FAM3D inhibits glucagon secretion via MKP1-dependent suppression of ERK1/2 signaling

• DOI: 10.1007/s10565-017-9387-8
• Publication Date: 2017-02-28T03:15:19Z
• Authors: Ting Cao; Dan Yang; Xiong Zhang; Yueqian Wang; Zhengdong Qiao; Lili Gao; Yongjun Liang; Bo Yu; Peng Zhang
• Keywords: 0303 health sciences; MAP Kinase Signaling System; Dual Specificity Phosphatase 1; Glucagon; Receptors, Formyl Peptide; Cell Line; Mice; 03 medical and health sciences; Proprotein Convertase 2; Diabetes Mellitus, Type 2; Glucagon-Secreting Cells; Enzyme Induction; Animals; Cytokines; Mitogen-Activated Protein Kinases; Pancreas

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.