Joya E Nahon1, Menno Hoekstra2, Vanessa van Harmelen3, Patrick C N Rensen4, Ko Willems van Dijk5, Sander Kooijman4, Miranda Van Eck2. 1. Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Gorlaeus Laboratories, Leiden University, 2333CC Leiden, The Netherlands. Electronic address: j.e.nahon@lacdr.leidenuniv.nl. 2. Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Gorlaeus Laboratories, Leiden University, 2333CC Leiden, The Netherlands. 3. Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 4. Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands. 5. Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Abstract
OBJECTIVE: Proteoglycan 4 (Prg4) has emerged from human association studies as a possible factor contributing to weight gain, dyslipidemia and insulin resistance. In the current study, we investigated the causal role of Prg4 in controlling lipid and glucose metabolism in mice. METHODS: Prg4 knockout (KO) mice and wild-type (WT) littermates were challenged with an obesogenic high-fat diet (45% of total calories as fat) for 16 weeks. To further stimulate the development of metabolic alterations, 10% fructose water was provided starting from week 13. RESULTS: Prg4 deficiency only tended to reduce diet-induced body weight gain, but significantly improved glucose handling (AUC: -29%; p < 0.05), which was also reflected by a tendency towards a reduced HOMA-IR score (-49%; p = 0.06 as compared to WT mice). This coincided with lower hepatic expression of glycolysis (Gck: -30%; p < 0.05) and lipogenesis (Acc: -21%; p < 0.05 and Scd1: -38%; p < 0.001) genes, which translated in significantly lower hepatic triglyceride levels (-56%; p < 0.001) in Prg4 KO mice as compared to WT mice. Prg4 KO mice likely had lower glucose utilization by skeletal muscle as compared to WT mice, judged by a significant reduction in the genes Glut4 (-29%; p < 0.01), Pfkm (-21%; p < 0.05) and Hk2 (-39%; p < 0.001). Moreover, Prg4 KO mice showed a favorable white adipose tissue phenotype with lower uptake of triglyceride-derived fatty acids (-46%; p < 0.05) and lower gene expression of inflammatory markers Cd68, Mcp1 and Tnfα (-65%, -81% and -63%, respectively; p < 0.01) than WT mice. CONCLUSION: Prg4 KO mice are protected from high-fat diet-induced glucose intolerance and fatty liver disease.
OBJECTIVE:Proteoglycan 4 (Prg4) has emerged from human association studies as a possible factor contributing to weight gain, dyslipidemia and insulin resistance. In the current study, we investigated the causal role of Prg4 in controlling lipid and glucose metabolism in mice. METHODS:Prg4 knockout (KO) mice and wild-type (WT) littermates were challenged with an obesogenic high-fat diet (45% of total calories as fat) for 16 weeks. To further stimulate the development of metabolic alterations, 10% fructosewater was provided starting from week 13. RESULTS:Prg4deficiency only tended to reduce diet-induced body weight gain, but significantly improved glucose handling (AUC: -29%; p < 0.05), which was also reflected by a tendency towards a reduced HOMA-IR score (-49%; p = 0.06 as compared to WT mice). This coincided with lower hepatic expression of glycolysis (Gck: -30%; p < 0.05) and lipogenesis (Acc: -21%; p < 0.05 and Scd1: -38%; p < 0.001) genes, which translated in significantly lower hepatic triglyceride levels (-56%; p < 0.001) in Prg4 KO mice as compared to WT mice. Prg4 KO mice likely had lower glucose utilization by skeletal muscle as compared to WT mice, judged by a significant reduction in the genes Glut4 (-29%; p < 0.01), Pfkm (-21%; p < 0.05) and Hk2 (-39%; p < 0.001). Moreover, Prg4 KO mice showed a favorable white adipose tissue phenotype with lower uptake of triglyceride-derived fatty acids (-46%; p < 0.05) and lower gene expression of inflammatory markers Cd68, Mcp1 and Tnfα (-65%, -81% and -63%, respectively; p < 0.01) than WT mice. CONCLUSION:Prg4 KO mice are protected from high-fat diet-induced glucose intolerance and fatty liver disease.
Authors: Francesco Dituri; Rosanna Scialpi; Tannin A Schmidt; Martina Frusciante; Serena Mancarella; Luigi Giovanni Lupo; Erica Villa; Gianluigi Giannelli Journal: Cell Death Dis Date: 2020-11-16 Impact factor: 8.469