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Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis
Binod Aryal, … , Yajaira Suárez, Carlos Fernández-Hernando
Binod Aryal, … , Yajaira Suárez, Carlos Fernández-Hernando
Published March 22, 2018
Citation Information: JCI Insight. 2018;3(6):e97918. https://doi.org/10.1172/jci.insight.97918.
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Research Article Metabolism Vascular biology

Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis

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Abstract

Alterations in ectopic lipid deposition and circulating lipids are major risk factors for developing cardiometabolic diseases. Angiopoietin-like protein 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL), controls fatty acid (FA) uptake in adipose and oxidative tissues and regulates circulating triacylglycerol-rich (TAG-rich) lipoproteins. Unfortunately, global depletion of ANGPTL4 results in severe metabolic abnormalities, inflammation, and fibrosis when mice are fed a high-fat diet (HFD), limiting our understanding of the contribution of ANGPTL4 in metabolic disorders. Here, we demonstrate that genetic ablation of ANGPTL4 in adipose tissue (AT) results in enhanced LPL activity, rapid clearance of circulating TAGs, increased AT lipolysis and FA oxidation, and decreased FA synthesis in AT. Most importantly, we found that absence of ANGPTL4 in AT prevents excessive ectopic lipid deposition in the liver and muscle, reducing novel PKC (nPKC) membrane translocation and enhancing insulin signaling. As a result, we observed a remarkable improvement in glucose tolerance in short-term HFD-fed AT-specific Angptl4-KO mice. Finally, lack of ANGPTL4 in AT enhances the clearance of proatherogenic lipoproteins, attenuates inflammation, and reduces atherosclerosis. Together, these findings uncovered an essential role of AT ANGPTL4 in regulating peripheral lipid deposition, influencing whole-body lipid and glucose metabolism and the progression of atherosclerosis.

Authors

Binod Aryal, Abhishek K. Singh, Xinbo Zhang, Luis Varela, Noemi Rotllan, Leigh Goedeke, Balkrishna Chaube, Joao-Paulo Camporez, Daniel F. Vatner, Tamas L. Horvath, Gerald I. Shulman, Yajaira Suárez, Carlos Fernández-Hernando

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Figure 1

Generation of ANGPTL4 conditional deficient mice.

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Generation of ANGPTL4 conditional deficient mice.
(A) Schematic diagram ...
(A) Schematic diagram of the inserted knockout-first allele. The cassette is composed of a short flippase recombination enzyme (Flp)-recognition target (FRT), reporter, and a Cre recombinase recognition target (loxP). The first FRT site is followed by the reporter, which is a reading frame–independent LacZ gene trap cassette: splice acceptor of mouse En2 exon 2 (En2-SA), the internal ribosome entry site from encephalomyocarditis virus (ECMV IRES), Escherichia coli lacZ gene encoding the reporter enzyme β-gal (lacZ), and simian virus 40 polyadenylation signal (pA). The first loxP site is followed by the neomycin selection cassette that is composed of the human β-actin promoter (hBactP) driving the neomycin resistance gene, pA, a second FRT site, and a second loxP site. A third loxP site is inserted downstream of the targeted exon. Angptl4 exons 4–6 are flanked by loxP sites. Mice with the floxed allele were generated by crossing the knockout-first mice with flp recombinase-deleter mice. Subsequently, these mice were bred with mice expressing Cre recombinase to produce tissue-specific ANGPTL4-knockout mice. Genotyping from Angptl4fl/fl mice showing bands from one, both, or none of the alleles floxed. (B) Representative Western blot analysis showing β-gal expression from different tissues from knockout-first allele in fed and fasted conditions. SKM, skeletal muscle. (C) Immunostaining showing β-gal expression in brown (BAT) and white adipose tissue (WAT). Inset shows whole-mount staining and magnification shows cross sections stained with β-gal. Scale bars: 100 μm.

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