Endothelial MRs Mediate Western Diet-Induced Lipid Disorders and Skeletal Muscle Insulin Resistance in Females.
endothelial cells
exosome
insulin resistance
mineralocorticoid receptor
obesity
skeletal muscle
Journal
Endocrinology
ISSN: 1945-7170
Titre abrégé: Endocrinology
Pays: United States
ID NLM: 0375040
Informations de publication
Date de publication:
06 06 2023
06 06 2023
Historique:
received:
18
04
2023
medline:
23
6
2023
pubmed:
8
6
2023
entrez:
8
6
2023
Statut:
ppublish
Résumé
Consumption of a Western diet (WD) consisting of excess fat and carbohydrates activates the renin-angiotensin-aldosterone system, which has emerged as an important risk factor for systemic and tissue insulin resistance. We recently discovered that activated mineralocorticoid receptors (MRs) in diet-induced obesity induce CD36 expression, increase ectopic lipid accumulation, and result in systemic and tissue insulin resistance. Here, we have further investigated whether endothelial cell (EC)-specific MR (ECMR) activation participates in WD-induced ectopic skeletal muscle lipid accumulation, insulin resistance, and dysfunction. Six-week-old female ECMR knockout (ECMR-/-) and wild-type (ECMR+/+) mice were fed either a WD or a chow diet for 16 weeks. ECMR-/- mice were found to have decreased WD-induced in vivo glucose intolerance and insulin resistance at 16 weeks. Improved insulin sensitivity was accompanied by increased glucose transporter type 4 expression in conjunction with improved soleus insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B and endothelial nitric oxide synthase activation. Additionally, ECMR-/- also blunted WD-induced increases in CD36 expression and associated elevations in soleus free fatty acid, total intramyocellular lipid content, oxidative stress, and soleus fibrosis. Moreover, in vitro and in vivo activation of ECMR increased EC-derived exosomal CD36 that was further taken up by skeletal muscle cells, leading to increased skeletal muscle CD36 levels. These findings indicate that in the context of an obesogenic WD, enhanced ECMR signaling increases EC-derived exosomal CD36 resulting in increased uptake and elevated concentrations of CD36 in skeletal muscle cells, contributing to increased lipid metabolic disorders and soleus insulin resistance.
Identifiants
pubmed: 37289042
pii: 7192100
doi: 10.1210/endocr/bqad091
pmc: PMC10284339
pii:
doi:
Substances chimiques
Receptors, Mineralocorticoid
0
Insulin
0
Lipids
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK124329
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL073101
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL107910
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.
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