Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling

J Mol Endocrinol. 2014 Dec;53(3):367-80. doi: 10.1530/JME-14-0065. Epub 2014 Oct 8.

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.

Keywords: free fatty acid receptor 2; inflammatory; peripheral blood mononuclear cells; short-chain fatty acids; type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Apoptosis / genetics*
  • Blood Glucose / metabolism
  • Case-Control Studies
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Genetic Association Studies
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System / physiology
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Cell Surface / genetics*
  • Young Adult

Substances

  • Blood Glucose
  • FFA2R protein, human
  • Receptors, Cell Surface