preadipocyte factor-1, adiponectin and leptin in white adipose tissue function, the aim of the present study was to analyze the mRNA expression of these proteins and of the inflammatory markers interleukin-6 and tumor necrosis factor-alpha in visceral and subcutaneous fat pads of rats with different metabolic disorders. We demonstrated highly divergent expression of preadipocyte factor-1, upregulated expression of adiponectin, interleukin-6 and TNF-alpha mRNA in adipose tissues of the diabetic Goto Kakizaki rat compared to the obese Zucker rat. This was correlated to an increased number of large adipocytes and serum levels of adiponectin. Furthermore, in all four strains studied (as above plus Wistar Furth and Zucker Lean), significant heterogeneity was evident in adipokine expression within specific adipose tissues previously defined as belonging to the visceral or subcutaneous fat depots. These results suggest that significantly increased levels of inflammation and redistribution of adipocyte size are mechanisms contributing to the development of type 2 diabetes in the GK rat.
Mol Cell Endocrinol 2009 Feb 27
PMID:Pref-1 and adipokine expression in adipose tissues of GK and Zucker rats. 1908 46

Inhibitors of the angiotensin-converting enzyme (ACE) decrease angiotensin II production and activate an intracellular signaling cascade that affects gene expression in endothelial cells. Because ACE inhibitors have been reported to delay the onset of type 2 diabetes, we determined ACE signaling-modulated gene expression in endothelial cells and adipocytes. Using differential gene expression analysis, several genes were identified that were 3-fold up- or down-regulated by ramiprilat in cells expressing wild-type ACE versus cells expressing a signaling-dead ACE mutant. One up-regulated gene was the cellular retinol-binding protein 1 (CRBP1). In adipocytes, the overexpression of CRBP1 enhanced (4- to 5-fold) the activity of promoters containing response elements for retinol-dependent nuclear receptors [retinoic acid receptor (RAR) and retinoid X receptor (RXR)] or peroxisome proliferator-activated receptors (PPAR). CRBP1 overexpression also enhanced the promoter activity (by 470 +/- 40%) and expression/release of the anti-inflammatory and antiatherogenic adipokine adiponectin (cellular adiponectin by 196 +/- 24%, soluble adiponectin by 228 +/- 74%). Significantly increased adiponectin secretion was also observed after ACE inhibitor treatment of human preadipocytes, an effect prevented by small interfering RNA against CRBP1. Furthermore, in ob/ob mice, ramipril markedly potentiated both the basal (approximately 2-fold) and rosiglitazonestimulated circulating levels of adiponectin. In patients with coronary artery disease or type 2 diabetes, ACE inhibition also significantly increased plasma adiponectin levels (1.6- or 2.1-fold, respectively). In summary, ACE inhibitors affect adipocyte homeostasis via CRBP1 through the activation of RAR/RXR-PPAR signaling and up-regulation of adiponectin. The latter may contribute to the beneficial effects of ACE inhibitors on the development of type 2 diabetes in patients with an activated renin-angiotensin system.
Mol Pharmacol 2009 Mar
PMID:Angiotensin-converting enzyme (ACE) inhibitors modulate cellular retinol-binding protein 1 and adiponectin expression in adipocytes via the ACE-dependent signaling cascade. 1911 89

In addition to the hallmark neurological manifestations of Huntington's disease (HD), weight loss with metabolic dysfunction is often observed in the later stages of disease progression and is associated with poor prognosis. The mechanism for weight loss in HD is unknown. Using two mouse models of HD, the R6/2 transgenic and CAG140 knock-in mouse strains, we demonstrate that adipose tissue dysfunction is detectable at early ages and becomes more pronounced as the disease progresses. Adipocytes acquire a 'de-differentiated' phenotype characterized by impaired expression of fat storage genes. In addition, HD mice exhibit reduced levels of leptin and adiponectin, adipose tissue-derived hormones that regulate food intake and glucose metabolism. Importantly, some of these changes occur prior to weight loss and development of some of the characteristic neurological symptoms. We demonstrate that impaired gene expression and lipid accumulation in adipocytes can be recapitulated by expression of an inducible mutant huntingtin transgene in an adipocyte cell line and that mutant huntingtin inhibits transcriptional activity of the PGC-1alpha co-activator in adipocytes, which may contribute to aberrant gene expression. Thus, our findings indicate that mutant huntingtin has direct detrimental effects in cell types other than neurons. The results also indicate that circulating adipose-tissue-derived hormones may be accessible markers for HD prognosis and progression and suggest that adipose tissue may be a useful therapeutic target to improve standard of life for HD patients.
Hum Mol Genet 2009 Mar 15
PMID:Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models. 1912 32

This study was performed to investigate the lipid-lowering, antioxidant, and hepato-protective effects of pinitol in dose-dependent manners in hamsters fed-high fat and high cholesterol (HFHC) diet. Pinitol supplementation (0.05%, P-I and 0.1% pinitol, P-II) with an HFHC diet (10% coconut oil plus 0.2% cholesterol) for 10 wks significantly lowered the white adipose tissue weights, hepatic lipid droplets, plasma glucose, total-cholesterol, nonHDL-cholesterol, total-cholesterol/HDL-cholesterol ratio, and hepatic lipid levels. Whereas it significantly increased the brown adipose tissue weight, plasma HDL-cholesterol, apolipoprotein A-I (apo A-I) concentrations, paraoxonase (PON) activity, and/or mRNA expression, compared to the HFHC control group. Plasma insulin and adiponectin levels were significantly lower and higher, respectively, in both P-I and P-II groups than the HFHC control group. Dietary pinitol significantly inhibited hepatic HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT), and cytochrome P4502E1 (CYP2E1) activities without altering their mRNA expressions compared to the control group. Pinitol significantly elevated the hepatic antioxidant enzyme activities, whereas it also significantly reduced the hepatic lipid peroxide and H2O2 production. Accordingly, these results indicate that both 0.05 and 0.1% pinitol supplementation may improve the lipid and antioxidant metabolism in HFHC diet-fed hamsters. In particular, pinitol supplementation was very effective on the elevation of antiatherogenic factors, including plasma HDL-cholesterol, apo A-I, adiponectin, and PON.
Mol Nutr Food Res 2009 Jun
PMID:Metabolic response of soy pinitol on lipid-lowering, antioxidant and hepatoprotective action in hamsters fed-high fat and high cholesterol diet. 1920 1

The discovery of leptin in 1994 marked the beginning of a new understanding about white adipose tissue (WAT) and modified a static vision of this tissue which was viewed up to the end of the 20th century as an inert tissue, devoted to body protection from heat loss and to passively storing energy. The identification of the product of the gene obese accentuated the role of adipose tissue in the physiopathology of obesity-linked diseases, and led to the discovery of various adipokines, many of a pro-inflammatory nature. It has become progressively manifest that WAT-derived adipokines can now be considered as the fulcrum between obesity-related environmental causes, such as nutrition and lifestyle, and the biochemical shifts that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. Herein, we review recent adipokine research, with particular emphasis to the role of leptin, adiponectin, resistin, and visfatin in chondrocyte function and skeleton, as well as in inflammatory and degenerative cartilage joint diseases.
J Mol Endocrinol 2009 Jul
PMID:Adipokines in the skeleton: influence on cartilage function and joint degenerative diseases. 1924 Jan 95

A recent study examined common genetic variants at the adiponectin locus (ADIPOQ) in two case-control colorectal cancer (CRC) series from the USA and reported a positive association between a single nucleotide polymorphism (SNP) in the 5' region of the gene (rs266729) and decreased disease risk. In an attempt to replicate the previously reported association, we examined data from two CRC genome-wide association studies based on the UK population. The first cohort comprised 931 familial colorectal tumour cases and 929 cancer-free controls. The second included 1216 individuals with Dukes stage B or C CRCs from two clinical trials and 1436 controls from the 1958 Birth Cohort. We tested associations between CRC risk and 82 SNPs in a region of 250 kb around the ADIPOQ gene; nine of these SNPs were located in the coding and promoter regions. None of the markers tested was significantly associated with CRC risk after correction for multiple testing under any of the models in any of the two cohorts. A meta-analysis of the data also failed to detect any association. We, therefore, failed to replicate an association between common variants at ADIPOQ and CRC risk in the UK, and suggest that the previous report is either population-specific or a false-positive result.
Hum Mol Genet 2009 May 15
PMID:Common variation at the adiponectin locus is not associated with colorectal cancer risk in the UK. 1926 63

Adiponectin stimulates cholesterol efflux in macrophages and low adiponectin may in part contribute to disturbed reverse cholesterol transport in type 2 diabetes. Monocytes express high levels of annexin A6 that could inhibit cholesterol efflux and it was investigated whether the atheroprotective effects of adiponectin are accompanied by changes in annexin A6 levels. Adiponectin reduces annexin A6 protein whereas mRNA levels are not affected. Adiponectin-mediated activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and AMP-activated protein kinase (AMPK) does not account for reduced annexin A6 expression. Further, fatty acids and lipopolysaccharide that are elevated in obesity do not influence annexin A6 protein levels. Annexin A6 in monocytes from overweight probands or type 2 diabetic patients is significantly elevated compared to monocytes of normal-weight controls. Monocytic annexin A6 positively correlates with body mass index and negatively with systemic adiponectin of the blood donors. Therefore, the current study demonstrates that adiponectin reduces annexin A6 in monocytes and thereby may enhance cholesterol efflux. In agreement with these in vitro finding an increase of monocytic annexin A6 in type 2 diabetes monocytes was observed.
Exp Mol Med 2009 Jul 31
PMID:Annexin A6 is highly abundant in monocytes of obese and type 2 diabetic individuals and is downregulated by adiponectin in vitro. 1932 30

This study was designed to investigate the effect of increased levels of HO-1 on hypertension exacerbated by diabetes. Diabetic spontaneously hypertensive rat (SHR) and WKY (control) animals were treated with streptozotocin (STZ) to induce diabetes and stannous chloride (SnCl(2)) to upregulate HO-1. Treatment with SnCl(2) not only attenuated the increase of blood pressure (p<0.01), but also increased HO-1 protein content, HO activity and plasma adiponectin levels, decreased the levels of superoxide and 3-nitrotyrosine (NT), respectively. Reduction in oxidative stress resulted in the increased expression of Bcl-2 and AKT with a concomitant reduction in circulating endothelial cells (CEC) in the peripheral blood (p<0.005) and an improvement of femoral reactivity (response to acetylcholine). Thus induction of HO-1 accompanied with increased plasma adiponectin levels in diabetic hypertensive rats alters the phenotype through a reduction in oxidative stress, thereby permitting endothelial cells to maintain an anti-apoptotic environment and the restoration of endothelial responses thus preventing hypertension.
Int J Mol Sci 2008 Dec
PMID:Upregulation of heme oxygenase-1 combined with increased adiponectin lowers blood pressure in diabetic spontaneously hypertensive rats through a reduction in endothelial cell dysfunction, apoptosis and oxidative stress. 1933 83

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of common hepatic disorders in western countries, with multiple consequences and its incidence is paralleling the increasing numbers of overweight and obese individuals worldwide. The pathogenesis of NAFLD is thought to be related mainly with insulin resistance (IR) syndrome and oxidative stress; the latter resulting from mitochondrial fatty acids (FFAs) oxidation, nuclear factor-kappaB (NFkappaB)-dependent inflammatory cytokine expression and adipocytokines may promote hepatocellular damage, inflammation, fibrosis and progressive liver disease. Adipocytokines and other recognized cytokines produced partially by inflammatory cells infiltrating adipose tissue, play an important role in the pathogenesis of IR and NAFLD, through complex and interactive paracrine and endocrine mechanisms. Some adipocytokines, including adiponectin and leptin decrease IR, while others, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and resistin enhance IR. The multi-hit hypothesis provides a model that summarizes the complex factors and interactions leading from adipocytokines, FFAs metabolism and IR to NAFLD. This review outlines the pathways involved in adipocytokines, IR and NAFLD sequence; the first part describes the impaired IR pathway leading to NAFLD and the second part the mechanisms by which adipocytokines influence IR and NAFLD development and progression. Understanding these complex mechanisms has evoked new therapeutic approaches, which may provide promising results to date.
Curr Mol Med 2009 Apr
PMID:Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. 1935 12


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