Malignant Tumors Enhance Release Of Akh/Glucagon To Cause Host Lipid Loss And Hyperglycemia

Insulin counter-regulator hormones like glucagon modulates systemic carbohydrate and lipid metabolism and energy homeostasis in a conserved manner in both vertebrates and invertebrates.In mammals,glucagon activates glucagon receptor(GCGR)in brain and peripheral organs such as liver,kidney,as well as adipose tissues,to promote glucose production,lipolysis,and systemic energy expenditure,leading to hyperglycemia,lipid loss,and weight decline.Glucagon release from a-cells is delicately regulated by both endocrinal and neural cues to maintain proper energy homeostasis.Much has been learned about hyperglycemia and/or lipid depletion caused by excessive glucagon secretion in diabetic subjects.However,whether and how glucagon release is aberrantly enhanced to impair systemic energy balance in catabolic diseases like cancer cachexia is largely unknown.Drosophila adipokinetic hormone(Akh),the homolog of mammalian glucagon,plays conserved roles in regulation of systemic lipid and carbohydrate homeostasis.Similarly,Drosophila Akh is secreted by neuroendocrine cells,referred as to Akh-producing cells(APCs),during fasting and activates AkhR/cAMP/Ca2+pathway and downstream transcriptional programs in the brain and fat body,to mobilize lipids and produce carbohydrates.We have previously uncovered the kinome participation in Akh signaling in the fat body and indicated Akh signaling pathway regulates systemic blood glucose level.When Pvfl/Pvr is activated,ERK knockdown can restore Akh transcription and release,while Mmp2 knockdown in APCs can only alleviate Akh release without affecting Akh transcription.In this study,we interestingly uncover that glucagon/Akh production is pathologically enhanced to result in lipid loss and hyperglycemia(major features of tumor-induced wasting or cancer cachexia)in both tumor-bearing mouse and Drosophila models.Integrating in vivo RNAi screening and genetic manipulation,we strikingly reveal that yki3SA tumors secrete a ligand Pvfl to activate its receptor Pvr in Akh-producing cells(APCs)and promote Akh secretion.The molecular mechanisms include that Pvfl/Pvr axis triggers Mmp2-associated extracellular matrix(ECM)remodeling in APCs and promote their innervation of upstream cholinergic neurons increase both mRNA level and release of Akh.We investigated Pvr downstream regulators and found that ERK knockdown restores both of them,while Mmp2 knockdown in APCs only alleviates Akh release without affecting Akh transcription,in the context of Pvfl/Pvr activation.These results suggest that Pvfl/Pvr axis in APCs promotes Akh release via not only ERK-associated Akh synthesis,but also Mmp2-induced Akh secretion.We further revealed that catabolic role of glucagon similar to Drosophila Akh,and the increase of circulating glucagon is related to ECM degradation of α-cells and acetylcholine neurons-α-cells innervation in tumor cachexia mice.Pharmaceutical inhibition of PDGFR/VEGFR,the homologs of fly Pvr,alleviates ECM degradation of α-cells,acetylcholine neurons-α-cells innervation,and glucagon release to improve hyperglycemia and lipid loss in a conserved manner.Therefore,we demonstrate that malignant tumors remotely trigger neural-associated Akh/glucagon secretion via PDGFR/VEGFR axis to cause host lipid loss and hyperglycemia.