TY - JOUR T1 - Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue JF - Gut JO - Gut SP - 1165 LP - 1174 DO - 10.1136/gutjnl-2014-308350 VL - 65 IS - 7 AU - Gunisha Sagar AU - Raghuwansh P Sah AU - Naureen Javeed AU - Shamit K Dutta AU - Thomas C Smyrk AU - Julie S Lau AU - Nino Giorgadze AU - Tamar Tchkonia AU - James L Kirkland AU - Suresh T Chari AU - Debabrata Mukhopadhyay Y1 - 2016/07/01 UR - http://gut.bmj.com/content/65/7/1165.abstract N2 - Background and objectives New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumour-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesise that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC-exosomes as the mediator of this lipolysis.Design Exosomes from patient-derived cell lines and from plasma of patients with PC and non-PC controls were isolated and characterised. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink Assay was used to study AM and adrenomedullin receptor (ADMR) interaction in adipocytes treated with exosomes.Results In murine and human adipocytes, we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by ADMR blockade. AM interacted with its receptor on the adipocytes, activated p38 and extracellular signal-regulated (ERK1/2) mitogen-activated protein kinases and promoted lipolysis by phosphorylating hormone-sensitive lipase. PKH67-labelled PC-exosomes were readily internalised into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis.Conclusions PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect. ER -