Deficiency in hormone-sensitive lipase accelerates the development of pancreatic cancer in conditional KrasG12D mice

Background: Hormone sensitive lipase (HSL) is a neutral lipase that preferentially catalyzes the hydrolysis of diacylglycerol contributing to triacylglycerol breakdown in the adipose tissue. HSL has been implicated to play a role in tumor cachexia, a debilitating syndrome characterized by progressive loss of adipose tissue. Consequently, pharmacological inhibitors of HSL have been proposed for the treatment of cancer-associated cachexia. In the present study we used the conditional KrasG12D (KC) mouse model of pancreatic ductal adenocarcinoma (PDAC) with a deficiency in HSL to determine the impact of HSL suppression on the development of PDAC.

Methods: KC;Hsl^+/+ and KC;Hsl^-/- mice were fed standard rodent chow for 20 weeks. At sacrifice, the incidence of PDAC was determined and inflammation in the mesenteric adipose tissue and pancreas was assessed histologically and by immunofluorescence. To determine statistical significance, ANOVA and two-tailed Student's t-tests were performed. To compare PDAC incidence, a two-sided Fisher's exact test was used.

Results: Compared to KC;Hsl^+/+ mice, KC;Hsl^-/- mice gained similar weight and displayed adipose tissue and pancreatic inflammation. In addition, KC;Hsl^-/- mice had reduced levels of plasma insulin and leptin. Importantly, the increased adipose tissue and pancreatic inflammation was associated with a significant increase in PDAC incidence in KC;Hsl^-/- mice.

Conclusions: HSL deficiency is associated with adipose tissue and pancreatic inflammation and accelerates PDAC development in the KC mouse model.