Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.34 (lipoprotein lipase)
7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adiponectin is a plasma protein expressed exclusively in adipose tissue. Adiponectin levels are linked to insulin sensitivity, but a direct effect of chronically elevated adiponectin on improved insulin sensitivity has not yet been demonstrated. We identified a dominant mutation in the collagenous domain of adiponectin that elevated circulating adiponectin values in mice by 3-fold. Adiponectinemia raised lipid clearance and lipoprotein lipase activity, and suppressed insulin-mediated endogenous glucose production. The induction of adiponectin during puberty and the sexual dimorphism in adult adiponectin values were preserved in these transgenic animals. As a result of elevated adiponectin, serum PRL values and brown adipose mass both increased. The effects on carbohydrate and lipid metabolism were associated with elevated phosphorylation of 5'-AMP-activated protein kinase in liver and elevated expression of peroxisomal proliferator-activated receptor gamma2, caveolin-1, and mitochondrial markers in white adipose tissue. These studies strongly suggest that increasing endogenous adiponectin levels has direct effects on insulin sensitivity and may induce similar physiological responses as prolonged treatment with peroxisomal proliferator-activated receptor gamma agonists.
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PMID:A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. 1457 79

Interconversion of bone marrow osteoblasts and adipocytes has been reported previously. However, the osteogenic potential of extramedullary adipocytes is not known. Thus, we incubated a pure culture of human subcutaneous adipocytes in control medium for 1-2 weeks. Afterward, the cells were incubated in either osteoblast medium (OB medium) containing various combinations of calcitriol, dexamethasone, ascorbic acid, and beta-glycerophosphate or in adipocyte medium (AD medium) containing HEPES, biotin, pantothenate, insulin, triiodothyronine, dexamethasone, and isobutylmethylxanthine for 4 weeks. Expression of osteoblastic and adipocytic phenotypes was examined by determination of lineage-specific mRNA markers and in vitro adipocyte and osteoblast formation. Cells were also implanted, mixed with hydroxyapatite-tricalcium phosphate powder, in the subcutaneous tissue of immunodeficient mice in order to assess in vivo bone formation potential. One week after incubation in control medium, cells formed fusiform elongated fibroblast-like cells. In OB medium, cells stained positive for alkaline phosphatase (AP) and expressed mRNAs encoding Cbfa1/Runx2, AP, and osteocalcin. In AD medium cells reacquired adipocyte morphology with multilocular lipid-filled cells. Also, the cells expressed adipocyte-specific mRNA markers: lipoprotein lipase and peroxisome proliferator-activated receptor gamma2. Bone was formed only in the in vivo implants of cells incubated in OB medium. In conclusion, extramedullary adipocytes can transdifferentiate to bone-forming cells. Because of their ease of isolation, adipocytes may be good candidates for tissue-engineering protocols aimed at creating bone tissue for the repair of nonunion fractures and large bone defects.
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PMID:Subcutaneous adipocytes can differentiate into bone-forming cells in vitro and in vivo. 1516 55

This study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), tumor necrosis factor-alpha (TNF-alpha)); iii) thermogenesis and free fatty acid (FFA) transport/catabolism (uncoupling protein-1 (UCP1), lipoprotein lipase (LPL), beta2- and beta3-adrenergic receptor (beta2AR, beta3AR), fatty acid transport protein-1 (FATP-1) and iv) lipoproteins (apoliprotein E (apoE), apo CIII). The 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated. The single gene mutations such as C105 T OB and Pro115 Gln PPAR-gamma2 linked to morbid obesity were not detected in our group. A weak correlation between obesity and certain gene polymorphisms was observed. Being overweight (25 < BMI > or = 30 kg/m2) significantly correlated with worse FFA tolerance in male PPAR-gamma2 12Pro, LPL-H (G) allele carriers. Insulin resistance was found in female PPAR-gamma2 Pro12, TNF-alpha (-308A) and LPL-H (G) allele carriers. Hypertension linked to the PPAR-gamma2 Pro allele carriers was characterized by high leptin output during OLTT. We conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.
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PMID:Analysis of candidate genes in Polish families with obesity. 1520 83

Human mesenchymal stem cells (hMSCs) have the capacity to differentiate along several pathways to form bone, cartilage, tendon, muscle, and adipose tissues. The adult hMSCs reside in vivo in the bone marrow in niches where oxygen concentration is far below the ambient air, which is the most commonly encountered laboratory condition. The study reported here was designed to determine whether oxygen has a role in the differentiation of hMSCs into adipocytes. Indeed, when exposed to atmosphere containing only 1% of oxygen, the formation of adipocyte-like phenotype with cytoplasmic lipid inclusions was observed. The effect of hypoxia on the expression of adipocyte-specific genes was determined by real-time reverse transcription polymerase chain reaction. Interestingly, neither of the two central regulators of adipogenesis--the transcription factors peroxisome proliferator-activated receptor gamma2 (PPAR-gamma2) and ADD1/SREBP1c-was induced. Furthermore, hypoxia did not have any effect on the transcription of early (lipoprotein lipase) or late (aP2) marker genes. By the same token, neither of the mature adipocyte-specific genes--leptin and adipophilin--was found responsive to the treatment. High level of induction, however, was observed with the PPAR-gamma-induced angiopoietin-related gene, PGAR. The lack of an adipocyte-specific transcription pattern thus indicates that despite accumulation of the lipid, true adipogenic differentiation did not take place. In conclusion, hypoxia appears to exert a potent lipogenic effect independent of PPAR-gamma2 maturation pathway.
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PMID:Induction of adipocyte-like phenotype in human mesenchymal stem cells by hypoxia. 1557 52

Although hypoxia and transforming growth factor-beta (TGF-beta) inhibit differentiation of adipocytes from preadipocytes and bone marrow-derived cells in several species, the relationship between hypoxia and TGF-beta signaling in adipocytogenesis is unknown. In this study, we evaluated the mechanisms of inhibition of adipocyte differentiation by hypoxia and TGF-beta in human and murine marrow stromal cells (MSCs) and the role of TGF-beta/Smad signaling in the inhibition of adipocytogenesis by hypoxia. Both hypoxia-mimetic deferoxamine mesylate (DFO) and TGF-beta1 inhibited adipocyte differentiation (1.0% versus the control at 15 microm DFO and 1.4% versus the control at 1 ng/ml TGF-beta1) and adipocyte gene expression (peroxisome proliferator-activated receptor-gamma2 and lipoprotein lipase) in human MSCs after 21 days of treatment. Hypoxia (2% O(2)) and DFO (but not TGF-beta1) increased hypoxia-inducible factor-1alpha as shown by Western blotting. Macroarrays and Western and Northern blot analyses showed that hypoxia activated the TGF-beta/Smad signaling pathway and that both hypoxia and TGF-beta1 modulated adipocyte differentiation pathways such as the insulin-, peroxisome proliferator-activated receptor-gamma-, phosphatidylinositol 3-kinase-, and MAPK-associated signaling pathways. Studies with mouse marrow stromal cell lines derived from Smad3(+/+) or Smad3(-/-) mice revealed that the TGF-beta type I receptor (ALK-5) and its intracellular signaling molecule Smad3 were necessary for the inhibition of adipocyte differentiation by both TGF-beta and hypoxia-mimetic DFO. Thus, the TGF-beta/Smad signaling pathway is required for hypoxia-mediated inhibition of adipocyte differentiation in MSCs.
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PMID:Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires transforming growth factor-beta/Smad3 signaling. 1584 40

Functional engineering of musculoskeletal tissues generally involves rapid expansion of progenitor cells in vitro while retaining their potential for further differentiation and then induction in specific culture conditions. The autologous adipose-derived stromal cells (ASCs) are considered to contain pluripotent mesenchymal stem cells. Imaging with expression of green fluorescent protein (GFP) facilitates the detailed research on ASCs physiological behavior during differentiation into a variety of cell lineages both in vitro and in vivo. In this study, we aimed to confirm the trans-germ plasticity of homogeneously marked ASCs from GFP transgenic mice. Simultaneously, the term and intensity of GFP expression in ASCs were also focused on during variant inductions, when cells were incubated with multiple growth factors and adjuvant. ASCs were harvested from inguinal fat pads of transgenic nude mice, passaged 3 times in monolayer cultures, and then transferred to osteogenic, adipogenic, neurogenic, and myogenic medium. The morphological characterization of inductive cells was observed using phase-contrast microscopy and histological staining such as alizarin red for mineralization nodules and oil red O for lipid accumulation. The expression of marker genes or proteins was measured using RT-PCR and immunocytochemical analysis. Collagen type I, osteopontin (OPN), and osteocalcin (OCN) were positive in osteogenic lineages, peroxisome proliferator-activated receptor(PPAR)-gamma2 and lipoprotein lipase (LPL) were positive in adipogenic ones, glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) were positive in neurogenic ones, and alpha-smooth muscle actin (alpha-SMA) was positive in myogenic ones. Moreover, the results of fluorescence microscopic imaging suggested that there was no significant decline of GFP expression during ASCs differentiation and the level of GFP maintained stable till differentiated ASCs showed apoptotic phenotype. So the endogenous GFP and multilineage potential of transgenic ASCs had no influences on each other. Since the population of GFP ASCs can be easily identified, it is proposed that they may be promising candidate seed cells for further studies on ASCs tissue engineering, especially the study on engineered tissues formed in vivo.
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PMID:Multilineage differentiation of adipose-derived stromal cells from GFP transgenic mice. 1647 77

We have previously identified four novel isoforms of PPAR-gamma transcripts in monkey macrophages (J. Zhou, K.M. Wilson, J.D. Medh, Genetic analysis of four novel peroxisome proliferator receptor-gamma splice variants in monkey macrophages. Biochem. Biophys. Res. Commun., 293 (2002) 274-283). The purpose of this study was to ascertain that these isoforms are also present in humans. Specific primers were designed to amplify individual isoform transcripts. The presence of PPAR-gamma4, PPAR-gamma5, and PPAR-gamma7 transcripts in human THP-1 macrophages was confirmed by RT-PCR and sequencing. A transcript corresponding to PPAR-gamma6 was not detected. The presence of novel full-length transcripts and protein was also ascertained by Northern and Western blot analysis. Treatment of THP-1 cells with 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) resulted in more than 20% induction in the expression of PPAR-gamma5 and PPAR-gamma7 transcripts by both Northern blot analysis and RT-PCR. Another PPAR-gamma ligand, troglitazone, induced expression of only PPAR-gamma5. Both ligands inhibited the expression of PPAR-gamma1 and PPAR-gamma2. Additionally, 15d-PGJ2 and troglitazone increased the level of apolipoprotein E transcript by 60% but decreased lipoprotein lipase expression by 15% in THP-1 cells. The differential regulation of PPAR-gamma transcripts suggests that each transcript isoform may contribute to macrophage function.
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PMID:Identification and regulation of novel PPAR-gamma splice variants in human THP-1 macrophages. 1654 39

Musculoskeletal tissues regeneration requires rapid expansion of seeding cells both in vitro and in vivo while maintaining their multilineage differentiation ability. Human adipose-derived stem cells (ASCs) are considered to contain multipotent mesenchymal stem cells. Monolayer cultures of human ASCs were isolated from human lipoaspirates and passaged 3 times and then infected with replication-incompetent adenoviral vectors carrying green fluorescent protein (Ad/GFP) genes. Then, Ad/GFP infected human ASCs were transferred to osteogenic, chondrogenic, adipogenic, and myogenic medium. The morphological characterization of induced cells was observed using phase-contrast microscopy and fluorescence microscopy. The expression of marker proteins or genes was measured by immunocytochemical and RT-PCR analysis. Osteopontin (OPN), and osteocalcin (OCN) were positive in osteogenic lineages, aggrecan and SOX9 were positive in chondrogenic ones, peroxisome proliferator-activated receptor (PPAR-gamma2) and lipoprotein lipase (LPL) were positive in adipogenic ones, and myogenin and myod1 was positive in myogenic ones. At the same time, the results of fluorescence microscopic imaging proved that the high level of GFP expression during ASCs differentiation maintained stable nearly 2 months. So the exogenous GFP and multilineage potential of human ASCs had no severe influences on each other. Since the human ASCs can be easily obtained and abundant, it is proposed that they may be promising candidate cells for further studies on tissue engineering. Imaging with expression of GFP facilitates the research on ASCs physiological behavior and application in tissue engineering during differentiation both in vitro and in vivo.
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PMID:Pluripotency potential of human adipose-derived stem cells marked with exogenous green fluorescent protein. 1671 63

Peroxisome proliferator-activated receptor gamma2 (PPARgamma) is a nuclear transcription factor that regulates adipocyte differentiation and lipogenic genes during adipogenesis. The activity of rodent PPARgamma is regulated by phosphorylation of serine 112. The current experiment was designed to study the ability of porcine PPARgamma to stimulate transdifferentiation of myoblasts to adipocytes by overexpressing wild-type PPARgamma or mutated PPARgamma (serine 112 was mutated to alanine) in mouse myoblast cells. The expression of adipogenic marker genes (adipocyte fatty acid binding protein, lipoprotein lipase, and glycerol-3 phosphate dehydrogenase) in cells stably expressing mutated porcine PPARgamma was greater than in cells with wild-type PPARgamma, indicating that the mutated PPARgamma has greater adipogenic capability than the wild-type PPARgamma. Under treatment with a ligand, both wild-type and mutant porcine PPARgamma-expressing C2C12 myoblasts differentiated into adipocytes in 10 d. The expression of myogenic marker genes (myogenin, myogenic regulatory factor-4) was suppressed in cells transfected with the mutated PPARgamma or wild-type PPARgamma. Moreover, wild-type and mutant PPARgamma were able to inhibit myogenesis without addition of a ligand. Our results suggest that porcine wild-type PPARgamma and mutated PPARgamma can both convert myoblast cells into adipocytes, and also that the ability to transdifferentiate was greater in cells containing the mutated PPARgamma than in cells containing the wild-type PPARgamma. Therefore, the existence of serine 112 in PPARgamma may have a role in regulating adipocyte differentiation.
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PMID:Porcine peroxisome proliferator-activated receptor gamma induces transdifferentiation of myocytes into adipocytes. 1697 66

Knowledge of the basic mechanisms controlling osteogenesis and adipogenesis might provide new insights into the prevention of osteoporosis and age-related osteopenia. With the help of magnetic cell sorting and fluorescence activated cell sorting (FACS), osteoblastic subpopulations of mesenchymal progenitor cells were characterized. Alkaline phosphatase (AP) negative cells expressed low levels of osteoblastic and adipocytic markers. AP positive cells expressed adipocytic markers more strongly than the AP negative cell populations, thus suggesting that committed osteoblasts exhibit a greater adipogenic potential. AP negative cells differentiated to the mature osteoblastic phenotype, as demonstrated by increased AP-activity and osteocalcin secretion under standard osteogenic culture conditions. Surprisingly, this was accompanied by increased expression of adipocytic gene markers such as peroxisome proliferator-activated receptor-gamma2, lipoprotein lipase and fatty acid binding protein. The induction of adipogenic markers was suppressed by transforming growth factor-beta1 (TGF-beta1) and promoted by bone morphogenetic protein 2 (BMP-2). Osteogenic culture conditions including BMP-2 induced both the formation of mineralized nodules and cytoplasmic lipid vacuoles. Upon immunogold electron microscopic analysis, osteoblastic and adipogenic marker proteins were detectable in the same cell. Our results suggest that osteogenic and adipogenic differentiation in human mesenchymal progenitor cells might not be exclusively reciprocal, but rather, a parallel event until late during osteoblast development.
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PMID:Coexpression of osteogenic and adipogenic differentiation markers in selected subpopulations of primary human mesenchymal progenitor cells. 1828 43


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