Impaired Adipose Anabolism in Pancreatic Cancer Cachexia Is Reversed by HuR Inhibition

BACKGROUND: Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC) and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice. METHODS: Adult C57BL/6J mice received orthotopic PDAC cell (KrasG12D; p53R172H/+; Pdx1-cre) (PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9 days after injection) were fasted for 24 h, or fasted 24 h and refed 24 h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH-3, 100 mg/kg) and subjected to the fast/refeed paradigm. We analysed body mass, gross fat pad mass and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3-L1 adipocytes in vitro and gonadal fat pads (gWAT) ex vivo. RESULTS: 3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) had lower expression of lipolysis and lipogenesis genes than control cells and did not display elevated lipolysis as measured by liberated glycerol. PDAC ...