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Publication
Endothelial APLNR regulates tissue fatty acid uptake and is essential for
apelin's glucose-lowering effects.
Authors Hwangbo C, Wu J, Papangeli I, Adachi T, Sharma B, Park S, Zhao L, Ju H, Go GW,
Cui G, Inayathullah M, Job JK, Rajadas J, Kwei SL, Li MO, Morrison AR,
Quertermous T, Mani A, Red-Horse K, Chun HJ
Submitted By Submitted Externally on 12/5/2017
Status Published
Journal Science translational medicine
Year 2017
Date Published 9/1/2017
Volume : Pages 9 : Not Specified
PubMed Reference 28904225
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.




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