Abstract
BackgroundFree 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.ResultsWe 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.ConclusionsIn 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.
Highlights
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)
We demonstrated that lipotoxicity affected glucose-stimulated insulin secretion (GSIS), attenuated activity of both insulin receptor substrate 1 (IRS-1) and protein kinase B (Akt), and downregulated INSR1β and FFAR1
Our findings suggest potential crosstalk between Akt-mammalian target of rapamycin (mTOR), IRS-1, and FFAR1 that may help to elucidate their roles in insulin sensitivity and β-cell function involved in type 2 diabetes (T2D)
Summary
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). Postprandial insulin secretion occurs in a multiphasic pattern that begins with glucose uptake by target tissues (muscle and adipocytes), followed by the stimulation of lipogenesis and attenuation of hepatic glucose production [1] Factors such as age, nutrient overload, inflammation, and adipokines affect insulin. The mammalian target of rapamycin (mTOR) pathway (downstream of PI3K) is involved in many human diseases, including T2D It plays important roles in cell proliferation, differentiation, and survival and is predominantly regulated by growth factors and nutrients. The significance of mTOR signaling in T2D has been previously reported and indicates a crucial role of mTOR/ S6K1 in the regulation of insulin resistance and β-cell mass and function [13]
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