한빛사 논문
Eunbyul Yeom 1,2,10, Hyemi Shin 3,10, Wonbeak Yoo4,10, Eunsung Jun5, Seokho Kim6, Seung Hyun Hong1, Dae-Woo Kwon 1,7, Tae Hoon Ryu1,7, Jae Myoung Suh3,*, Song Cheol Kim8,*, Kyu-Sun Lee 1,7,* and Kweon Yu1,7,9,*
1Metabolism and Neurophysiology Research Group, Disease Target Structure Research Center, KRIBB, Daejeon, Korea. 2Tunneling Nanotube Research Center, Korea University, Seoul, Korea. 3Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea. 4Environmental Disease Research Center, KRIBB, Daejeon, Korea. 5Department of Convergence Medicine and Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Institute for Life Sciences, AMIST, Asan Medical Center, Seoul, Korea. 6Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Korea. 7Department of Functional Genomics, UST, Daejeon, Korea. 8Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Asan Biomedical Engineering Research Center, AMIST, Seoul, Korea. 9Convergence Research Center of Dementia, KIST, Seoul, Korea. 10These authors contributed equally:
Eunbyul Yeom, Hyemi Shin, Wonbeak Yoo.
*Correspondence to Jae Myoung Suh or Song Cheol Kim or Kyu-Sun Lee or Kweon Yu.
Abstract
In patients with advanced-stage cancer, cancer-associated anorexia affects treatment success and patient survival. However, the underlying mechanism is poorly understood. Here, we show that Dilp8, a Drosophila homologue of mammalian insulin-like 3 peptide (INSL3), is secreted from tumour tissues and induces anorexia through the Lgr3 receptor in the brain. Activated Dilp8-Lgr3 signalling upregulated anorexigenic nucleobinding 1 (NUCB1) and downregulated orexigenic short neuropeptide F (sNPF) and NPF expression in the brain. In the cancer condition, the protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF. INSL3 levels were increased in tumour-implanted mice and INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation. Food consumption was significantly reduced in intracerebrospinal INSL3-injected mice. In patients with pancreatic cancer, higher serum INSL3 levels increased anorexia. These results indicate that tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals.
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