Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.
3T3-L1 Cells
Adipocytes
/ metabolism
Adipose Tissue, White
/ cytology
Adolescent
Adult
Aged
Animals
CHO Cells
Cohort Studies
Cricetulus
Cross-Sectional Studies
Diabetes Mellitus, Type 2
/ blood
Diet, High-Fat
/ adverse effects
Disease Models, Animal
Female
Gene Knockdown Techniques
Glucose
/ metabolism
HEK293 Cells
Hep G2 Cells
Humans
Insulin
/ metabolism
Insulin Resistance
Islets of Langerhans
/ metabolism
Liver
/ metabolism
Male
Membrane Proteins
/ administration & dosage
Mice
Mice, Knockout
Middle Aged
NIH 3T3 Cells
Prediabetic State
/ blood
Primary Cell Culture
Proteins
/ analysis
Receptors, G-Protein-Coupled
/ blood
Recombinant Fusion Proteins
/ administration & dosage
Young Adult
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 05 2021
20 05 2021
Historique:
received:
12
11
2020
accepted:
12
03
2021
entrez:
21
5
2021
pubmed:
22
5
2021
medline:
2
6
2021
Statut:
epublish
Résumé
The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.
Identifiants
pubmed: 34016966
doi: 10.1038/s41467-021-22579-1
pii: 10.1038/s41467-021-22579-1
pmc: PMC8137956
doi:
Substances chimiques
ADGRF5 protein, human
0
FNDC4 protein, human
0
Frcp1 protein, mouse
0
Gpr116 protein, mouse
0
Insulin
0
Membrane Proteins
0
Proteins
0
Receptors, G-Protein-Coupled
0
Recombinant Fusion Proteins
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2999Références
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