Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system.
Humans
Insulin Resistance
Induced Pluripotent Stem Cells
/ metabolism
Hepatocytes
/ metabolism
Liver
/ metabolism
Inflammation
/ metabolism
Adipocytes
/ metabolism
Macrophages
/ metabolism
Fatty Liver
/ metabolism
Glucagon-Like Peptide-1 Receptor
/ metabolism
Adipose Tissue
/ metabolism
Microphysiological Systems
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 Sep 2024
12 Sep 2024
Historique:
received:
16
01
2024
accepted:
28
08
2024
medline:
13
9
2024
pubmed:
13
9
2024
entrez:
12
9
2024
Statut:
epublish
Résumé
Interactions between adipose tissue, liver and immune system are at the center of metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. To address the need for an accurate in vitro model, we establish an interconnected microphysiological system (MPS) containing white adipocytes, hepatocytes and proinflammatory macrophages derived from isogenic human induced pluripotent stem cells. Using this MPS, we find that increasing the adipocyte-to-hepatocyte ratio moderately affects hepatocyte function, whereas macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease. We also use our MPS to identify and characterize pharmacological intervention strategies for hepatic steatosis and systemic insulin resistance and find that the glucagon-like peptide-1 receptor agonist semaglutide improves hepatocyte function by acting specifically on adipocytes. These results establish our MPS modeling the adipose tissue-liver axis as an alternative to animal models for mechanistic studies or drug discovery in metabolic diseases.
Identifiants
pubmed: 39266553
doi: 10.1038/s41467-024-52258-w
pii: 10.1038/s41467-024-52258-w
doi:
Substances chimiques
Glucagon-Like Peptide-1 Receptor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7991Subventions
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : UG3DK120004
Organisme : NIAMS NIH HHS
ID : R01 AR066735
Pays : United States
Organisme : NIDDK NIH HHS
ID : UG3 DK120004
Pays : United States
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : P30DK026743
Organisme : NIDDK NIH HHS
ID : UG3 DK120004
Pays : United States
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : GR 5417/1-1
Informations de copyright
© 2024. The Author(s).
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