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

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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.

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Acknowledgements

This study was supported by Pudong Bureau of Health and Family Planning Grants (Grant No. PwRd2013-08, No. PWZxq2014-08), Shanghai Commission of Science and Technology Grant (Grant No. 124119b1800), Shanghai Pujiang Telant Project Grant (No. 14PJ1407800), as well as Shanghai Bureau of Health and Family Planning Grant (Grant No. 20124443). These supports are gratefully acknowledged. The authors also express thanks to Dr. Yi Zhang and Dr. Weihai Ying for spending their precious time on proofreading and English language editing.

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Authors and Affiliations

  1. Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China

    Ting Cao, Dan Yang, Yueqian Wang, Zhengdong Qiao, Lili Gao, Yongjun Liang & Peng Zhang

  2. Department of Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China

    Xiong Zhang, Bo Yu & Peng Zhang

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  1. Ting Cao
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  2. Dan Yang
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Correspondence to Bo Yu or Peng Zhang.

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Bo Yu and Peng Zhang are co-corresponding authors.

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Cao, T., Yang, D., Zhang, X. et al. FAM3D inhibits glucagon secretion via MKP1-dependent suppression of ERK1/2 signaling. Cell Biol Toxicol 33, 457–466 (2017). https://doi.org/10.1007/s10565-017-9387-8

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