Leiden University Scholarly Publications

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Proteoglycan 4 (Prg4) is highly expressed in metabolic tissues. The proteoglycan is a target gene for the nuclear receptor peroxisome proliferator receptor gamma which acts as metabolic switch. So, our aim was to investigate the function of Prg4 in metabolism.

Male Prg4 knock-out (KO) mice and wild-type (WT) littermates were challenged with a obesogenic

36

Proteoglycan 4 (Prg4) is highly expressed in metabolic tissues. The proteoglycan is a target gene for the nuclear receptor peroxisome proliferator receptor gamma which acts as metabolic switch. So, our aim was to investigate the function of Prg4 in metabolism.

Male Prg4 knock-out (KO) mice and wild-type (WT) littermates were challenged with a obesogenic high fat diet (45% kcal lard fat) for 16 weeks. To stimulate the development of a diabetic phenotype, 10% fructose water was provided. Mice were subjected to an oral glucose tolerance test to investigate glucose handling. Flux studies with glycerol [3H]oleate-labeled VLDL-like particles were performed to determine the uptake of triglyceride-derived fatty acids in metabolically active organs.

No significant difference in body weight was observed between both groups. However, both plasma triglyceride levels (-16%; p<0.05) and hepatic triglyceride levels (2.3-fold decrease, p<0.001) were decreased in Prg4 KO mice as compared to WT mice. The decreased hepatic steatosis in Prg4 KO mice is most likely driven by decreased de novo lipogenesis, as judged by the significantly reduced expression of lipogenic genes ACC and SCD1 (-21% and -38%; p<0.05) and a similar hepatic uptake of the radiolabeled triglyceride-derived fatty acids. White adipose tissue of Prg4 KO mice showed decreased uptake of triglyceride-derived fatty acids (-46%; p<0.05). The expression of CD68 and MCP1 was lower in Prg4 KO adipose tissue as compared to that of WT controls (2.9- and 5.1-fold decrease; p<0.01), indicating reduced adipose tissue inflammation. The favorable white adipose tissue phenotype in Prg4 KO mice as compared to WT mice coincided with improved glucose handling during an oral glucose tolerance test (AUC: -29%; p<0.05).

Prg4 KO and WT mice have

a similar obesogenic potential, however Prg4 KO mice are protected from high fat diet-induced metabolic disruptions.