Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue

Philip M.M Ruppert,Charlotte C.J.R Michielsen,Eric J Hazebroek,Ali Pirayesh,Gunilla Olivecrona,Lydia A Afman,Sander Kersten

doi:10.1016/j.molmet.2020.101033

Philip M.M Ruppert, Charlotte C.J.R Michielsen + Show 5 more

Open Access

https://doi.org/10.1016/j.molmet.2020.101033

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Abstract

ObjectiveStudies in mice have shown that the decrease in lipoprotein lipase (LPL) activity in adipose tissue upon fasting is mediated by induction of the inhibitor ANGPTL4. Here, we aimed to validate this concept in humans by determining the effect of a prolonged fast on ANGPTL4 and LPL gene and protein expression in human subcutaneous adipose tissue. MethodsTwenty-three volunteers ate a standardized meal at 18.00 h and fasted until 20.00 h the next day. Blood was drawn and periumbilical adipose tissue biopsies were collected 2 h and 26 h after the meal. ResultsConsistent with previous mouse data, LPL activity in human adipose tissue was significantly decreased by fasting (−60%), concurrent with increased ANGPTL4 mRNA (+90%) and decreased ANGPTL8 mRNA (−94%). ANGPTL4 protein levels in adipose tissue were also significantly increased by fasting (+46%), whereas LPL mRNA and protein levels remained unchanged. In agreement with the adipose tissue data, plasma ANGPTL4 levels increased upon fasting (+100%), whereas plasma ANGPTL8 decreased (−79%). Insulin, levels of which significantly decreased upon fasting, downregulated ANGPTL4 mRNA and protein in primary human adipocytes. By contrast, cortisol, levels of which significantly increased upon fasting, upregulated ANGPTL4 mRNA and protein in primary human adipocytes as did fatty acids. ConclusionANGPTL4 levels in human adipose tissue are increased by fasting, likely via increased plasma cortisol and free fatty acids and decreased plasma insulin, resulting in decreased LPL activity.This clinical trial was registered with identifier NCT03757767.

Highlights

Elevated plasma triglyceride levels are associated with an elevated risk of atherosclerotic cardiovascular disease [1e4]
In this paper we show that a 24-hour fast in human volunteers markedly reduces lipoprotein lipase (LPL) activity in subcutaneous adipose tissue, concomitant with significant increases in adipose tissue Angiopoietin-like 4 (ANGPTL4) mRNA, adipose tissue ANGPTL4 protein, and plasma ANGPTL4 levels
Our results strongly support the notion derived from studies in rodents that local upregulation of ANGPTL4 mediates the decrease in LPL activity and associated lipid storage in adipose tissue during fasting in humans

Summary

Introduction

Elevated plasma triglyceride levels are associated with an elevated risk of atherosclerotic cardiovascular disease [1e4]. Triglycerides are mainly transported in the blood as part of intestine-derived chylomicrons and liver-derived very-low density lipoproteins (VLDLs). The triglycerides in these lipoprotein particles are cleared from the bloodstream through the action of lipoprotein lipase (LPL) [5,6]. ANGPTL3 is secreted by the liver as a complex with ANGPTL8 and regulates postprandial LPL activity in adipose tissue and muscle in an endocrine fashion [21,22]. The combined action of ANGPTL3/ANGPTL8 reduces the clearance of plasma triglycerides in Abbreviations: ANGPTL4, Angiopoietin-like 4; ANGPTL8, Angiopoietin-like 8; SVF, Stromal vascular fraction; WAT, White adipose tissue

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