Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adipocyte fatty acid-binding protein, aP2 or ALBP, is an abundant cytosolic protein postulated to function in binding and intracellular transport of long-chain fatty acids. In this report, we investigated levels of aP2 mRNA and protein and transcriptional activity of the aP2 gene in tissues from streptozotocin-diabetic rats at different time periods following the induction of diabetes. An average 75% decrease in mRNA for aP2 (relative to mRNA for beta-actin) was observed in all diabetic rats at 7 days post-STZ injection. Insulin supplementation rapidly (2 h) restored aP2 mRNA and the insulin effect was cycloheximide-sensitive. Nuclear transcription assays measured a 60% decrease in transcription of the aP2 gene in diabetic rats that was reversed by insulin administration. Levels of aP2 protein were still high, in some cases, 1 day after the decrease in mRNA levels consistent with a long half-life of the protein. Decreases in aP2 protein were rapidly reversed by insulin administration. There were no changes in aP2 protein in the absence of changes in aP2 mRNA supporting a pretranslational mechanism of regulation. The decrease in aP2 mRNA was delayed in onset when compared with the rapid decline (at day 2 of diabetes) of mRNA for the lipogenic enzyme, fatty acid synthase, and with the accelerated depletion of adipose tissue lipid. Adipose tissue weight and lipid content had decreased by more than 80% 3 days before any significant changes in aP2 expression were observed. Changes in aP2 could not be related to changes in the levels of circulating fatty acids that regulate aP2 expression in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of the adipocyte fatty acid-binding protein in streptozotocin-diabetes: effects of insulin deficiency and supplementation. 769 43

High-fat-fed C57Bl/6J FABP4/aP2 null mice develop obesity but not the related hyperglycemia or hyperinsulinemia characteristic of type II diabetes. FABP4/aP2 protein's function to bind fatty acids in the adipocytes may promote total body energy homeostasis by linking energy depots to the ability to express signaling molecules similar to leptin. To test this hypothesis, proteomic analysis of serum proteins from high-fat-fed wild-type and FABP4/aP2 null mice revealed that the GDF-3/Vgr-2 protein, a bone morphogenetic protein, was upregulated in C57Bl/6J FABP4/aP2 null mice. The increase in serum GDF-3/Vgr-2 protein was correlated with a 27-fold increase in adipose GDF-3/Vgr-2 mRNA. In contrast, leptin expression was unaltered between FABP4/aP2 null and wild-type animals. The expression of GDF-3/Vgr-2 mRNA was not substantially different in adipose tissue of db/db and tb/tb mice compared to wild-type controls. The expression of GDF-3/Vgr-2 mRNA was dependent upon the age and diet of the animals, declining as a function of age in high-fat-fed wild-type animals while increasing in the FABP4/aP2 null strain. These results identify GDF-3/Vgr-2 as an age- and fat-regulated, adipose-derived cytokine suggesting a linkage between adipocyte fatty acid metabolism and the expression of the bone morphogenetic family of differentiation regulators.
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PMID:Upregulation of bone morphogenetic protein GDF-3/Vgr-2 expression in adipose tissue of FABP4/aP2 null mice. 1139 90

The time-limiting step in HTS often is the development of an appropriate assay. In addition, hits from HTS fairly often turn out to be false positives and generally display unfavorable properties for further development. Here we describe an alternative process for hit generation, applied to the human adipocyte fatty acid binding protein FABP4. A small molecular ligand for FABP4 that blocks the binding of endogenous ligands may be developed into a drug for the treatment of type-2 diabetes. Using NMR spectroscopy, we screened FABP4 for low-affinity binders in a diversity library consisting of small soluble scaffolds, which yielded 52 initial hits in total. The potencies of these hits were ranked, and crystal structures of FABP4 complexes for two of the hits were obtained. The structural data were subsequently used to direct similarity searches for available analogues, as well as chemical synthesis of 12 novel analogues. In this way, a series of three selective FABP4 ligands with attractive pharmacochemical profiles and potencies of 10 microM or better was obtained.
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PMID:Structure-based screening as applied to human FABP4: a highly efficient alternative to HTS for hit generation. 1235 31

The critical initiating event in atherogenesis involves the invasion of monocytes through the endothelial wall of arteries, and their transformation from macrophages into foam cells. Human THP-1 monocytic cells can be induced to differentiate into macrophages by phorbol myristate acetate (PMA) treatment, and can then be converted into foam cells by exposure to oxidized low-density lipoprotein (oxLDL). To define genes that are specifically expressed during the transformation of macrophages into foam cells, we have performed a subtractive library screening utilizing mRNA isolated from THP-1 macrophages and foam cells. From this analysis, we have identified adipocyte lipid binding protein (ALBP/aP2) as a gene that is highly upregulated in foam cells in response to oxLDL. Furthermore, overexpression the ALBP gene using an adenovirus construct enhanced the accumulation of cholesterol ester in macrophage foam cells, probably due to an increase in transcription since oxLDL enhanced ALBP promoter activity in experiments using a promoter-luciferase reporter gene construct. The induction of ALBP by oxLDL probably involved activation of peroxisome proliferator-activated receptor gamma (PPARgamma) transcription factors, since four different endogenous PPARgamma ligands, including 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE), two oxidized lipid components of oxLDL, as well as 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2) and retinoic acid (RA), all induced ALBP expression in macrophage/foam cells. Finally, ALBP was found to be highly expressed in vivo in macrophage/foam cells of human atherosclerotic plaques. These observations suggest that oxLDL-mediated increase in ALBP gene expression accelerate cholesterol ester accumulation, and that this is an important component of the genetic program regulating conversion of macrophages to foam cells. The observation that ALBP is readily detected in foam cells in active atherosclerotic lesions implicates a role for ALBP in human vascular disease. The induction of ALPB expression by oxLDL likely involves activation of PPARgamma by components of oxLDL (9-HODE and 13-HODE) that also function as PPARgamma ligands. Our results add to the concern that the clinical use of insulin-sensitizing PPARgamma agonists (i.e. thiazolidinediones) to treat Type 2 Diabetes could exacerbate atherosclerosis, and highlight the need for clinical trials that address this issue.
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PMID:The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. 1241 76

Obesity and type 2 diabetes are closely related, multifactorial metabolic conditions characterized by alterations in energy metabolism and glucose homeostasis, respectively. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that regulates genes involved in lipid and glucose homeostasis, including the adipocyte-specific fatty acid-binding protein (FABP4). In turn, FABP4 binds fatty acids and transports them to the nucleus where the FABP4/fatty acid complex activates PPARgamma in a positive feedback loop. In this study, we tested the hypothesis that the polymorphisms, FABP4-376 and PPARgamma Pro12Ala, interactively influence insulin sensitivity and body composition in nondiabetic, Hispanic and non-Hispanic white males (n = 314) participating in the San Luis Valley Diabetes Study (SLVDS). Although the individual sites were not statistically significantly associated with any of the outcomes, we found statistically significant interaction terms in 2-way analysis of covariance (ANCOVA) models for homeostasis model assessment of insulin resistance (HOMA-IR) (P =.014) and lean mass (P =.019). While the PPARgamma Pro12Ala site was the only statistically significant predictor of fat mass in the 2-way model (P =.012), the FABP4 and PPARgamma main effect terms individually became stronger when considered in one model compared with the analysis of each polymorphism separately. These findings provide evidence that FABP4 and PPARgamma work together to influence a biologic pathway affecting insulin sensitivity and body composition, illustrating the importance of investigating the joint effect of genes in determining susceptibility for complex disease.
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PMID:Genetic variation in fatty acid-binding protein-4 and peroxisome proliferator-activated receptor gamma interactively influence insulin sensitivity and body composition in males. 1501 41

Wnt is a family of secreted signaling proteins that regulate diverse developmental processes. Activation of canonical Wnt signaling by Wnt10b inhibits differentiation of preadipocytes in vitro. To determine whether Wnt signaling blocks adipogenesis in vivo, we created transgenic mice in which Wnt10b is expressed from the FABP4 promoter. Expression of Wnt10b in adipose impairs development of this tissue throughout the body, with a decline of approximately 50% in total body fat and a reduction of approximately 60% in weight of epididymal and perirenal depots. FABP4-Wnt10b mice resist accumulation of adipose tissue when fed a high fat diet. Furthermore, transgenic mice are more glucose-tolerant and insulin-sensitive than wild type mice. Expression of Wnt10b from the FABP4 promoter also blocks development of brown adipose tissue. Interscapular tissue of FABP4-Wnt10b mice has the visual appearance of white adipose tissue but expresses neither brown (e.g. uncoupling protein 1) nor white adipocyte markers. Transgenic mice are unable to maintain a core body temperature when placed in a cold environment, providing further evidence that Wnt10b inhibits development of brown adipose tissue. Although food intake is not altered in FABP4-Wnt10b mice, oxygen consumption is decreased. Thus, FABP4-Wnt10b mice on a chow diet gain more weight than controls, largely because of an increase in weight of skin. In summary, inhibition by Wnt10b of white and brown adipose tissue development results in lean mice without lipodystrophic diabetes.
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PMID:Wnt10b inhibits development of white and brown adipose tissues. 1519 75

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes and cancer. Although obesity is a multi-factorial heterogeneous condition, fat accumulation in visceral depots is most highly associated with these risks. Pathological glucocorticoid excess (i.e. in Cushing's syndrome) is a recognised, reversible cause of visceral fat accumulation. The aim of this study was to identify depot-specific glucocorticoid-target genes in adipocyte precursor cells (preadipocytes) using Affymetrix microarray technique. Confluent preadipocytes from subcutaneous (SC) and omental (OM) adipose tissue collected from five female patients were treated for 24 h with 100 nM cortisol (F), RNA was pooled and hybridised to the Affymetrix U133 microarray set. We identified 72 upregulated and 30 downregulated genes by F in SC cells. In OM preadipocytes, 56 genes were increased and 19 were decreased. Among the most interesting were transcription factors, markers of adipocyte differentiation and glucose metabolism, cell adhesion and growth arrest protein factors involved in G-coupled and Wnt signalling. The Affymetrix data have been confirmed by quantitative real-time PCR for ten specific genes, including HSD11B1, GR, C/EBPalpha, C/EBPbeta, IL-6, FABP4, APOD, IRS2, AGTR1 and GHR. One of the most upregulated genes in OM but not in SC cells was HSD11B1. The GR was similarly expressed and not regulated by glucocorticoids in SC and OM human preadipocytes. C/EBPalpha was expressed in SC preadipocytes and upregulated by F, but was below the detection level in OM cells. C/EBPbeta was highly expressed both in SC and in OM preadipocytes, but was not regulated by F. Our results provide insight into the genes involved in the regulation of adipocyte differentiation by cortisol, highlighting the depot specifically in human adipose tissue.
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PMID:Expression profiling of 11beta-hydroxysteroid dehydrogenase type-1 and glucocorticoid-target genes in subcutaneous and omental human preadipocytes. 1703 48

The Wnt family of secreted signaling molecules has profound effects on diverse developmental processes, including the fate of mesenchymal progenitors. While activation of Wnt signaling blocks adipogenesis, inhibition of endogenous Wnt/beta-catenin signaling by Wnt10b promotes spontaneous preadipocyte differentiation. Transgenic mice with expression of Wnt10b from the FABP4 promoter (FABP4-Wnt10b) have less adipose tissue when maintained on a normal chow diet and are resistant to diet-induced obesity. Here we demonstrate that FABP4-Wnt10b mice largely avert weight gain and metabolic abnormalities associated with genetic obesity. FABP4-Wnt10b mice do not gain significant body weight on the ob/ob background, and at 8 weeks of age, they have an approximately 70% reduction in visceral and subcutaneous adipose tissues compared with ob/ob mice. Similarly, on the lethal yellow agouti (A(y)) background, FABP4-Wnt10b mice have 50-70% less adipose tissue weight and circulating leptin at 5 months of age. Wnt10b-Ay mice are more glucose tolerant and insulin sensitive than A(y) controls, perhaps due to reduced expression and circulation of resistin. Reduced expression of inflammatory cytokines may also contribute to improved glucose homeostasis.
Diabetes 2007 Feb
PMID:Wnt10b inhibits obesity in ob/ob and agouti mice. 1725 72

To describe the function in terms of gene expression, and to find new factors, we performed random complementary DNA (cDNA) sequencing using a 3'-directed cDNA library that faithfully represents the composition of the messenger RNA (mRNA). Through a systematic search of active genes in adipose tissue, we found adiponectin, encoded by the most abundantly expressed gene in adipose tissue, termed apM1 (adipose most abundant gene transcript-1). Fat specific gene library generated in this Japanese Human Genome Project identified many other key molecules of this tissue such as leptin, PPARgamma and aP2 (adipocyte fatty acid binding protein, FABP4), in addition to apM1. Following 10 years, hundreds of clinical studies implicated the critical role of adiponectin in the metabolic syndrome. Also organized establishment of aP2 related mice model revealed the impact of this cytoplasmic fatty acid binding protein in the development of metabolic syndrome. In summary, investigating fat specific genes was amazingly powerful for analyses of the physiology of this tissue, as well as the etiology and complications of obesity.
Diabetes Res Clin Pract 2007 Sep
PMID:Role of adiponectin and adipocyte fatty acid binding protein in the metabolic syndrome. 1748 68

Diabetes mellitus is one of the most common endocrine disorders. It affects almost 6% of the world's population, and its prevalence continues to increase. The causes of diabetes mellitus are multifactorial, and in the general population both genetic and environmental factors contribute evenly to its development. Several genes have been consistently associated with type 2 diabetes mellitus; however, it is not clear how many of those translate into increased cardiovascular disease risk. Recent evidence suggests that genetic variation at the CALPN10, FABP4, GK, GST, PPARA, and PPARG loci may confer higher cardiovascular disease risk in patients with type 2 diabetes mellitus. However, the evidence is scattered and inconclusive and its translation into practical clinical testing will require studies properly designed to examine not only simple genetic associations but also gene-gene and gene-environment interactions.
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PMID:Genetic links between diabetes mellitus and coronary atherosclerosis. 1824 14


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