RESUMEN
Abstract This study aimed to investigate the acute effects of oleic acid (OA) on glucose homeostasis in mice fed a standard chow diet (SCD) and a high-fructose, high-fat diet (HFrHFD); moreover, the role of free fatty acid receptor 1 (FFAR1) was evaluated. The mice in the two groups were further divided into three subgroups as follows: control, OA (40 mg/kg), and OA + GW1100 (0.4 mg/kg, selective FFAR1 blocker). After a 16-week feeding period, the mice received the drugs via intraperitoneal (i.p.) injection followed by an i.p. glucose tolerance test (IPGTT) 30 min later. After 3 days, the mice received the same drugs to examine the effects of the drugs on the hepatic levels of phosphatidylinositol-4,5-bisphosphate (PIP2) and diacylglycerol (DAG). OA in the SCD-fed mice significantly increased the blood glucose level (48%, P < 0.001) after 30 min of glucose load compared to that in the control group, but did not affect the levels of PIP2 and DAG. Pre-injection with GW1100 significantly decreased the area under the curve of the IPGTT (28%, P < 0.05) in the SCD group compared to that in the SCD + OA group. OA reduced the blood glucose level (35%, P < 0.001) after 120 min of glucose load in the HFrHFD-fed mice; in addition, it increased hepatic PIP2 (160%, P < 0.01) and decreased hepatic DAG (60%, P < 0.001) levels. Pre-injection with GW1100 blocked the effects of OA on hepatic PIP2 and DAG without affecting the glucose tolerance. In conclusion, OA acutely impaired the glucose tolerance in the SCD-fed mice by acting on FFAR1 but did not improve it in the HFrHFD-fed mice.
RESUMEN
BACKGROUND: Free fatty acid receptor 1 (FFAR1) is G-protein coupled receptor predominantly expressed in pancreatic ß-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 ß-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 ß-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 ß-cells. Key players of the insulin signaling pathway, such as mTOR, Akt, IRS-1, and the insulin receptor (INSR1ß), 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 INSR1ß and FFAR1. Moreover, transient knockdown of FFAR1 led to a reduction in IRS-1 mRNA expression and an increase in INSR1ß; 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 ß-cells under lipotoxic conditions.