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

Abstract

Aims/hypothesis Angiopoietin-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.Methods We 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. Results Mice 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/interpretation Despite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism.

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

“…Early work on ANGPTL4 in rodents was performed using whole-body transgenic or knockout mouse models that limit our ability to understand the specific role of ANGPTL4 in vital metabolic tissues. Therefore, most of the conclusions drawn from these studies have been contradictory (13,21,(26)(27)(28)(29)(30).…”

Can targeting ANGPTL proteins improve glucose tolerance?

“…A potential confounding factor in any study that measures glucose tolerance in ANGPTL4-deficient mice is the acute phase response observed when high-fat feeding these mice [22]. As reported in this issue of Diabetologia , Janssen et al overcome this issue by feeding Angptl4 knockout mice with a diet high in unsaturated fatty acids [27]. Although the knockout mice still manifest some signs of increased inflammation on this diet, they do not manifest the acute phase response or the lethal chylous ascites of Angptl4 knockout mice fed a diet high in saturated fatty acids.…”

“…In the studies of Janssen et al and Vatner et al, improved glucose tolerance was accompanied by increased fat mass [27, 31]. One appealing model for this phenomenon is that increased LPL activity in adipose tissue funnels more lipids to adipose, preventing ectopic lipid deposition in other tissues such as liver, and thus preventing insulin resistance (Fig.…”

“…In fact, they did not examine fatty acid delivery to liver or to any tissue other than adipose. Janssen et al also show increased visceral fat mass in ANGPTL4-deficient mice [27], but changes in the partitioning of circulating lipids were not examined. Thus, although attractive, a model wherein targeting ANGPTL proteins increases the partitioning of fat to adipose tissue, thus preventing ectopic lipid deposition and glucose intolerance will need to be supported by further studies.…”

“…A concept raised by both the Janssen et al and Vatner et al studies is the importance of establishing the location in which ANGPTL proteins act [27, 31]. In the study by Janssen et al [27], Angptl4 knockout mice fed a high-fat diet have increased body weight and visceral fat mass compared with wild-type mice on the same diet.…”