title: FAM3D inhibits glucagon secretion via MKP1-dependent suppression of ERK1/2 signaling.
abstract: Dysregulated glucagon secretion is a hallmark of type 2 diabetes (T2D). To date, few effective therapeutic agents target on deranged glucagon secretion. Family with sequence similarity 3 member D (FAM3D) is a novel gut-derived cytokine-like protein, and its secretion timing is contrary to that of glucagon. However, the roles of FAM3D in metabolic disorder and its biological functions are largely unknown. In the present study, we investigated whether FAM3D modulates glucagon production in mouse pancreatic alpha TC1 clone 6 (αTC1-6) cells. Glucagon secretion, prohormone convertase 2 (PC2) activity, and mitogen-activated protein kinase (MAPK) pathway were assessed. Exogenous FAM3D inhibited glucagon secretion, PC2 activity, as well as extracellular-regulated protein kinase 1/2 (ERK1/2) signaling and induced MAPK phosphatase 1 (MKP1) expression. Moreover, knockdown of MKP1 and inhibition of ERK1/2 abolished and potentiated the inhibitory effect of FAM3D on glucagon secretion, respectively. Taken together, FAM3D inhibits glucagon secretion via MKP1-dependent suppression of ERK1/2 signaling. These results provide rationale for developing the therapeutic potential of FAM3D for dysregulated glucagon secretion and T2D.
authors.affiliation: Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Cao
authors.affiliation: Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
authors.forename: Yueqian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Qiao
authors.affiliation: Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Gao
authors.affiliation: Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. yubo120@hotmail.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.affiliation: Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China. zhangpg@yahoo.com.|Department of Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. zhangpg@yahoo.com.
authors.forename: Peng
authors.identifier: 0000-0002-2194-8760
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005934:Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism
chemical_list: D016207:Cytokines; C580702:FAM3D protein, mouse; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse; D005934:Glucagon; D020928:Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C473668:Pcsk2 protein, mouse; D045706:Proprotein Convertase 2
keywords: ERK1/2 signaling; FAM3D; Glucagon secretion; Prohormone convertase 2; Type 2 diabetes