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Article ; Online: Therapeutic Genome Editing With CRISPR/Cas9 in a Humanized Mouse Model Ameliorates α1-antitrypsin Deficiency Phenotype.

Bjursell, Mikael / Porritt, Michelle J / Ericson, Elke / Taheri-Ghahfarokhi, Amir / Clausen, Maryam / Magnusson, Lisa / Admyre, Therese / Nitsch, Roberto / Mayr, Lorenz / Aasehaug, Leif / Seeliger, Frank / Maresca, Marcello / Bohlooly-Y, Mohammad / Wiseman, John

EBioMedicine

2018 Volume 29, Page(s) 104–111

Abstract: α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene ... ...

Abstract	α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene in which a point mutation (commonly referred to as PiZ) causes aggregation of the miss-folded protein in hepatocytes resulting in subsequent liver damage. In an attempt to rescue the pathologic liver phenotype of a mouse model of human AAT deficiency (AATD), we used adenovirus to deliver Cas9 and a guide-RNA (gRNA) molecule targeting hSERPINA1. Our single dose therapeutic gene editing approach completely reverted the phenotype associated with the PiZ mutation, including circulating transaminase and human AAT (hAAT) protein levels, liver fibrosis and protein aggregation. Furthermore, liver histology was significantly improved regarding inflammation and overall morphology in hSERPINA1 gene edited PiZ mice. Genomic analysis confirmed significant disruption to the hSERPINA1 transgene resulting in a reduction of hAAT protein levels and quantitative mRNA analysis showed a reduction in fibrosis and hepatocyte proliferation as a result of editing. Our findings indicate that therapeutic gene editing in hepatocytes is possible in an AATD mouse model.
MeSH term(s)	Adenoviridae/genetics ; Animals ; CRISPR-Cas Systems ; Cell Proliferation ; Disease Models, Animal ; Gene Editing ; Gene Expression ; Genetic Vectors/genetics ; Humans ; Mice ; Mice, Transgenic ; Phenotype ; Transduction, Genetic ; Transgenes ; alpha 1-Antitrypsin/blood ; alpha 1-Antitrypsin/genetics ; alpha 1-Antitrypsin/metabolism ; alpha 1-Antitrypsin Deficiency/genetics ; alpha 1-Antitrypsin Deficiency/metabolism ; alpha 1-Antitrypsin Deficiency/pathology ; alpha 1-Antitrypsin Deficiency/therapy
Chemical Substances	alpha 1-Antitrypsin
Language	English
Publishing date	2018-02-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2018.02.015
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Zs.A 7090: Show issues

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Article ; Online: Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery.

Lundin, Anders / Porritt, Michelle J / Jaiswal, Himjyot / Seeliger, Frank / Johansson, Camilla / Bidar, Abdel Wahad / Badertscher, Lukas / Wimberger, Sandra / Davies, Emma J / Hardaker, Elizabeth / Martins, Carla P / James, Emily / Admyre, Therese / Taheri-Ghahfarokhi, Amir / Bradley, Jenna / Schantz, Anna / Alaeimahabadi, Babak / Clausen, Maryam / Xu, Xiufeng /

Mayr, Lorenz M / Nitsch, Roberto / Bohlooly-Y, Mohammad / Barry, Simon T / Maresca, Marcello

Nature communications

2020 Volume 11, Issue 1, Page(s) 4903

Abstract: The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with ...

Abstract	The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; CRISPR-Associated Protein 9/genetics ; CRISPR-Cas Systems/genetics ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Cell Line, Tumor ; Doxycycline/pharmacology ; Drug Discovery/methods ; Drug Screening Assays, Antitumor/methods ; Female ; Gene Editing/methods ; Gene Expression/drug effects ; Gene Expression/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Genetic Vectors/genetics ; HEK293 Cells ; High-Throughput Screening Assays/methods ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Male ; Mice ; Mice, Transgenic ; RNA, Guide, CRISPR-Cas Systems/genetics ; Recombination, Genetic/drug effects ; Reproducibility of Results ; Transcriptional Activation/drug effects ; Transfection/methods ; Transgenes/genetics
Chemical Substances	Antineoplastic Agents ; RNA, Guide, CRISPR-Cas Systems ; CRISPR-Associated Protein 9 (EC 3.1.-) ; Cas9 endonuclease Streptococcus pyogenes (EC 3.1.-) ; Doxycycline (N12000U13O)
Language	English
Publishing date	2020-09-29
Publishing country	England
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-18548-9
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Article ; Online: Cardiac-Specific Overexpression of Oxytocin Receptor Leads to Cardiomyopathy in Mice.

Jung, Christian / Wernly, Bernhard / Bjursell, Mikael / Wiseman, John / Admyre, Therese / Wikström, Johannes / Palmér, Malin / Seeliger, Frank / Lichtenauer, Michael / Franz, Marcus / Frick, Charlotte / Andersson, Ann-Katrin / Elg, Margareta / Pernow, John / Sjöquist, Per-Ove / Bohlooly-Y, Mohammad / Wang, Qing-Dong

Journal of cardiac failure

2018 Volume 24, Issue 7, Page(s) 470–478

Abstract: Background: Oxytocin (Oxt) and its receptor (Oxtr) gene system has been implicated in cardiomyogenesis and cardioprotection; however, effects of chronic activation of Oxtr are not known. We generated and investigated transgenic (TG) mice that ... ...

Abstract	Background: Oxytocin (Oxt) and its receptor (Oxtr) gene system has been implicated in cardiomyogenesis and cardioprotection; however, effects of chronic activation of Oxtr are not known. We generated and investigated transgenic (TG) mice that overexpress Oxtr specifically in the heart. Methods and results: Cardiac-specific overexpression of Oxtr was obtained by having the α-major histocompatibility complex promoter drive the mouse Oxtr gene (α-Mhc-Oxtr). Left ventricular (LV) function and remodeling were assessed by magnetic resonance imaging and echocardiography. In α-Mhc-Oxtr TG mice, LV ejection fraction was severely compromised at 14 weeks of age compared with wild-type (WT) littermates (25 ± 6% vs 63 ± 3%; P < .001). LV end-diastolic volume was larger in the TG mice (103 ± 6 µL vs 67 ± 5 µL; P < .001). α-Mhc-Oxtr TG animals displayed cardiac fibrosis, atrial thrombus, and increased expression of pro-fibrogenic genes. Mortality of α-Mhc-Oxtr TG animals was 45% compared with 0% (P < .0001) of WT littermates by 20 weeks of age. Most cardiomyocytes of α-Mhc-Oxtr TG animals but not WT littermates (68.0 ± 12.1% vs 5.6 ± 2.4%; P = .008) were positive in staining for nuclear factor of activated T cells (NFAT). To study if thrombin inhibitor prevents thrombus formation, a cohort of 7-week-old α-Mhc-Oxtr TG mice were treated for 12 weeks with AZD0837, a potent thrombin inhibitor. Treatment with AZD0837 reduced thrombus formation (P < .05) and tended to attenuate fibrosis and increase survival. Conclusions: Cardiac-specific overexpression of Oxtr had negative consequences on LV function and survival in mice. The present findings necessitate further studies to investigate potential adverse effects of chronic Oxt administration. We provide a possible mechanism of Oxtr overexpression leading to heart failure by nuclear factor of activated T cell signaling. The recapitulation of human heart failure and the beneficial effects of the antithrombin inhibitor render the α-Mhc-Oxtr TG mice a promising tool in drug discovery for heart failure.
MeSH term(s)	Animals ; Cardiomyopathies/diagnosis ; Cardiomyopathies/genetics ; Cardiomyopathies/metabolism ; Disease Models, Animal ; Echocardiography ; Gene Expression Regulation ; Magnetic Resonance Imaging, Cine ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myocardium/metabolism ; Myocardium/pathology ; RNA/genetics ; Real-Time Polymerase Chain Reaction ; Receptors, Oxytocin/biosynthesis ; Receptors, Oxytocin/genetics
Chemical Substances	OXTR protein, mouse ; Receptors, Oxytocin ; RNA (63231-63-0)
Language	English
Publishing date	2018-05-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	1281194-4
ISSN	1532-8414 ; 1071-9164
ISSN (online)	1532-8414
ISSN	1071-9164
DOI	10.1016/j.cardfail.2018.05.004
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Zs.A 4340: Show issues

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Article ; Online: AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue.

Nature metabolism

2019 Volume 1, Issue 3, Page(s) 340–349

MeSH term(s)	Adenylate Kinase/metabolism ; Adipose Tissue, White/physiology ; Animals ; Diet ; Enzyme Activation ; Female ; Male ; Mice ; Mice, Transgenic ; Obesity/etiology ; Obesity/prevention & control ; Subcutaneous Fat/physiology ; Thermogenesis/physiology ; Uncoupling Protein 1/physiology
Chemical Substances	Ucp1 protein, mouse ; Uncoupling Protein 1 ; Adenylate Kinase (EC 2.7.4.3)
Language	English
Publishing date	2019-02-25
Publishing country	Germany
Document type	Letter ; Research Support, Non-U.S. Gov't
ISSN	2522-5812
ISSN (online)	2522-5812
DOI	10.1038/s42255-019-0036-9
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Article ; Online: Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet.

Bjursell, Mikael / Admyre, Therése / Göransson, Melker / Marley, Anna E / Smith, David M / Oscarsson, Jan / Bohlooly-Y, Mohammad

American journal of physiology. Endocrinology and metabolism

2011 Volume 300, Issue 1, Page(s) E211–20

Abstract: Free fatty acid receptor 2 (Ffar2), also known as GPR43, is activated by short-chain fatty acids (SCFA) and expressed in intestine, adipocytes, and immune cells, suggesting involvement in lipid and immune regulation. In the present study, Ffar2-deficient ...

Abstract	Free fatty acid receptor 2 (Ffar2), also known as GPR43, is activated by short-chain fatty acids (SCFA) and expressed in intestine, adipocytes, and immune cells, suggesting involvement in lipid and immune regulation. In the present study, Ffar2-deficient mice (Ffar2-KO) were given a high-fat diet (HFD) or chow diet and studied with respect to lipid and energy metabolism. On a HFD, Ffar2-KO mice had lower body fat mass and increased lean body mass. The changed body composition was accompanied by improved glucose control and lower HOMA index, indicating improved insulin sensitivity in Ffar2-KO mice. Moreover, the Ffar2-KO mice had higher energy expenditure accompanied by higher core body temperature and increased food intake. The liver weight and content of triglycerides as well as plasma levels of cholesterol were lower in the Ffar2-KO mice fed a HFD. A histological examination unveiled decreased lipid interspersed in brown adipose tissue of the Ffar2-KO mice. Interestingly, no significant differences in white adipose tissue (WAT) cell size were observed, but significantly lower macrophage content was detected in WAT from HFD-fed Ffar2-KO compared with wild-type mice. In conclusion, Ffar2 deficiency protects from HFD-induced obesity and dyslipidemia at least partly via increased energy expenditure.
MeSH term(s)	Adipose Tissue, Brown/pathology ; Adipose Tissue, White/pathology ; Animals ; Body Composition ; Body Temperature Regulation ; Diet ; Dietary Fats/administration & dosage ; Dyslipidemias/blood ; Dyslipidemias/prevention & control ; Energy Metabolism ; Fatty Liver/metabolism ; Fatty Liver/prevention & control ; Homeostasis ; Hyperglycemia/prevention & control ; Hypoglycemia/prevention & control ; Insulin Resistance ; Macrophages/metabolism ; Male ; Mice ; Mice, 129 Strain ; Mice, Knockout ; Obesity/blood ; Obesity/genetics ; Obesity/pathology ; Obesity/prevention & control ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/physiology
Chemical Substances	Dietary Fats ; Ffar2 protein, mouse ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2011-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00229.2010
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Article ; Online: The beneficial effects of n-3 polyunsaturated fatty acids on diet induced obesity and impaired glucose control do not require Gpr120.

Bjursell, Mikael / Xu, Xiufeng / Admyre, Therése / Böttcher, Gerhard / Lundin, Sofia / Nilsson, Ralf / Stone, Virginia M / Morgan, Noel G / Lam, Yan Y / Storlien, Leonard H / Lindén, Daniel / Smith, David M / Bohlooly-Y, Mohammad / Oscarsson, Jan

PloS one

2014 Volume 9, Issue 12, Page(s) e114942

Abstract: GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose ... ...

Abstract	GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids.
MeSH term(s)	Animals ; Body Composition ; Body Weight ; Diet, High-Fat/methods ; Energy Metabolism ; Fatty Acids/administration & dosage ; Fatty Acids, Omega-3/administration & dosage ; Glucose/metabolism ; Intestines/metabolism ; Lung/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Obesity/etiology ; Obesity/genetics ; Obesity/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Fatty Acids ; Fatty Acids, Omega-3 ; O3far1 protein, mouse ; Receptors, G-Protein-Coupled ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0114942
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Article ; Online: Inhibition of AMP deaminase activity does not improve glucose control in rodent models of insulin resistance or diabetes.

Admyre, Therese / Amrot-Fors, Lena / Andersson, Maria / Bauer, Martin / Bjursell, Mikael / Drmota, Tomas / Hallen, Stefan / Hartleib-Geschwindner, Judith / Lindmark, Bo / Liu, Jianming / Löfgren, Lars / Rohman, Mattias / Selmi, Nidhal / Wallenius, Kristina

Chemistry & biology

2014 Volume 21, Issue 11, Page(s) 1486–1496

Abstract: Inhibition of AMP deaminase (AMPD) holds the potential to elevate intracellular adenosine and AMP levels and, therefore, to augment adenosine signaling and activation of AMP-activated protein kinase (AMPK). To test the latter hypothesis, novel AMPD pan ... ...

Abstract	Inhibition of AMP deaminase (AMPD) holds the potential to elevate intracellular adenosine and AMP levels and, therefore, to augment adenosine signaling and activation of AMP-activated protein kinase (AMPK). To test the latter hypothesis, novel AMPD pan inhibitors were synthesized and explored using a panel of in vitro, ex vivo, and in vivo models focusing on confirming AMPD inhibitory potency and the potential of AMPD inhibition to improve glucose control in vivo. Repeated dosing of selected inhibitors did not improve glucose control in insulin-resistant or diabetic rodent disease models. Mice with genetic deletion of the muscle-specific isoform Ampd1 did not showany favorable metabolic phenotype despite being challenged with high-fat diet feeding. Therefore, these results do not support the development of AMPD inhibitors for the treatment of type 2 diabetes.
MeSH term(s)	AMP Deaminase/antagonists & inhibitors ; AMP Deaminase/genetics ; AMP Deaminase/metabolism ; Animals ; Blood Glucose/analysis ; Cells, Cultured ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Experimental/enzymology ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diet, High-Fat ; Disease Models, Animal ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Female ; Hepatocytes/cytology ; Hepatocytes/drug effects ; Hepatocytes/enzymology ; Insulin/blood ; Insulin Resistance ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Obese ; Obesity/drug therapy ; Obesity/enzymology ; Obesity/metabolism ; Obesity/pathology ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Small Molecule Libraries/therapeutic use
Chemical Substances	Blood Glucose ; Enzyme Inhibitors ; Insulin ; Recombinant Proteins ; Small Molecule Libraries ; AMP Deaminase (EC 3.5.4.6) ; AMPD1 protein, mouse (EC 3.5.4.6)
Language	English
Publishing date	2014-11-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	917827-2
ISSN	1879-1301 ; 1074-5521
ISSN (online)	1879-1301
ISSN	1074-5521
DOI	10.1016/j.chembiol.2014.09.011
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Zs.A 4429: Show issues

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Article ; Online: Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

Bjursell, Mikael / Wedin, Marianne / Admyre, Therése / Hermansson, Majlis / Böttcher, Gerhard / Göransson, Melker / Lindén, Daniel / Bamberg, Krister / Oscarsson, Jan / Bohlooly-Y, Mohammad

PloS one

2013 Volume 8, Issue 5, Page(s) e64721

Abstract: Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha- ... ...

Abstract	Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.
MeSH term(s)	Adipose Tissue, White/metabolism ; Adipose Tissue, White/pathology ; Aging ; Animals ; Blood Glucose ; Body Composition ; Body Weight ; Cell Size ; Energy Intake ; Energy Metabolism ; Fatty Liver/metabolism ; Female ; Glucose/metabolism ; Lipid Metabolism ; Liver/metabolism ; Liver/pathology ; Liver/physiopathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity ; Non-alcoholic Fatty Liver Disease ; Organ Size ; Receptors, Cytoplasmic and Nuclear/deficiency ; Receptors, Cytoplasmic and Nuclear/genetics ; Skin/pathology ; Triglycerides/metabolism
Chemical Substances	Blood Glucose ; Receptors, Cytoplasmic and Nuclear ; Triglycerides ; farnesoid X-activated receptor (0C5V0MRU6P) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2013-05-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0064721
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Article ; Online: Heparanase affects food intake and regulates energy balance in mice.

Karlsson-Lindahl, Linda / Schmidt, Linnéa / Haage, David / Hansson, Caroline / Taube, Magdalena / Egecioglu, Emil / Egeciouglu, Emil / Tan, Ying-xia / Admyre, Therese / Jansson, John-Olov / Vlodavsky, Israel / Li, Jin-Ping / Lindahl, Ulf / Dickson, Suzanne L

PloS one

2012 Volume 7, Issue 3, Page(s) e34313

Abstract: Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be ... ...

Abstract	Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be structurally modified by the enzyme heparanase. Here we tested the hypothesis that heparanase plays a role in food intake behaviour and energy balance regulation by analysing body weight, body composition and food intake in genetically modified mice that either lack or overexpress heparanase. We also assessed food intake and body weight following acute central intracerebroventricular administration of heparanase; such treatment reduced food intake in wildtype mice, an effect that was abolished in mice lacking MC4R. By contrast, heparanase knockout mice on a high-fat diet showed increased food intake and maturity-onset obesity, with up to a 40% increase in body fat. Mice overexpressing heparanase displayed essentially the opposite phenotypes, with a reduced fat mass. These results implicate heparanase in energy balance control via the central melanocortin system. Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of heparan sulfate chains presumably linked to syndecan-3.
MeSH term(s)	Agouti-Related Protein/metabolism ; Animals ; Body Composition ; Body Weight ; Crosses, Genetic ; Dietary Fats ; Eating/genetics ; Eating/physiology ; Energy Metabolism/genetics ; Feeding Behavior ; Female ; Gene Expression Regulation, Enzymologic ; Glucuronidase/pharmacology ; Infusions, Intraventricular ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptor, Melanocortin, Type 4/genetics ; Receptor, Melanocortin, Type 4/metabolism ; Signal Transduction ; Syndecan-3/metabolism ; alpha-MSH/metabolism
Chemical Substances	Agouti-Related Protein ; Agrp protein, mouse ; Dietary Fats ; MC4R protein, mouse ; Receptor, Melanocortin, Type 4 ; Syndecan-3 ; alpha-MSH (581-05-5) ; heparanase (EC 3.2.1.-) ; Glucuronidase (EC 3.2.1.31)
Language	English
Publishing date	2012-03-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0034313
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Article ; Online: Monoclonal antibody targeting of fibroblast growth factor receptor 1c ameliorates obesity and glucose intolerance via central mechanisms.

Lelliott, Christopher J / Ahnmark, Andrea / Admyre, Therese / Ahlstedt, Ingela / Irving, Lorraine / Keyes, Feenagh / Patterson, Laurel / Mumphrey, Michael B / Bjursell, Mikael / Gorman, Tracy / Bohlooly-Y, Mohammad / Buchanan, Andrew / Harrison, Paula / Vaughan, Tristan / Berthoud, Hans-Rudolf / Lindén, Daniel

PloS one

2014 Volume 9, Issue 11, Page(s) e112109

Abstract: We have generated a novel monoclonal antibody targeting human FGFR1c (R1c mAb) that caused profound body weight and body fat loss in diet-induced obese mice due to decreased food intake (with energy expenditure unaltered), in turn improving glucose ... ...

Abstract	We have generated a novel monoclonal antibody targeting human FGFR1c (R1c mAb) that caused profound body weight and body fat loss in diet-induced obese mice due to decreased food intake (with energy expenditure unaltered), in turn improving glucose control. R1c mAb also caused weight loss in leptin-deficient ob/ob mice, leptin receptor-mutant db/db mice, and in mice lacking either the melanocortin 4 receptor or the melanin-concentrating hormone receptor 1. In addition, R1c mAb did not change hypothalamic mRNA expression levels of Agrp, Cart, Pomc, Npy, Crh, Mch, or Orexin, suggesting that R1c mAb could cause food intake inhibition and body weight loss via other mechanisms in the brain. Interestingly, peripherally administered R1c mAb accumulated in the median eminence, adjacent arcuate nucleus and in the circumventricular organs where it activated the early response gene c-Fos. As a plausible mechanism and coinciding with the initiation of food intake suppression, R1c mAb induced hypothalamic expression levels of the cytokines Monocyte chemoattractant protein 1 and 3 and ERK1/2 and p70 S6 kinase 1 activation.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Arcuate Nucleus of Hypothalamus/drug effects ; Arcuate Nucleus of Hypothalamus/metabolism ; Arcuate Nucleus of Hypothalamus/physiopathology ; Chemokine CCL2/agonists ; Chemokine CCL2/genetics ; Chemokine CCL2/metabolism ; Chemokine CCL7/agonists ; Chemokine CCL7/genetics ; Chemokine CCL7/metabolism ; Circumventricular Organs/drug effects ; Circumventricular Organs/metabolism ; Circumventricular Organs/physiopathology ; Eating/drug effects ; Energy Metabolism ; Female ; Gene Expression Regulation ; Glucose Intolerance/drug therapy ; Glucose Intolerance/genetics ; Glucose Intolerance/metabolism ; Glucose Intolerance/physiopathology ; Humans ; Hypothalamus/drug effects ; Hypothalamus/metabolism ; Hypothalamus/physiopathology ; Leptin/deficiency ; Leptin/genetics ; Mice ; Mice, Knockout ; Mice, Obese ; Mitogen-Activated Protein Kinases/genetics ; Mitogen-Activated Protein Kinases/metabolism ; Obesity/drug therapy ; Obesity/genetics ; Obesity/metabolism ; Obesity/physiopathology ; Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors ; Receptor, Fibroblast Growth Factor, Type 1/genetics ; Receptor, Fibroblast Growth Factor, Type 1/metabolism ; Receptor, Melanocortin, Type 4/deficiency ; Receptor, Melanocortin, Type 4/genetics ; Receptors, Somatostatin/deficiency ; Receptors, Somatostatin/genetics ; Ribosomal Protein S6 Kinases, 70-kDa/genetics ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Serum Response Factor/agonists ; Serum Response Factor/genetics ; Serum Response Factor/metabolism ; Signal Transduction
Chemical Substances	Antibodies, Monoclonal ; Chemokine CCL2 ; Chemokine CCL7 ; Leptin ; MC4R protein, mouse ; Mch1r protein, mouse ; Receptor, Melanocortin, Type 4 ; Receptors, Somatostatin ; Serum Response Factor ; FGFR1 protein, human (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 1 (EC 2.7.10.1) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0112109
Database	MEDical Literature Analysis and Retrieval System OnLINE

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