Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many biological activities of all-trans-retinoic acid (RA) are mediated by the ligand-activated transcription factors termed retinoic acid receptors (RARs), but this hormone can also activate the nuclear receptor peroxisome proliferation-activated receptor beta/delta (PPARbeta/delta). We show here that adipocyte differentiation is accompanied by a shift in RA signaling which, in mature adipocytes, allows RA to activate both RARs and PPARbeta/delta, thereby enhancing lipolysis and depleting lipid stores. In vivo studies using a dietary-induced mouse model of obesity indicated that onset of obesity is accompanied by downregulation of adipose PPARbeta/delta expression and activity. RA treatment of obese mice induced expression of PPARbeta/delta and RAR target genes involved in regulation of lipid homeostasis, leading to weight loss and improved insulin responsiveness. RA treatment also restored adipose PPARbeta/delta expression. The data indicate that suppression of obesity and insulin resistance by RA is largely mediated by PPARbeta/delta and is further enhanced by activation of RARs. By targeting two nuclear receptors, RA may be a uniquely efficacious agent in the therapy and prevention of the metabolic syndrome.
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PMID:All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. 1936 26

Retinol-binding protein-4 (RBP4) is an emerging candidate drug target for type 2 diabetes and lipofuscin-mediated macular degeneration. The retinoic acid derivative fenretinide (N-(4-hydroxyphenyl) retinamide; HPR) exerts therapeutic effects in mouse models of obesity, diabetes, and Stargardt's disease by targeting RBP4. Fenretinide competes with retinoids for RBP4 binding, disrupts RBP4-transthyretin (TTR) complexes, and results in urinary secretion of RBP4 and systemic depletion of retinol. To enable the search for nonretinoid molecules with fenretinide-like activities we developed a HTS-compatible homogeneous TR-FRET assay monitoring the displacement of retinoic acid derivatives from RBP4 in high-density 384-well and 1536-well microtiter plate formats. The retinoid displacement assay proved to be highly sensitive and robust after miniaturization with IC(50)s for fenretinide and retinol ranging around 50 and 100 nM, respectively, and Z'-factors around 0.7. In addition, a surface plasmon resonance (SPR)-based secondary assay was developed to interrogate small molecule RBP4 binders for their ability to modulate the RBP4-TTR interaction. Finally, a 1.6 x 10(6) compound library was screened against the retinoid displacement assay. Several potent retinoid competitors were identified that also appeared to disrupt RBP4-TTR complexes. Some of these compounds could potentially serve as valuable tools to further probe RBP4 biology in the future.
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PMID:Time-resolved fluorescence resonance energy transfer and surface plasmon resonance-based assays for retinoid and transthyretin binding to retinol-binding protein 4. 1948 4

The uncoupling protein-1 (UCP1) is the molecular effector of thermogenesis in brown adipocytes, a process in which there is a renewed interest after the recent recognition of its relevance in adult humans. Typical white adipocytes do not express UCP1. We investigated the capacity of retinoic acid (RA), the carboxylic acid form of vitamin A and a known positive regulator of UCP1 gene transcription in brown adipocytes, to stimulate UCP1 expression in adipocytes differentiated in culture from primary mouse embryonic fibroblasts (MEFs), which are commonly used as white adipocyte model cells. Exposure to all-trans RA (ATRA), but not to rosiglitazone or isoproterenol, potently induced UCP1 expression at both the mRNA and protein level in MEF-derived adipocytes, in a dose-dependent manner. The effect on UCP1 mRNA was reproduced by retinoid receptor agonists and by retinaldehyde, required p38 mitogen-activated protein kinase activity (p38 MAPK), and appeared to be dissociated from increases in mitochondria biogenesis and oxidative capacity. MEF-derived adipocytes exhibited a high mRNA expression level of the brown fat determination factor PRDM16. The results highlight a specific potential of retinoids to induce UCP1 gene expression in adipose cells, and may have implications for the elucidation of the signaling pathways to the UCP1 gene, as well as for research using MEF-derived adipocytes.
Obesity (Silver Spring) 2010 Apr
PMID:Induction of uncoupling protein-1 in mouse embryonic fibroblast-derived adipocytes by retinoic acid. 1983 71

Retinol-binding protein 4 (RBP4) is a recently identified adipokine that was involved in insulin resistance. RBP4 is predominantly expressed from the liver in normal metabolic state to transport retinoids throughout the body, but the exact physiological function and the regulatory mechanisms of adipocyte-derived RBP4 have not been revealed. We conducted the genetic analysis about metabolic parameters in Japanese and Mongolian; the minor allele carriers of regulatory single-nucleotide polymorphism (SNP -803G>A) showed significantly higher BMI in Japanese men (P = 0.009) and women (P = 0.017), and in Mongolian women (P = 0.009). Relative quantification of RBP4 transcripts in -803GA heterozygotes showed that the minor allele-linked haplotype-derived mRNA was significantly more abundant than the transcript from major allele. RBP4 promoter assay in 3T3L1 adipocytes revealed that the minor allele increased the promoter activity double to triple and the administration of 9-cis-retinoic acid (RA) and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) enhanced the activity. Multiple alignment analysis of human, mouse, rat, and cattle RBP4 promoter suggested conserved seven transcription factor binding motifs. Electrophoretic mobility shift assay showed the -803G>A SNP modulate the affinity against unidentified DNA-binding factor, which was assumed to be a suppressive factor. These results collectively suggested that the minor allele of RBP4 regulatory SNP enhanced the expression in adipocytes, which may be associated with the adipogenesis.
Obesity (Silver Spring) 2010 May
PMID:Regulatory SNP in the RBP4 gene modified the expression in adipocytes and associated with BMI. 1985 3

Regular consumption of green tea benefits people in prevention from cardiovascular disorders, obesity as well as neurodegenerative diseases. (-)-Epigallocatechin-3-gallate (EGCG) is regarded as the most biologically active catechin in green tea. However, the stability and bioavailability of EGCG are restricted. The purpose of the present study was to investigate whether a pro-drug, a fully acetylated EGCG (pEGCG), could be more effective in neuroprotection in Parkinsonism mimic cellular model. Retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cells were pre-treated with different concentrations of EGCG and pEGCG for 30 min and followed by incubation of 25 microM 6-hydroxydopamine (6-OHDA) for 24h. We found that a broad dosage range of pEGCG (from 0.1 to 10 microM) could significantly reduce lactate dehydrogenase release. Likewise, 10 microM of pEGCG was effective in reducing caspase-3 activity, while EGCG at all concentrations tested in the model failed to attenuate caspase-3 activity induced by 6-OHDA. Furthermore, Western-blot analysis showed that Akt could be one of the specific signaling pathways stimulated by pEGCG in neuroprotection. It was demonstrated that 25 microM of 6-OHDA significantly suppressed the phosphorylation level of Akt. Only pEGCG at 10 microM markedly increased its phosphorylation level compared to 6-OHDA alone. Taken together, as pEGCG has higher stability and bioavailability for further investigation, it could be a potential neuroprotective agent and our current findings may offer certain clues for optimizing its application in future.
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PMID:A pro-drug of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) prevents differentiated SH-SY5Y cells from toxicity induced by 6-hydroxydopamine. 2002 75

Retinoic acid (RA) was found to be a ligand for peroxisome proliferation-activated receptor delta (PPARdelta) as well as the classical RA receptor (RAR). Carrier proteins that move the RA from the cytosol into the nucleus are the fatty acid-binding protein 5 (FABP5), activating PPARdelta, and the cellular retinoic acid-binding protein II (CRABPII), activating RAR. The ratio of FABP5/CRABPII concentrations determines which receptor is activated. By activating PPARdelta, RA was found to induce expression of genes affecting lipid and glucose homeostasis, in particular, leading to expression of the insulin-signaling gene PDK1 and improvement of insulin action. Hence, RA stimulates lipolysis and reduces triglyceride content. In vivo, obesity has led to downregulation of adipose PPARdelta expression. RA implantation into obese mice has caused upregulation of levels of PPARdelta and consequent weight loss as well as increased expression of PPARdelta target genes, including the insulin-signaling gene PDK1.
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PMID:Retinoic acid activation of peroxisome proliferation-activated receptor delta represses obesity and insulin resistance. 2004 1

Although the regulation of osteoblast and adipocyte differentiation from mesenchymal stem cells has been studied for some time, very little is known about what regulates their appearance in discrete regions of the embryo. Here we show that, as in other vertebrates, zebrafish osteoblasts and adipocytes originate in part from cephalic neural crest (CNC) precursors. We investigated the roles that the retinoic acid (RA) and Peroxisome proliferator-activated receptor gamma (Pparg) pathways play in vivo and found that both pathways act on CNC to direct adipocyte differentiation at the expense of osteoblast formation. In addition, we identify two distinct roles for RA in the osteoblast lineage: an early role in blocking the recruitment of osteoblasts and a later role in mature osteoblasts to promote bone matrix synthesis. These findings might help to increase our understanding of skeletal and obesity-related diseases and aid in the development of stem cell-based regenerative therapies.
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PMID:Regulation of neural crest cell fate by the retinoic acid and Pparg signalling pathways. 2008 Nov 87

Thyroid hormone receptor (TR) and liver X-receptor (LXR) are the master regulators of lipid metabolism. Remarkably, a mouse with a targeted deletion of both LXR alpha and LXR beta is resistant to western diet-induced obesity, and exhibits ectopic liver expression of the thyroid hormone activating type 2 deiodinase (D2). We hypothesized that LXR/retinoid X-receptor (RXR) signaling inhibits hepatic D2 expression, and studied this using a luciferase reporter containing the human DIO2 (hDIO2) promoter in HepG2 cells. Given that, in contrast to mammals, the chicken liver normally expresses D2, the chicken DIO2 (cDIO2) promoter was also studied. 22(R)-OH-cholesterol negatively regulated hDIO2 in a dose-dependent manner (100 microM, approximately twofold), while it failed to affect the cDIO2 promoter. Truncations in the hDIO2 promoter identified the region -901 to -584 bp as critical for negative regulation. We also investigated if 9-cis retinoic acid (9-cis RA), the ligand for the heterodimeric partner of TR and LXR, RXR, could regulate the hDIO2 promoter. Notably, 9-cis RA repressed the hDIO2 luciferase reporter (1 microM, approximately fourfold) in a dose-dependent manner, while coexpression of an inactive mutant RXR abolished this effect. However, it is unlikely that RXR homodimers mediate the repression of hDIO2 since mutagenesis of a DR-1 at -506 bp did not interfere with 9-cis RA-mediated repression. Our data indicate that hDIO2 transcription is negatively regulated by both 22(R)-OH-cholesterol and 9-cis RA, which is consistent with LXR/RXR involvement. In vivo, the inhibition of D2-mediated tri-iodothyronine (T(3)) production by cholesterol/9-cis RA could function as a feedback loop, given that T(3) decreases hepatic cholesterol levels.
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PMID:Regulation of thyroid hormone activation via the liver X-receptor/retinoid X-receptor pathway. 2017 47

Numerous physiological processes require retinoids, including development, nervous system function, immune responsiveness, proliferation, differentiation, and all aspects of reproduction. Reliable retinoid quantification requires suitable handling and, in some cases, resolution of geometric isomers that have different biological activities. Here we describe procedures for reliable and accurate quantification of retinoids, including detailed descriptions for handling retinoids, preparing standard solutions, collecting samples and harvesting tissues, extracting samples, resolving isomers, and detecting with high sensitivity. Sample-specific strategies are provided for optimizing quantification. Approaches to evaluate assay performance also are provided. Retinoid assays described here for mice also are applicable to other organisms including zebrafish, rat, rabbit, and human and for cells in culture. Retinoid quantification, especially that of retinoic acid, should provide insight into many diseases, including Alzheimer's disease, type 2 diabetes, obesity, and cancer.
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PMID:Quantification of endogenous retinoids. 2055 20

Increasing evidence has been provided for a connection between retinoid metabolism and the activity of peroxisome proliferator receptors (Ppars) in the control of body fat reserves. Two different precursors for retinoids exist in the diet as preformed vitamin A (all-trans-retinol) and provitamin A (beta,beta-carotene). For retinoid production, beta,beta-carotene is converted to retinaldehyde by beta,beta-carotene monooxygenase 1 (Bcmo1). Previous analysis showed that Bcmo1 knock-out mice develop dyslipidemia and are more susceptible to diet-induced obesity. However, the role of Bcmo1 for adipocyte retinoid metabolism has yet not been well defined. Here, we showed that Bcmo1 mRNA and protein expression are induced during adipogenesis in NIH 3T3-L1 cells. In mature adipocytes, beta,beta-carotene but not all-trans-retinol was metabolized to retinoic acid (RA). RA decreased the expression of Ppar gamma and CCAAT/enhancer-binding protein alpha, key lipogenic transcription factors, and reduced the lipid content of mature adipocytes. This process was inhibited by the retinoic acid receptor antagonist LE450, showing that it involves canonical retinoid signaling. Accordingly, gavage of beta,beta-carotene but not all-trans-retinol induced retinoid signaling and decreased Ppar gamma expression in white adipose tissue of vitamin A-deficient mice. Our study identifies beta,beta-carotene as a critical physiological precursor for RA production in adipocytes and implicates provitamin A as a dietary regulator of body fat reserves.
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PMID:Beta,beta-carotene decreases peroxisome proliferator receptor gamma activity and reduces lipid storage capacity of adipocytes in a beta,beta-carotene oxygenase 1-dependent manner. 2057 61


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