Adult mice are unresponsive to AAV8-Gremlin1 gene therapy targeting the liver

Autor: Jenny M. Hoffmann, Ivet Elias, Roxana Khatib Shahidi, Jeremie Boucher, Ann Hammarstedt, Christopher Church, Shahram Hedjazifar, Fatima Bosch, Laurianne Bonnet, Ritesh K. Baboota, Ulf Smith, Stephanie Heasman
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Physiology
Adipose tissue
Type 2 diabetes
Biochemistry
Teràpia gènica
Mice
Endocrinology
Intraperitoneal Injections
Fibrosis
Brown adipose tissue
Medicine and Health Sciences
Insulin
Immune Response
Routes of Administration
Multidisciplinary
Chemistry
Animal Models
Dependovirus
Recombinant Proteins
medicine.anatomical_structure
Adipose Tissue
Experimental Organism Systems
Physiological Parameters
Liver
Connective Tissue
Intercellular Signaling Peptides and Proteins
Medicine
Anatomy
medicine.symptom
Gremlin (protein)
Injections
Intraperitoneal
Research Article
medicine.medical_specialty
Science
Immunology
Genetic Vectors
Mouse Models
Inflammation
Research and Analysis Methods
Diet
High-Fat
Cell Line
03 medical and health sciences
Model Organisms
Signs and Symptoms
In vivo
3T3-L1 Cells
Internal medicine
medicine
Animals
Humans
Secretion
Obesity
Diabetic Endocrinology
Pharmacology
030102 biochemistry & molecular biology
Body Weight
Biology and Life Sciences
Kidneys
Renal System
Genetic Therapy
Glucose Tolerance Test
medicine.disease
Hormones
Disease Models
Animal
Biological Tissue
030104 developmental biology
Animal Studies
Clinical Medicine
Insulin Resistance
Zdroj: PLoS ONE, Vol 16, Iss 2, p e0247300 (2021)
Dipòsit Digital de Documents de la UAB
Universitat Autònoma de Barcelona
PLoS ONE
ISSN: 1932-6203
Popis: Objective Gremlin 1 (GREM1) is a secreted BMP2/4 inhibitor which regulates commitment and differentiation of human adipose precursor cells and prevents the browning effect of BMP4. GREM1 is an insulin antagonist and serum levels are high in type 2 diabetes (T2D). We here examined in vivo effects of AAV8 (Adeno-Associated Viral vectors of serotype eight) GREM 1 targeting the liver in mature mice to increase its systemic secretion and also, in a separate study, injected recombinant GREM 1 intraperitoneally. The objective was to characterize systemic effects of GREM 1 on insulin sensitivity, glucose tolerance, body weight, adipose cell browning and other local tissue effects. Methods Adult mice were injected with AAV8 vectors expressing GREM1 in the liver or receiving regular intra-peritoneal injections of recombinant GREM1 protein. The mice were fed with a low fat or high fat diet (HFD) and followed over time. Results Liver-targeted AAV8-GREM1 did not alter body weight, whole-body glucose and insulin tolerance, or adipose tissue gene expression. Although GREM1 protein accumulated in liver cells, GREM1 serum levels were not increased suggesting that it may not have been normally processed for secretion. Hepatic lipid accumulation, inflammation and fibrosis were also not changed. Repeated intraperitoneal rec-GREM1 injections for 5 weeks were also without effects on body weight and insulin sensitivity. UCP1 was slightly but significantly reduced in both white and brown adipose tissue but this was not of sufficient magnitude to alter body weight. We validated that recombinant GREM1 inhibited BMP4-induced pSMAD1/5/9 in murine cells in vitro, but saw no direct inhibitory effect on insulin signalling and pAkt (ser 473 and thr 308) activation. Conclusion GREM1 accumulates intracellularly when overexpressed in the liver cells of mature mice and is apparently not normally processed/secreted. However, also repeated intraperitoneal injections were without effects on body weight and insulin sensitivity and adipose tissue UCP1 levels were only marginally reduced. These results suggest that mature mice do not readily respond to GREMLIN 1 but treatment of murine cells with GREMLIN 1 protein in vitro validated its inhibitory effect on BMP4 signalling while insulin signalling was not altered.
Databáze: OpenAIRE
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