Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells

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Abstract

BACKGROUND: Free fatty acid receptor 1 (FFAR1) is G-protein coupled receptor predominantly expressed in pancreatic β-cells that is activated by a variety of free fatty acids (FFAs). Once activated, it promotes glucose-stimulated insulin secretion (GSIS). However, increased levels of FFAs lead to lipotoxicity, inducing loss of β-cell function. FFAR1 plays a key role in the development of type 2 diabetes (T2D), and previous studies have indicated the importance of developing anti-diabetic therapies against FFAR1, although its role in the regulation of β-cell function remains unclear. The present study investigated the role of FFAR1 under lipotoxic conditions using palmitic acid (PA). The rat insulinoma 1 clone 832/13 (INS-1 832/13) cell line was used as a model as it physiologically resembles native pancreatic β-cells. Key players of the insulin signaling pathway, such as mTOR, Akt, IRS-1, and the insulin receptor (INSR1β), were selected as candidates to be analyzed under lipotoxic conditions.

RESULTS: We revealed that PA-induced lipotoxicity affected GSIS in INS-1 cells and negatively modulated the activity of both IRS-1 and Akt. Reduced phosphorylation of both IRS-1 S636/639 and Akt S473 was observed, in addition to decreased expression of both INSR1β and FFAR1. Moreover, transient knockdown of FFAR1 led to a reduction in IRS-1 mRNA expression and an increase in INSR1β mRNA. Finally, PA affected localization of FFAR1 from the cytoplasm to the perinucleus.

CONCLUSIONS: In conclusion, our study suggests a novel regulatory involvement of FFAR1 in crosstalk with mTOR-Akt and IRS-1 signaling in β-cells under lipotoxic conditions.

Original languageEnglish
Pages (from-to)44
Number of pages1
JournalBiological Research
Volume52
Issue number1
DOIs
Publication statusPublished - 19 Aug 2019

Keywords

  • Akt
  • FFAR1
  • INSR
  • IRS-1
  • Insulin resistance
  • Lipotoxicity
  • Palmitic acid
  • Type 2 diabetes
  • mTOR
  • β-cells

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  • Prizes

    Best Poster Award

    Marafie, Sulaiman (Recipient), 13 Oct 2019

    Prize

    Activities

    • 1 Participating in a conference, workshop, ...

    Diabetes Asia Conference 2019

    Sulaiman Marafie (Participant)

    10 Oct 201913 Oct 2019

    Activity: Participating in or organising an event typesParticipating in a conference, workshop, ...

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