Regulation of fat partitioning by ANGPTL4

Abstract

Altered triglyceride metabolism and changes in fatty acid partitioning are major contributors to metabolic diseases including metabolic syndrome, diabetes, and atherosclerosis. The triglycerides in plasma lipoproteins are hydrolyzed by lipoprotein lipase (LPL), and the levels of LPL activity in the capillary beds of peripheral tissues such as heart, skeletal muscle, and adipose serve as the primary determinant dietary fat delivery to those tissues. LPL activity is regulated by a variety of extracellular proteins including angiopoietin-like 4 (ANGPTL4). ANGPTL4 regulates plasma triglyceride metabolism by inactivating LPL. ANGPTL4 is most highly expressed in adipose tissue and liver, but it is also expressed at lower levels in muscle, heart, kidney, and intestine. It also circulates in plasma. Using whole-body and tissue-specific ANGPTL4 knockout mice we sought to determine where and when ANGPTL4 acts on LPL, and how the action of ANGPTL4 alters lipid partitioning. We found that ANGPTL4-deficiency specifically increases the uptake of triglyceride-derived fatty acids into adipose tissue, and that is effect is observed most prominently in the fasted state. Adipose-specific knockout of ANGPTL4 could wholly recapitulate the plasma triglyceride and fat partitioning phenotypes of whole-body ANGPTL4 knockouts, supporting the idea that adipose-derived ANGPTL4 is the primary driver of ANGPTL4’s effect on plasma triglycerides. Our data also suggest that ANGPTL4 expressed in adipose primarily acts locally to suppress LPL activity in the fasted state. Consistent with other reports, we also found that adipose-specific deletion of ANGPTL4 leads to short-term improvement in glucose tolerance in mice fed a high fat diet. However, we found that this improvement disappears with age. Moreover, we found that in wild-type mice LPL activity, ANGPTL4 expression, and lipid portioning are all altered with age. As age is also an important risk factor for metabolic disease, these finding suggest that age-induced changes in triglyceride metabolism may contribute to the increased risk of metabolic disease associated with aging.