Obesity-related hypoxia via miR-128 decreases insulin-receptor expression in human and mouse adipose tissue promoting systemic insulin resistance.
Adipocytes
/ metabolism
Adipose Tissue
/ metabolism
Aged
Animals
Biomarkers
Body Mass Index
Cell Line
Comorbidity
Disease Models, Animal
Female
Gene Expression Regulation
Glucose
/ metabolism
Humans
Hypoxia
/ genetics
Insulin Resistance
/ genetics
Male
Mice
MicroRNAs
/ genetics
Middle Aged
Obesity
/ genetics
RNA Interference
Receptor, Insulin
/ genetics
Adipose-tissue dysfunction
Hypoxia
Insulin receptor
Insulin resistance
Obesity
mRNA decay
miRNA
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Sep 2020
Sep 2020
Historique:
received:
01
05
2020
revised:
05
07
2020
accepted:
08
07
2020
pubmed:
3
8
2020
medline:
29
6
2021
entrez:
3
8
2020
Statut:
ppublish
Résumé
Insulin resistance in visceral adipose tissue (VAT), skeletal muscle and liver is a prominent feature of most patients with obesity. How this association arises remains poorly understood. The objective of this study was to demonstrate that the decrease in insulin receptor (INSR) expression and insulin signaling in VAT from obese individuals is an early molecular manifestation that might play a crucial role in the cascade of events leading to systemic insulin resistance. To clarify the role of INSR and insulin signaling in adipose tissue dysfunction in obesity, we first measured INSR expression in VAT samples from normal-weight subjects and patients with different degrees of obesity. We complemented these studies with experiments on high-fat diet (HFD)-induced obese mice, and in human and murine adipocyte cultures, in both normoxic and hypoxic conditions. An inverse correlation was observed between increasing body mass index and decreasing INSR expression in VAT of obese humans. Our results indicate that VAT-specific downregulation of INSR is an early event in obesity-related adipose cell dysfunction, which increases systemic insulin resistance in both obese humans and mice. We also provide evidence that obesity-related hypoxia in VAT plays a determinant role in this scenario by decreasing INSR mRNA stability. This decreased stability is through the activation of a miRNA (miR-128) that downregulates INSR expression in adipocytes. We present a novel pathogenic mechanism of reduced INSR expression and insulin signaling in adipocytes. Our data provide a new explanation linking obesity with systemic insulin resistance. This work was partly supported by a grant from Nutramed (PON 03PE000_78_1) and by the European Commission (FESR FSE 2014-2020 and Regione Calabria).
Sections du résumé
BACKGROUND
BACKGROUND
Insulin resistance in visceral adipose tissue (VAT), skeletal muscle and liver is a prominent feature of most patients with obesity. How this association arises remains poorly understood. The objective of this study was to demonstrate that the decrease in insulin receptor (INSR) expression and insulin signaling in VAT from obese individuals is an early molecular manifestation that might play a crucial role in the cascade of events leading to systemic insulin resistance.
METHODS
METHODS
To clarify the role of INSR and insulin signaling in adipose tissue dysfunction in obesity, we first measured INSR expression in VAT samples from normal-weight subjects and patients with different degrees of obesity. We complemented these studies with experiments on high-fat diet (HFD)-induced obese mice, and in human and murine adipocyte cultures, in both normoxic and hypoxic conditions.
FINDINGS
RESULTS
An inverse correlation was observed between increasing body mass index and decreasing INSR expression in VAT of obese humans. Our results indicate that VAT-specific downregulation of INSR is an early event in obesity-related adipose cell dysfunction, which increases systemic insulin resistance in both obese humans and mice. We also provide evidence that obesity-related hypoxia in VAT plays a determinant role in this scenario by decreasing INSR mRNA stability. This decreased stability is through the activation of a miRNA (miR-128) that downregulates INSR expression in adipocytes.
INTERPRETATION
CONCLUSIONS
We present a novel pathogenic mechanism of reduced INSR expression and insulin signaling in adipocytes. Our data provide a new explanation linking obesity with systemic insulin resistance.
FUNDING
BACKGROUND
This work was partly supported by a grant from Nutramed (PON 03PE000_78_1) and by the European Commission (FESR FSE 2014-2020 and Regione Calabria).
Identifiants
pubmed: 32739259
pii: S2352-3964(20)30287-5
doi: 10.1016/j.ebiom.2020.102912
pmc: PMC7502675
pii:
doi:
Substances chimiques
Biomarkers
0
MIRN128 microRNA, human
0
MicroRNAs
0
Receptor, Insulin
EC 2.7.10.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
102912Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare no conflicts of interest.
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