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

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 8

ANGPTL4 deficiency in adipose tissue (AT) reduces inflammation.

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ANGPTL4 deficiency in adipose tissue (AT) reduces inflammation. (A–G) Pl...
(A–G) Plasma concentration of indicated cytokines from WT mice and in mice with AT-specific knockout of ANGPTL4 (Ad-KO) mice fed a Western diet (WD) for 16 weeks measured by ELISA (n = 7–11). (H and I) Immunostaining showing the expression of ICAM-1 (H) and VCAM-1 (I) along with CD31 in section from aortic root atherosclerotic lesions of WT and Ad-KO mice fed a WD for 4 weeks (n = 3). The scheme on the left shows the region from which sections were taken. Panels on the right of each image show quantification of staining expressed as percentage of lesion area. AR, aortic root; L, lesion. (J and K) Immunostaining showing the expression of ICAM-1 (J) and VCAM-1 (K) along with CD31 in a section from the lesser (LC) curvature of aortic arch of WT and Ad-KO mice fed a WD for 4 weeks (n = 3). The scheme on the left shows the region from which sections were taken. Panels on the right of each image shows quantification of staining expressed as positive area per unit length of endothelium. Scale bars: 62 μm (H–K). All data are the mean ± SEM. *P ≤ 0.05 by comparison with data from Ad-KO with WT mice by unpaired t test.