Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota

Aafke W F Janssen,Ko Willems Van Dijk,Sander Kersten,Barbara Bartosinska,Daniel Eberhard,Saeed Katiraei

doi:10.1007/s00125-018-4583-5

Abstract

Aims/hypothesisAngiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4−/− mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity.MethodsWe chronically fed wild-type (WT) and Angptl4−/− mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests.ResultsMice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4−/− mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4−/− mice.Conclusions/interpretationDespite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism.

Highlights

Obesity is often accompanied by insulin resistance, which greatly increases the risk of cardiometabolic complications [1]
Plasma serum amyloid A concentrations were low in Angptl4−/− mice fed a diet rich in unsaturated fatty acids compared with Angptl4−/− mice fed a diet rich in saturated fatty acids [16, 17], and were not significantly elevated compared with WT mice (Fig. 1a)
We investigated the role of angiopoietinlike 4 (ANGPTL4) in metabolic dysfunction in mice with diet-induced obesity

Summary

Introduction

Obesity is often accompanied by insulin resistance, which greatly increases the risk of cardiometabolic complications [1]. Part of the effect of insulin resistance on cardiometabolic risk is conferred by changes in plasma lipoproteins. A particular class of lipoproteins are triacylglycerol-rich lipoproteins, consisting of chylomicrons and VLDL [2]. Triacylglycerol-rich lipoproteins are quickly captured and hydrolysed by lipoprotein lipase (LPL) in the capillaries of fat and muscle tissue [3,4,5]. The resulting fatty acids are taken up by underlying fat and muscle cells, and are either stored as triacylglycerols or used as fuel [3]. To ensure that the rate of uptake of fatty acids matches local energy demands, the activity of LPL is carefully regulated.

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