Owing to its role in lipid metabolism, angiopoietin-like 4 (ANGPTL4) has emerged as a potential therapeutic target for cardiometabolic dysfunction, but its role in glucose metabolism and obesity is less clear. ANGPTL4, which is ubiquitously expressed in mice and humans, is a member of a group of angiopoietin-like proteins that regulate lipoprotein lipase (LPL) activity. LPL is responsible for hydrolysing triacylglycerol-rich lipoproteins into fatty acids in the capillaries of muscle and adipose tissue. ANGPTL4 also regulates pancreatic lipase, which is involved in the hydrolysis of dietary triacylglycerols in the gastrointestinal tract.

Credit: Jennie Vallis/Macmillan Publishers Limited

Studies in mice have implicated ANGPTL4 in glucose metabolism, but to date its role in diet-induced obesity has remained unclear, as Angptl4-knockout mice develop inflammation when fed a high-fat diet (HFD). Now, new research published in Diabetologia describes the influence of ANGPTL4 on metabolic dysfunction in a mouse model of diet-induced obesity.

“10 years ago we performed a diet-induced obesity study in Angptl4-knockout mice to study the role of ANGPTL4 in obesity and associated insulin resistance. To our surprise, the mice developed a severe inflammatory phenotype, which could be linked to the mesenteric lymph nodes,” explains corresponding author Sander Kersten. “This severe phenotype precluded investigation of the role of ANGPTL4 in insulin resistance.”

Subsequently, while investigating the role of ANGPTL4 in glucose homeostasis, Kersten and colleagues discovered that when Angptl4-knockout mice are fed a diet of unsaturated fatty acids, they do not develop the lethal phenotype. In the present study, the authors took advantage of this finding and induced obesity by feeding Angptl4-knockout and wild-type mice a diet rich in unsaturated free fatty acids. In addition, to mimic a Western-style diet, the investigators added cholesterol to the chow and fructose to the drinking water. The authors performed a metabolic characterization of the mice, including glucose homeostasis via intraperitoneal glucose and insulin tolerance tests.

The researchers found that Angptl4-knockout mice had much better glucose tolerance than wild-type mice, despite being more obese

The researchers found that Angptl4-knockout mice had much better glucose tolerance than wild-type mice, despite being more obese. Although the observation that ANGPTL4-deficient mice store more fat is not new, this study presents evidence for the uncoupling of obesity and glucose intolerance.

Next, Kersten and colleagues investigated the role of the gut microbiota in glucose tolerance in obese Angptl4-knockout mice. Previous studies have implicated the gut microbiota in insulin secretion and research suggests that ANGPTL4 is linked to the gut microbiota. In the colon of Angptl4-knockout mice, levels of propionate and butyrate were lower and levels of succinate were higher than in wild-type mice, suggesting that the composition of the gut microbiota differs between Angptl4-knockout mice and wild-type mice, a finding that was confirmed by 16S-ribosomal RNA sequencing. Furthermore, by suppressing the gut bacteria with orally administered antibiotics, the authors were able to abolish the improved glucose tolerance of obese Angptl4-knockout mice, which suggests that the gut microbiota is involved in mediating the effect of ANGPTL4 on glucose tolerance.

“The next step is to characterize the tissue-specific functions of ANGPTL4 using appropriate mouse models. The inactivation of ANGPTL4 is currently being explored as a therapeutic strategy for dyslipidaemia,” concludes Kersten. “Based on our work, the inactivation of ANGPTL4 might also improve other features of metabolic dysfunction, in particular glucose intolerance.”