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Sci Transl Med. 2017 Sep 13;9(407). pii: eaad4000. doi: 10.1126/scitranslmed.aad4000.

Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects.

Author information

1
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT 06511, USA.
2
Department of Biology, Stanford University, Stanford, CA 94304, USA.
3
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
4
Biomaterials and Advanced Drug Delivery Laboratory, Stanford University, Stanford, CA 94304, USA.
5
Section of Plastic and Reconstructive Surgery, Yale School of Medicine, New Haven, CT 06511, USA.
6
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Division of Cardiovascular Medicine, Stanford University, Stanford, CA 94304, USA.
8
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT 06511, USA. hyung.chun@yale.edu.

Abstract

Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (AplnrECKO ) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln-/- and AplnrECKO mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln-/- mice. The impaired glucose utilization in the AplnrECKO mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.

PMID:
28904225
PMCID:
PMC5703224
DOI:
10.1126/scitranslmed.aad4000
[Indexed for MEDLINE]
Free PMC Article

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