Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis
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
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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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 4

Adipose ANGPTL4 loss enhances lipolysis and oxidative metabolism but reduces endogenous lipogenesis.

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Adipose ANGPTL4 loss enhances lipolysis and oxidative metabolism but red...
(A) Representative H&E-stained sections of white adipose tissue (WAT) isolated from WT mice and in mice with AT-specific knockout of ANGPTL4 (Ad-KO) fed a high-fat diet (HFD) for 4 weeks. Quantification of adipocyte size (right) (n = 3). Scale bars: 200 μm. (B) Ex vivo lipolysis of WAT isolated from WT and Ad-KO mice and treated with vehicle (V) or isoproterenol (Iso) (n = 3). FFA, free fatty acid. (C) In vivo lipolysis in 8-week-old WT and Ad-KO mice (n = 3). NEFA, nonesterified fatty acid. (D) Western blot analysis of indicated proteins in WAT from WT and Ad-KO mice after 4 weeks on HFD (n = 3). Densitometric analysis of the blots is shown on the right panel. (E) Ex vivo fatty acid oxidation of WAT isolated from WT and Ad-KO mice (n = 3). (F) mRNA expression of indicated genes in WAT from WT and Ad-KO mice fed an HFD for 4 weeks (n = 3). (G) Representative Western blot analysis of indicated proteins in WAT from WT and Ad-KO mice fed an HFD for 4 weeks (n = 3). Densitometric analysis of the blots is shown on the right panel. PGC-1α, PPARγ coactivator 1α; UCP-1, uncoupling protein 1. (H) Ex vivo fatty acid synthase (FASN) activity was measured in isolated WAT of WT and Ad-KO mice (n = 3). All data represent the mean ± SEM. *P ≤ 0.05 comparing Ad-KO with WT mice using unpaired t test.