Insulin sensitization by hepatic FoxO deletion is insufficient to lower atherosclerosis in mice.
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
18 Oct 2023
18 Oct 2023
Historique:
pubmed:
31
10
2023
medline:
31
10
2023
entrez:
31
10
2023
Statut:
epublish
Résumé
Type 2 diabetes is associated with an increased risk of atherosclerotic cardiovascular disease. It has been suggested that insulin resistance underlies this link, possibly by altering the functions of cells in the artery wall. We aimed to test whether improving systemic insulin sensitivity reduces atherosclerosis. We used mice that are established to have improved systemic insulin sensitivity: those lacking FoxO transcription factors in hepatocytes. Three hepatic FoxO isoforms (FoxO1, FoxO3, and FoxO4) function together to promote hepatic glucose output, and ablating them lowers glucose production, lowers circulating glucose and insulin, and improves systemic insulin sensitivity. We made these mice susceptible to atherosclerosis in two different ways, by injecting them with gain-of-function AAV8.mPcsk9 We verified that hepatic FoxO ablation improves systemic insulin sensitivity in these atherosclerotic settings. We observed that FoxO deficiency caused no reductions in atherosclerosis, and in some cases increased atherosclerosis. These phenotypes coincided with large increases in circulating triglycerides in FoxO-ablated mice. These findings suggest that systemic insulin sensitization is insufficient to reduce atherosclerosis.
Sections du résumé
Background–
UNASSIGNED
Type 2 diabetes is associated with an increased risk of atherosclerotic cardiovascular disease. It has been suggested that insulin resistance underlies this link, possibly by altering the functions of cells in the artery wall. We aimed to test whether improving systemic insulin sensitivity reduces atherosclerosis.
Methods–
UNASSIGNED
We used mice that are established to have improved systemic insulin sensitivity: those lacking FoxO transcription factors in hepatocytes. Three hepatic FoxO isoforms (FoxO1, FoxO3, and FoxO4) function together to promote hepatic glucose output, and ablating them lowers glucose production, lowers circulating glucose and insulin, and improves systemic insulin sensitivity. We made these mice susceptible to atherosclerosis in two different ways, by injecting them with gain-of-function AAV8.mPcsk9
Results–
UNASSIGNED
We verified that hepatic FoxO ablation improves systemic insulin sensitivity in these atherosclerotic settings. We observed that FoxO deficiency caused no reductions in atherosclerosis, and in some cases increased atherosclerosis. These phenotypes coincided with large increases in circulating triglycerides in FoxO-ablated mice.
Conclusions–
UNASSIGNED
These findings suggest that systemic insulin sensitization is insufficient to reduce atherosclerosis.
Identifiants
pubmed: 37905094
doi: 10.1101/2023.10.14.562366
pmc: PMC10614776
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL125649
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007328
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL120826
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001873
Pays : United States
Déclaration de conflit d'intérêts
Conflict of interest statement. The authors have declared that no conflict of interest exists.
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