Research ArticleMetabolic Disease

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

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Science Translational Medicine  13 Sep 2017:
Vol. 9, Issue 407, eaad4000
DOI: 10.1126/scitranslmed.aad4000

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An apelin a day keeps the doctor away

Apelin is an atheroprotective protein, which promotes insulin sensitivity and metabolic health, but the details of its signaling are not well understood. Hwangbo et al. discovered that the apelin receptor is predominantly localized in endothelial cells of metabolic organs, such as muscle and adipose tissues, and that it functions, in part, by inhibiting fatty acid binding protein 4 (FABP4) activity. The authors also found that inhibition of FABP4 can reverse the metabolic disease phenotype associated with defective apelin signaling and thus improve fatty acid uptake, glucose utilization, and insulin sensitivity.

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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