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Article: Wnt/beta-catenin signaling in adipogenesis and metabolism.

Prestwich, Tyler C / Macdougald, Ormond A

2007 Volume 19, Issue 6, Page(s) 612–617

Abstract: Adipocyte differentiation consists of a complex series of events in which scores of cellular and extracellular factors interact to transform a fibroblast-like preadipocyte into a mature, lipid-filled adipocyte. Many of the pathways influencing this ... ...

Abstract	Adipocyte differentiation consists of a complex series of events in which scores of cellular and extracellular factors interact to transform a fibroblast-like preadipocyte into a mature, lipid-filled adipocyte. Many of the pathways influencing this process have been identified using well-characterized preadipocyte culture systems and have subsequently been confirmed in animal models. Research conducted over the past decade has established the Wnt/beta-catenin signaling pathway as an important regulator of adipocyte differentiation. While initial reports implicated activators of Wnt/beta-catenin signaling as potent inhibitors of adipogenesis, recent investigations of mesenchymal cell fate, obesity, and type 2 diabetes highlight significant additional roles for Wnt signaling in metabolism and adipocyte biology.
MeSH term(s)	Adipogenesis/physiology ; Adipose Tissue/metabolism ; Animals ; Cell Differentiation ; Humans ; Signal Transduction/physiology ; Wnt Proteins/physiology ; beta Catenin/physiology
Chemical Substances	Wnt Proteins ; beta Catenin
Language	English
Publishing date	2007-11-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2007.09.014
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Zs.A 2963: Show issues

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Article ; Online: Hyperphagia and obesity in female mice lacking tissue inhibitor of metalloproteinase-1.

Gerin, Isabelle / Louis, Gwendolyn W / Zhang, Xuan / Prestwich, Tyler C / Kumar, T Rajendra / Myers, Martin G / Macdougald, Ormond A / Nothnick, Warren B

Endocrinology

2008 Volume 150, Issue 4, Page(s) 1697–1704

Abstract: Certain matrix metalloproteinases and their regulators, the tissue inhibitors of metalloproteinases (TIMPs), are involved in development and remodeling of adipose tissue. In studying Timp1( ... ) mice, which have a null mutation in Timp1 (Timp1(-/-)), ...

Abstract	Certain matrix metalloproteinases and their regulators, the tissue inhibitors of metalloproteinases (TIMPs), are involved in development and remodeling of adipose tissue. In studying Timp1(<tm1Pds>) mice, which have a null mutation in Timp1 (Timp1(-/-)), we observed that females exhibit increased body weight by 3 months of age due to increased total body lipid and adipose tissue. Whereas Timp1(-/-) mice have increased size and number of adipocytes, they also display increased food intake despite hyperleptinemia, suggesting that alterations in hypothalamic leptin action or responsiveness may underlie their weight gain. Indeed, leptin promotes the expression of Timp1 mRNA in the hypothalamus, and leptin signaling via signal transducer and activator of transcription-3 mediates the expression of hypothalamic Timp1. Furthermore, Timp1(-/-) mice demonstrate increased food intake and altered expression of certain hypothalamic neuropeptide genes prior to elevated weight gain. Thus, whereas previous data suggested roles for matrix metalloproteinases and TIMPs in the regulation of adipose tissue, these data reveal that Timp1 mRNA is induced by leptin in the hypothalamus and that expression and action of Timp1 contributes to the regulation of feeding and energy balance.
MeSH term(s)	Absorptiometry, Photon ; Adipocytes/cytology ; Adipocytes/metabolism ; Aging/physiology ; Animals ; Body Weight/drug effects ; Eating/drug effects ; Eating/genetics ; Energy Metabolism/drug effects ; Energy Metabolism/genetics ; Female ; Gene Expression/drug effects ; Glucose Tolerance Test ; Hyperphagia/genetics ; Leptin/blood ; Leptin/pharmacology ; Male ; Mice ; Mice, Mutant Strains ; Obesity/genetics ; Polymerase Chain Reaction ; Tissue Inhibitor of Metalloproteinase-1/deficiency ; Tissue Inhibitor of Metalloproteinase-1/genetics ; Tissue Inhibitor of Metalloproteinase-1/physiology
Chemical Substances	Leptin ; Tissue Inhibitor of Metalloproteinase-1
Language	English
Publishing date	2008-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2008-1409
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Article ; Online: Secreted frizzled-related protein 5 suppresses adipocyte mitochondrial metabolism through WNT inhibition.

Mori, Hiroyuki / Prestwich, Tyler C / Reid, Michael A / Longo, Kenneth A / Gerin, Isabelle / Cawthorn, William P / Susulic, Vedrana S / Krishnan, Venkatesh / Greenfield, Andy / Macdougald, Ormond A

The Journal of clinical investigation

2012 Volume 122, Issue 7, Page(s) 2405–2416

Abstract: Preadipocytes secrete several WNT family proteins that act through autocrine/paracrine mechanisms to inhibit adipogenesis. The activity of WNT ligands is often decreased by secreted frizzled-related proteins (SFRPs). Sfrp5 is strongly induced during ... ...

Abstract	Preadipocytes secrete several WNT family proteins that act through autocrine/paracrine mechanisms to inhibit adipogenesis. The activity of WNT ligands is often decreased by secreted frizzled-related proteins (SFRPs). Sfrp5 is strongly induced during adipocyte differentiation and increases in adipocytes during obesity, presumably to counteract WNT signaling. We tested the hypothesis that obesity-induced Sfrp5 expression promotes the development of new adipocytes by inhibiting endogenous suppressors of adipogenesis. As predicted, mice that lack functional SFRP5 were resistant to diet-induced obesity. However, counter to our hypothesis, we found that adipose tissue of SFRP5-deficient mice had similar numbers of adipocytes, but a reduction in large adipocytes. Transplantation of adipose tissue from SFRP5-deficient mice into leptin receptor-deficient mice indicated that the effects of SFRP5 deficiency are tissue-autonomous. Mitochondrial gene expression was increased in adipose tissue and cultured adipocytes from SFRP5-deficient mice. In adipocytes, lack of SFRP5 stimulated oxidative capacity through increased mitochondrial activity, which was mediated in part by PGC1α and mitochondrial transcription factor A. WNT3a also increased oxygen consumption and the expression of mitochondrial genes. Thus, our findings support a model of adipogenesis in which SFRP5 inhibits WNT signaling to suppress oxidative metabolism and stimulate adipocyte growth during obesity.
MeSH term(s)	3T3-L1 Cells ; Adaptor Proteins, Signal Transducing ; Adipocytes/metabolism ; Adipogenesis ; Adipose Tissue, White/pathology ; Animals ; Cell Enlargement ; Cells, Cultured ; Ear, External/pathology ; Energy Metabolism ; Extracellular Matrix/metabolism ; Female ; Glucose/metabolism ; Insulin Resistance ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; Intercellular Signaling Peptides and Proteins/physiology ; Leptin/blood ; Male ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; Obesity/blood ; Obesity/metabolism ; Obesity/pathology ; Oxygen Consumption ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Transcription, Genetic ; Transcriptional Activation ; Wnt Signaling Pathway ; Wnt3A Protein/metabolism ; Wnt3A Protein/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Intercellular Signaling Peptides and Proteins ; Leptin ; RNA, Messenger ; Sfrp5 protein, mouse ; Wnt3A Protein ; Wnt3a protein, mouse ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2012-06-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI63604
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Article: Synthesis and evaluation of fluorogenic substrates for phospholipase D and phospholipase C.

Rose, Tyler M / Prestwich, Glenn D

Organic letters

2006 Volume 8, Issue 12, Page(s) 2575–2578

Abstract: ... synthesized by an enzyme-assisted strategy. The analogues were evaluated as substrates for phospholipases C ...

Abstract	Fluorogenic analogues of phosphatidylcholine and lysophosphatidylcholine, DDPB and lysoDDPB, were synthesized by an enzyme-assisted strategy. The analogues were evaluated as substrates for phospholipases C and D and lysophospholipase D. DDPB was cleaved by bacterial and plant phospholipase D (PLD) enzymes and represents the first direct fluorogenic substrate for real-time measurement of PLD activity. Both fluorogenic substrates have potential in screening for PLD and PC-PLC inhibitors and for monitoring spatiotemporal changes in PLD activity in cells. [structure: see text]
MeSH term(s)	Bacillus cereus/enzymology ; Clostridium perfringens/enzymology ; Enzyme Activation/physiology ; Fluorescent Dyes/chemical synthesis ; Fluorescent Dyes/metabolism ; Lysophosphatidylcholines/chemical synthesis ; Lysophosphatidylcholines/metabolism ; Phosphatidylcholines/chemical synthesis ; Phosphatidylcholines/metabolism ; Phospholipase D/chemistry ; Phospholipase D/metabolism ; Phosphoric Diester Hydrolases/metabolism ; Spider Venoms/enzymology ; Spider Venoms/metabolism ; Type C Phospholipases/chemistry ; Type C Phospholipases/metabolism
Chemical Substances	Fluorescent Dyes ; Lysophosphatidylcholines ; Phosphatidylcholines ; Spider Venoms ; loxosceles venom ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; Type C Phospholipases (EC 3.1.4.-) ; Phospholipase D (EC 3.1.4.4)
Language	English
Publishing date	2006-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1523-7060
ISSN	1523-7060
DOI	10.1021/ol060773d
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Article: Postoperative pericardial adhesion prevention using Carbylan-SX in a rabbit model.

Connors, Rafe C / Muir, Jeffery J / Liu, Yanchun / Reiss, G Russell / Kouretas, Peter C / Whitten, Matthew G / Sorenson, Tyler K / Prestwich, Glenn D / Bull, David A

The Journal of surgical research

2007 Volume 140, Issue 2, Page(s) 237–242

Abstract: Introduction: The presence of dense adhesions within the pericardial space complicates reoperative cardiac surgery. Prior attempts to reduce adhesion formation after primary cardiac surgery using medications or biomaterials have had variable success. ... ...

Abstract	Introduction: The presence of dense adhesions within the pericardial space complicates reoperative cardiac surgery. Prior attempts to reduce adhesion formation after primary cardiac surgery using medications or biomaterials have had variable success. Carbylan-SX (Carbylan Biosurgery Inc., Palo Alto, CA) is a hyaluronan-based biomaterial, which has been shown to be effective at reducing adhesions in a nonthoracic rat model. This study evaluates whether Carbylan-SX can effectively reduce postoperative adhesions within the pericardial cavity. Methods: Thirty-eight New Zealand white rabbits underwent a left lateral thoracotomy. A pericardiotomy was made and epicardial adhesions were induced on the anterior surface of the heart using a Dremel device (Racine, WI). The rabbits were divided into four groups: controls with abrasions only receiving no treatment (n=10), Carbylan-SX films (n=10), Carbylan-SX aerosolized hydrogel (n=10), and Seprafilm (n=8). The pericardial sac and chest were subsequently closed. Rabbits were sacrificed at a mean of 15 days. For histological analysis, each heart was divided into 12 separate 1 mm sections. Computer imaging software was used to measure the adhesion thickness and the mean of 12 random measurements for each animal was recorded and statistical analysis performed. Results: Histological analysis revealed all treatment groups to be significantly better than the control (2159 mum thickness, P<0.0001) at preventing adhesions. The Carbylan-SX film and Carbylan-SX aerosolized hydrogel both proved to be better at preventing adhesions than Seprafilm (Genzyme Corp., Cambridge, MA) with an average adhesion thickness of 454 and 577 microm, respectively, compared with 1319 microm for Seprafilm (P<0.0001 and P<0.0005, respectively). The Carbylan-SX film and Carbylan-SX aerosolized hydrogel were equally effective at preventing adhesion formation. Conclusion: Carbylan-SX film and Carbylan-SX aerosolized crosslinkable hydrogel are equally effective methods of reducing postoperative pericardial adhesions within the pericardial cavity. Both the Carbylan-SX film and aerosolized hydrogel showed a significantly greater reduction in adhesions than Seprafilm. Clinical application of Carbylan-SX could have significant therapeutic implications in the future.
MeSH term(s)	Animals ; Cardiac Surgical Procedures/methods ; Disease Models, Animal ; Gelatin/therapeutic use ; Hyaluronic Acid/analogs & derivatives ; Hyaluronic Acid/therapeutic use ; Hydrogels/therapeutic use ; Male ; Pericardium/pathology ; Pericardium/surgery ; Polyethylene Glycols/therapeutic use ; Postoperative Complications/pathology ; Postoperative Complications/prevention & control ; Rabbits ; Tissue Adhesions/pathology ; Tissue Adhesions/prevention & control
Chemical Substances	Hydrogels ; carbylan-SX ; gelatin film ; Polyethylene Glycols (30IQX730WE) ; Gelatin (9000-70-8) ; Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2007-06-15
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	80170-7
ISSN	1095-8673 ; 0022-4804
ISSN (online)	1095-8673
ISSN	0022-4804
DOI	10.1016/j.jss.2007.03.014
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Article: Wnt10b inhibits obesity in ob/ob and agouti mice.

Wright, Wendy S / Longo, Kenneth A / Dolinsky, Vernon W / Gerin, Isabelle / Kang, Sona / Bennett, Christina N / Chiang, Shian-Huey / Prestwich, Tyler C / Gress, Catherine / Burant, Charles F / Susulic, Vedrana S / MacDougald, Ormond A

Diabetes

2006 Volume 56, Issue 2, Page(s) 295–303

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Adipose Tissue/physiology ; Agouti Signaling Protein ; Animals ; Blood Glucose/physiology ; Disease Models, Animal ; Energy Intake/physiology ; Fatty Acid-Binding Proteins/physiology ; Female ; Insulin Resistance/physiology ; Intercellular Signaling Peptides and Proteins/genetics ; Leptin/deficiency ; Leptin/genetics ; Male ; Mice ; Mice, Transgenic ; Obesity/genetics ; Obesity/physiopathology ; Oxygen Consumption/physiology ; Panniculitis/physiopathology ; Proto-Oncogene Proteins/physiology ; Wnt Proteins/physiology
Chemical Substances	Agouti Signaling Protein ; Blood Glucose ; Fabp4 protein, mouse ; Fatty Acid-Binding Proteins ; Intercellular Signaling Peptides and Proteins ; Leptin ; Proto-Oncogene Proteins ; Wnt Proteins ; Wnt10b protein, mouse
Language	English
Publishing date	2006-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db06-1339
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Article: Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells.

Ren, Juan / Xiao, Yi-jin / Singh, Lisam Shanjukumar / Zhao, Xiaoxian / Zhao, Zhenwen / Feng, Li / Rose, Tyler M / Prestwich, Glenn D / Xu, Yan

Cancer research

2006 Volume 66, Issue 6, Page(s) 3006–3014

Abstract: Lysophosphatidic acid (LPA) is both a potential marker and a therapeutic target for ovarian cancer. It is critical to identify the sources of elevated LPA levels in ascites and blood of patients with ovarian cancer. We show here that human peritoneal ... ...

Abstract	Lysophosphatidic acid (LPA) is both a potential marker and a therapeutic target for ovarian cancer. It is critical to identify the sources of elevated LPA levels in ascites and blood of patients with ovarian cancer. We show here that human peritoneal mesothelial cells constitutively produce LPA, which accounts for a significant portion of the chemotactic activity of the conditioned medium from peritoneal mesothelial cells to ovarian cancer cells. Both production of LPA by peritoneal mesothelial cells and the chemotactic activity in the conditioned medium can be blocked by HELSS [an inhibitor of the calcium-independent phospholipase A(2) (iPLA(2))] and AACOCF(3) [an inhibitor of both cytosolic PLA(2) (cPLA(2)) and iPLA(2)]. Moreover, cell-based enzymatic activity assays for PLA(2) indicate that peritoneal mesothelial cells have strong constitutive PLA(2) activity. Receptors for LPA, LPA(2), and LPA(3) are involved in the conditioned medium-induced chemotactic activity. Invasion of ovarian cancer cells into peritoneal mesothelial cells has also been analyzed and shown to require PLA(2), LPA receptors, and the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. Thus, we show here, for the first time, that human peritoneal mesothelial cells constitutively produce bioactive lipid signaling molecules, such as LPA, via iPLA(2) and/or cPLA(2) activities. Conditioned medium from peritoneal mesothelial cells stimulate migration, adhesion, and invasion of ovarian cancer cells, and may play similar roles in vivo.
MeSH term(s)	Arachidonic Acids/pharmacology ; Cell Adhesion/physiology ; Cell Line, Tumor ; Cell Movement/physiology ; Collagen Type I ; Culture Media, Conditioned ; Cytosol/enzymology ; Epithelium/enzymology ; Epithelium/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Group VI Phospholipases A2 ; Humans ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/metabolism ; Lysophospholipids/biosynthesis ; Lysophospholipids/physiology ; Naphthalenes/pharmacology ; Ovarian Neoplasms/enzymology ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Peritoneal Cavity/pathology ; Peritoneum/enzymology ; Peritoneum/metabolism ; Phosphodiesterase Inhibitors/pharmacology ; Phospholipases A/antagonists & inhibitors ; Phospholipases A/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Pyrones/pharmacology
Chemical Substances	Arachidonic Acids ; Collagen Type I ; Culture Media, Conditioned ; Isoenzymes ; Lysophospholipids ; Naphthalenes ; Phosphodiesterase Inhibitors ; Pyrones ; arachidonyltrifluoromethane (00XIW1CR0F) ; 6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one (88070-98-8) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Phospholipases A (EC 3.1.1.32) ; Group VI Phospholipases A2 (EC 3.1.1.4) ; PLA2G6 protein, human (EC 3.1.1.4) ; lysophosphatidic acid (PG6M3969SG)
Language	English
Publishing date	2006-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-05-1292
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Article: Wnt/beta-catenin signaling in adipogenesis and metabolism.

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Article ; Online: Hyperphagia and obesity in female mice lacking tissue inhibitor of metalloproteinase-1.

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Article ; Online: Secreted frizzled-related protein 5 suppresses adipocyte mitochondrial metabolism through WNT inhibition.

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Article: Synthesis and evaluation of fluorogenic substrates for phospholipase D and phospholipase C.

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Article: Postoperative pericardial adhesion prevention using Carbylan-SX in a rabbit model.

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Article: Wnt10b inhibits obesity in ob/ob and agouti mice.

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Article: Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells.

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