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

JCI Insight. 2018 Mar 22;3(6):e97918. doi: 10.1172/jci.insight.97918.


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.

Keywords: Adipose tissue; Atherosclerosis; Carbohydrate metabolism; Metabolism; Vascular Biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Alleles
  • Angiopoietin-Like Protein 4 / genetics
  • Angiopoietin-Like Protein 4 / metabolism*
  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Body Weight
  • Chemokines / blood
  • Cytokines / blood
  • Diet, High-Fat
  • Diet, Western
  • Fatty Acids / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Glucose / metabolism*
  • Insulin / metabolism
  • Integrases / genetics
  • Intercellular Signaling Peptides and Proteins / blood
  • Lipid Metabolism
  • Lipoprotein Lipase
  • Lipoproteins / metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscles / metabolism
  • Obesity
  • Proprotein Convertase 9
  • Triglycerides


  • Angiopoietin-Like Protein 4
  • Angptl4 protein, mouse
  • Chemokines
  • Cytokines
  • Fatty Acids
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Lipoproteins
  • Triglycerides
  • Cre recombinase
  • Integrases
  • Lipoprotein Lipase
  • Proprotein Convertase 9
  • Glucose