Andrea Ahnmark
AstraZeneca
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Publication
Featured researches published by Andrea Ahnmark.
Diabetes | 2007
Mikael Bjursell; Andrea Ahnmark; Mohammad Bohlooly-Y; Lena William-Olsson; Magdalena Rhedin; Xiao-Rong Peng; Karolina Ploj; Anna-Karin Gerdin; Gunnel Arnerup; Anders Elmgren; Anna-Lena Berg; Jan Oscarsson; Daniel Lindén
The adipocyte-derived hormone adiponectin regulates glucose and lipid metabolism and influences the risk for developing obesity, type 2 diabetes, and cardiovascular disease. Adiponectin binds to two different seven-transmembrane domain receptors termed AdipoR1 and AdipoR2. To study the physiological importance of these receptors, AdipoR1 gene knockout mice (AdipoR1−/−) and AdipoR2 gene knockout mice (AdipoR2−/−) were generated. AdipoR1−/− mice showed increased adiposity associated with decreased glucose tolerance, spontaneous locomotor activity, and energy expenditure. However, AdipoR2−/− mice were lean and resistant to high-fat diet–induced obesity associated with improved glucose tolerance and higher spontaneous locomotor activity and energy expenditure and reduced plasma cholesterol levels. Thus, AdipoR1 and AdipoR2 are clearly involved in energy metabolism but have opposing effects.
The FASEB Journal | 2006
Daniel Lindén; Lena William-Olsson; Andrea Ahnmark; Kim Ekroos; Carina Hallberg; Helena Peilot Sjögren; Bruno Becker; Lennart Svensson; John C. Clapham; Jan Oscarsson; Sandra A. Schreyer
Glycerol‐3‐phosphate acyltransferase (GPAT) catalyzes the first committed step in triacylglycerol (TAG) and phospholipid biosynthesis. GPAT activity has been identified in both ER and mitochondrial subcellular fractions. The ER activity dominates in most tissues except in liver, where the mitochondrial isoform (mtGPAT) can constitute up to 50% of the total activity. To study the in vivo effects of hepatic mtGPAT overexpression, mice were transduced with adenoviruses expressing either murine mtGPAT or a catalytically inactive variant of the enzyme. Overexpressing mtGPAT resulted in massive 12‐and 7‐fold accumulation of liver TAG and diacylglycerol, respectively but had no effect on phospholipid or cholesterol ester content. Histological analysis showed extensive lipid accumulation in hepatocytes. Furthermore, mtGPAT transduction markedly increased adipocyte differentiation‐related protein and stearoyl‐CoA desaturase‐1 (SCD‐1) in the liver. In line with increased SCD‐1 expression, 18:1 and 16:1 in the hepatic TAG fraction increased. In addition, mtGPAT overexpression decreased ex vivo fatty acid oxidation, increased liver TAG secretion rate 2‐fold, and increased plasma TAG and cholesterol levels. These results support the hypothesis that increased hepatic mtGPAT activity associated with obesity and insulin resistance contributes to increased TAG biosynthesis and inhibition of fatty acid oxidation, responses that would promote hepatic steatosis and dyslipidemia.—Lindén, D., William‐Olsson, L., Ahnmark, A., Ekroos, K., Hallberg, C., Sjögren, H. P., Becker, B., Svensson, L., Clapham, J. C., Oscarsson, J., Schreyer, S. Liver‐directed overexpression of mitochondrial glycerol‐3‐phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation. FASEB J. 20, 434–443 (2006)
Arteriosclerosis, Thrombosis, and Vascular Biology | 2007
Christopher J. Lelliott; Anna Ljungberg; Andrea Ahnmark; Lena William-Olsson; Kim Ekroos; Anders Elmgren; Gunnel Arnerup; Carol C. Shoulders; Jan Oscarsson; Daniel Lindén
Objective—Previous studies have indicated that the hyperlipidemia and gene expression changes induced by a short-term high-fat diet (HFD) are mediated through the peroxisome proliferator-activated receptor &ggr; coactivator (PGC)-1&bgr;, and that in vitro both PGC-1&bgr; and PGC −1&agr; increase PPAR&agr;-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPAR&agr; agonist Wy14,643 (Wy). Methods and Results—C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1&agr; or PGC-1&bgr;. On chow, hepatic PGC-1&bgr; overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPAR&agr; and hepatic lipase mRNA levels were reduced. PGC-1&bgr; overexpression blunted Wy-mediated changes in expression levels of PPAR&agr; and downstream genes. Furthermore, PGC-1&bgr; did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1&bgr; and PGC-1&agr; overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1&bgr; overexpression decreased hepatic SREBP-1c, yet increased FAS and ACC&agr; mRNA and plasma triglyceride levels. Conclusions—Hepatic PGC-1&bgr; overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1&bgr; overexpression reduced the potentially beneficial effects of PPAR&agr; activation on gene expression. Thus, inhibition of hepatic PGC-1&bgr; may provide a therapy for treating combined hyperlipidemia.
Biochemical and Biophysical Research Communications | 2008
Misak Yazdi; Andrea Ahnmark; Lena William-Olsson; Michael Snaith; Nigel Turner; Fredrik Osla; Marianne Wedin; Anna-Karin Asztély; Anders Elmgren; Mohammad Bohlooly-Y; Sandra A. Schreyer; Daniel Lindén
Glycerol-3-phosphate acyltransferase (GPAT) is involved in triacylglycerol (TAG) and phospholipid synthesis, catalyzing the first committed step. In order to further investigate the in vivo importance of the dominating mitochondrial variant, GPAT1, a novel GPAT1(-/-) mouse model was generated and studied. Female GPAT1(-/-) mice had reduced body weight-gain and adiposity when fed chow diet compared with littermate wild-type controls. Furthermore, GPAT1(-/-) females on chow diet showed decreased liver TAG content, plasma cholesterol and TAG levels and increased ex vivo liver fatty acid oxidation and plasma ketone bodies. However, these beneficial effects were abolished and the glucose tolerance tended to be impaired when GPAT1(-/-) females were fed a long-term high-fat diet (HFD). GPAT1-deficiency was not associated with altered whole body energy expenditure or respiratory exchange ratio. In addition, there were no changes in male GPAT1(-/-) mice fed either diet except for increased plasma ketone bodies on chow diet, indicating a gender-specific phenotype. Thus, GPAT1-deficiency does not protect against HFD-induced obesity, hepatic steatosis or whole body glucose intolerance.
PLOS ONE | 2014
Christopher J. Lelliott; Andrea Ahnmark; Therese Admyre; Ingela Ahlstedt; Lorraine Irving; Feenagh Keyes; Laurel M. Patterson; Michael B. Mumphrey; Mikael Bjursell; Tracy Gorman; Mohammad Bohlooly-Y; Andrew Buchanan; Paula Harrison; Tristan J. Vaughan; Hans-Rudolf Berthoud; Daniel Lindén
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.
PLOS ONE | 2013
Anna Lindgren; Malin Levin; Sandra Rodrigo Blomqvist; Johannes Wikström; Andrea Ahnmark; Christina K. Mogensen; Gerhard Böttcher; Mohammad Bohlooly-Y; Jan Borén; Li-Ming Gan; Daniel Lindén
Adiponectin has been shown to have beneficial cardiovascular effects and to signal through the adiponectin receptors, AdipoR1 and AdipoR2. The original aim of this study was to investigate the effect of combined AdipoR1 and AdipoR2 deficiency (AdipoR1-/-AdipoR2-/-) on atherosclerosis. However, we made the interesting observation that AdipoR1 -/- AdipoR2 -/- leads to embryonic lethality demonstrating the critical importance of the adiponectin signalling system during development. We then investigated the effect of AdipoR2-ablation on the progression of atherosclerosis in apolipoprotein E deficient (ApoE -/-) mice. AdipoR2-/-ApoE-/- mice fed an atherogenic diet had decreased plaque area in the brachiocephalic artery compared with AdipoR2 +/+ApoE-/- littermate controls as visualized in vivo using an ultrasound biomicroscope and confirmed by histological analyses. The decreased plaque area in the brachiocephalic artery could not be explained by plasma cholesterol levels or inflammatory status. However, accumulation of neutral lipids was decreased in peritoneal macrophages from AdipoR2-/-ApoE-/- mice after incubation with oxidized LDL. This effect was associated with lower CD36 and higher ABCA1 mRNA levels in peritoneal macrophages from AdipoR2-/-ApoE-/- mice compared with AdipoR2+/+ApoE-/- controls after incubation with oxidized LDL. In summary, we show that adiponectin receptors are crucial during embryonic development and that AdipoR2-deficiency slows down the progression of atherosclerosis in the brachiocephalic artery of ApoE-deficient mice.
Journal of Pharmacokinetics and Pharmacodynamics | 2016
Magnus Trägårdh; Michael J. Chappell; Andrea Ahnmark; Daniel Lindén; Neil D. Evans; Peter Gennemark
Input estimation is employed in cases where it is desirable to recover the form of an input function which cannot be directly observed and for which there is no model for the generating process. In pharmacokinetic and pharmacodynamic modelling, input estimation in linear systems (deconvolution) is well established, while the nonlinear case is largely unexplored. In this paper, a rigorous definition of the input-estimation problem is given, and the choices involved in terms of modelling assumptions and estimation algorithms are discussed. In particular, the paper covers Maximum a Posteriori estimates using techniques from optimal control theory, and full Bayesian estimation using Markov Chain Monte Carlo (MCMC) approaches. These techniques are implemented using the optimisation software CasADi, and applied to two example problems: one where the oral absorption rate and bioavailability of the drug eflornithine are estimated using pharmacokinetic data from rats, and one where energy intake is estimated from body-mass measurements of mice exposed to monoclonal antibodies targeting the fibroblast growth factor receptor (FGFR) 1c. The results from the analysis are used to highlight the strengths and weaknesses of the methods used when applied to sparsely sampled data. The presented methods for optimal control are fast and robust, and can be recommended for use in drug discovery. The MCMC-based methods can have long running times and require more expertise from the user. The rigorous definition together with the illustrative examples and suggestions for software serve as a highly promising starting point for application of input-estimation methods to problems in drug discovery.
PLOS ONE | 2017
Linda Sundström; Susanna Myhre; Monika Sundqvist; Andrea Ahnmark; William Mccoull; Piotr Raubo; Sam D. Groombridge; Magnus Polla; Ann-Christin Nyström; Lisbeth Kristensson; Mats Någård; Maria Sörhede Winzell
The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests. In vitro, in GPR120 overexpressing cells, both agonists signaled through Gαq, Gαs and the β-arrestin pathway. However, in mouse islets the signaling pathway was different since the agonists reduced cAMP production. The GPR120 agonists stimulated GLP-1 secretion both in vitro in STC-1 cells and in vivo following oral administration. In vivo GPR120 activation induced significant glucose lowering and increased insulin secretion after intravenous glucose administration in lean mice, while the agonists had no effect in GPR120 null mice. Exendin 9–39, a GLP-1 receptor antagonist, abolished the GPR120 induced effects on glucose and insulin following an intravenous glucose challenge. In conclusion, GLP-1 secretion is an important mechanism behind the acute glucose lowering effect following specific GPR120 activation.
Journal of Pharmaceutical Sciences | 2015
Pia Davidsson; Ann‐Sofi Söderling; Lena Svensson; Andrea Ahnmark; Christine Flodin; Ewa Wanag; Valentina Screpanti-Sundqvist; Peter Gennemark
Tissue distribution and pharmacokinetics (PK) of full-length nontargeted antibody and its antigen-binding fragment (FAb) were evaluated for a range of tissues primarily of interest for cardiovascular and metabolic diseases. Mice were intravenously injected with a dose of 10 mg/kg of either human IgG1or its FAb fragment; perfused tissues were collected at a range of time points over 3 weeks for the human IgG1 antibody and 1 week for the human FAb antibody. Tissues were homogenized and antibody concentrations were measured by specific immunoassays on the Gyros system. Exposure in terms of maximum concentration (Cmax ) and area under the curve was assessed for all nine tissues. Tissue exposure of full-length antibody relative to plasma exposure was found to be between 1% and 10%, except for brain (0.2%). Relative concentrations of FAb antibody were the same, except for kidney tissue, where the antibody concentration was found to be ten times higher than in plasma. However, the absolute tissue uptake of full-length IgG was significantly higher than the absolute tissue uptake of the FAb antibody. This study provides a reference PK state for full-length whole and FAb antibodies in tissues related to cardiovascular and metabolic diseases that do not include antigen or antibody binding.
Toxicology and Applied Pharmacology | 2018
Nicholas Buss; Jean-Martin Lapointe; Lolke de Haan; Sally Price; Andrea Ahnmark; Lorraine Irving; Andrew Buchanan; Feenagh Keyes; Pia Davidsson; Rakesh Dixit; Daniel Lindén
ABSTRACT Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti‐FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c‐specific mAbs or an FGFR1c/FGFR4‐specific mAb at 10mg/kg for up to 4weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro‐tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb‐treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF‐FGFR1c pathway with anti‐FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti‐obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug‐induced valvulopathy is considered FGFR1c‐mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves. HIGHLIGHTSAssessed potential toxicity of three anti‐FGFR1c mAbs in rats after repeated dosingAll three mAbs caused significant reductions in food intake and weight lossMicroscopically, thickening of the diaphyseal cortex of long bones observed.Endocardial myxomatous change affecting all valves also observedPresence of FGFR1 mRNA in the heart valves observed using in situ hybridization