title: Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling.
abstract: Recent reports have highlighted the roles of free fatty acid receptor 2 (FFAR2) in the regulation of metabolic and inflammatory processes. However, the potential function of FFAR2 in type 1 diabetes (T1D) remains unexplored. Our results indicated that the mRNA level of FFAR2 was upregulated in peripheral blood mononuclear cells of T1D patients. The human FFAR2 promoter regions were cloned, and luciferase reporter assays revealed that NFκB activation induced FFAR2 expression. Furthermore, we showed that FFAR2 activation by overexpression induced cell apoptosis through ERK signaling. Finally, treatment with the FFAR2 agonists acetate or phenylacetamide 1 attenuated the inflammatory response in multiple-low-dose streptozocin-induced diabetic mice, and improved the impaired glucose tolerance. These results indicate that FFAR2 may play a protective role by inducing apoptosis of infiltrated macrophage in the pancreas through its feedback upregulation and activation, thus, in turn, improving glucose homeostasis in diabetic mice. These findings highlight FFAR2 as a potential therapeutic target of T1D, representing a link between immune response and glucose homeostasis.
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Shi
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Weiqiong
authors.initials: W
authors.lastname: Gu
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Minglan
authors.initials: M
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhai
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Peishun
authors.initials: P
authors.lastname: Shou
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanghai Institute of Endocrinology and MetabolismEndocrine and Metabolic E-Institutes of Shanghai Universities (EISU), Shanghai Clinical Center for Endocrine and Metabolic Diseases and Key Laboratory for Endocrinology and Metabolism of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197th Ruijin 2nd Road, Shanghai 200025, ChinaLaboratory of Endocrinology and MetabolismKey Laboratory of Stem Cell BiologyInstitute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China gning@sibs.ac.cn.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000235:genetics*; D055815:Young Adult; D043562:Receptors, G-Protein-Coupled
chemical_list: D001786:Blood Glucose; D011956:Receptors, Cell Surface; C473103:FFAR2 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: free fatty acid receptor 2; inflammatory; peripheral blood mononuclear cells; short-chain fatty acids; type 1 diabetes