Portal de investigação
Generation of an Obese Diabetic Mouse Model upon Conditional Atrx Disruption
Data de publicação:
Autores da FMUP
Participantes de fora da FMUP
- Gaspar, TB
- Jesus, TT
- Azevedo, MT
- Macedo, S
- Soares, MA
- Martins, RS
- Leite, R
- Rodrigues, L
- Rodrigues, DF
- Cardoso, L
- Borges, I
- Canberk, S
- Gärtner, F
- Miranda-Alves, L
- Vinagre, J
Unidades de investigação
Abstract
Simple Summary: ATRX mutations occur in up to 17% of human pancreatic neuroendocrine tumours (PanNETs), and recent evidence points towards its inability to drive PanNET formation in mouse pancreas while predisposing individuals to inflammageing. Aiming to explore the additional nontumourigenic consequences of Atrx deletion, we characterised an aged series of Atrx conditional disruption in fi cells using the Pdx1 promoter. Homozygous mice (P.AtrxHOM) exhibited obesity, diabetes, glucose intolerance, and pancreatic adiposity at a higher extent than age- and sex-matched controls (P.AtrxWT). Atrx loss was recently ascertained as insufficient to drive pancreatic neuroendocrine tumour (PanNET) formation in mice islets. We have identified a preponderant role of Atrx in the endocrine dysfunction in a Rip-Cre;AtrxKO genetically engineered mouse model (GEMM). To validate the impact of a different Cre-driver line, we used similar methodologies and characterised the Pdx1Cre;AtrxKO (P.AtrxKO) GEMM to search for PanNET formation and endocrine fitness disruption for a period of up to 24 months. Male and female mice presented different phenotypes. Compared to P.AtrxWT, P.AtrxHOM males were heavier during the entire study period, hyperglycaemic between 3 and 12 mo., and glucose intolerant only from 6 mo.; in contrast, P.AtrxHOM females started exhibiting increased weight gains later (after 6 mo.), but diabetes or glucose intolerance was detected by 3 mo. Overall, all studied mice were overweight or obese from early ages, which challenged the histopathological evaluation of the pancreas and liver, especially after 12 mo. Noteworthily, losing Atrx predisposed mice to an increase in intrapancreatic fatty infiltration (FI), peripancreatic fat deposition, and macrovesicular steatosis. As expected, no animal developed PanNETs. An obese diabetic GEMM of disrupted Atrx is presented as potentially useful for metabolic studies and as a putative candidate for inserting additional tumourigenic genetic events.
Dados da publicação
- ISSN/ISSNe:
- 2072-6694, 2072-6694
- Tipo:
- Article
- Páginas:
- 3018-
- Link para outro recurso:
- www.scopus.com
Cancers Multidisciplinary Digital Publishing Institute (MDPI)
Documentos
- Não há documentos
Filiações
Keywords
- Atrx; conditional mouse model; endocrine dysfunction; fatty pancreas; pancreatic fatty replacement; hyperglycaemia; hepatic stetosis; inflammageing; obesity; Pdx1-Cre
Financiamento
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Citar a publicação
Gaspar TB,Jesus TT,Azevedo MT,Macedo S,Soares MA,Martins RS,Leite R,Rodrigues L,Rodrigues DF,Cardoso L,Borges I,Canberk S,Gärtner F,Miranda L,Lopes JM,Soares P,Vinagre J. Generation of an Obese Diabetic Mouse Model upon Conditional Atrx Disruption. Cancers. 2023. 15. (11):p. 3018-3018. IF:5,200. (2).
