However Gingrich and Hen reported that absence of the

However, Gingrich and Hen reported that absence of the gene at all stages of ontogenesis of mice may interfere with the normal developmental program and/or the organism may undergo changes in other systems to compensate for gene absence (46). In addition, potentially altered maternal behavior of GPR40/FFAR1 KO dams might have a great impact on the resulting phenotype of adult KO offspring because of significant role of maternal behavior in the expression of a phenotype change in adult mice (47), (48). Therefore, we cannot excluded that obtained behavioral and physiological changes can be attributed to above-mentioned factors.
Conflict of interest
Acknowledgments This study was supported by 1) Grants-in-Aid and Special Coordination Funds from the Kobe Gakuin University Joint Research (A), 2) the Takeda Pharmaceutical Sciences and 3) a Grants-in-Aid for Scientific Research (C) (15K10566) from the Ministry of Education, Culture, Sports, Science and Technology, Japan and the Takeda Science Foundation.
Introduction Free fatty acids (FFAs) play an essential role in the regulation of insulin secretion. At low glucose levels, FFAs are used as a substrate for generation of ATP and maintain insulin secretion [1]. At high glucose conditions, β-oxidation is inhibited by a product of the glycolytic pathway, malonyl-CoA, and fatty acids are directed towards formation of triacylglycerol (TAG) [2], [3]. The anabolic and catabolic reactions between long-chain acyl Co-As (LC-CoA) and TAG, known as glycerolipid/free fatty BAY 80-6946 synthesis (GL/FFA) cycle, produce lipid signaling molecules including LC-CoAs, phosphatic acids, monoacylglycerol and diacylglycerol (DAG), all of which stimulate insulin secretion [4]. In addition to its role as a nutrient, FFAs serve as ligands and influence insulin secretion by interacting with G-protein coupled receptors (GPCRs) on the plasma membrane [5], [6]. One of the GPCRs that is highly expressed in beta cells is the free fatty acid receptor 1 (FFAR1 or GPR40) [5], [6]. Activation of the receptor leads to activation of phospholipase C (PLC) and hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into DAG and inositol triphosphate (IP3). DAG and IP3 potentiate insulin secretion by activating protein kinase C (PKC) and triggering ER Ca release, respectively [7], [8]. Recently, FFAR1 agonists have been developed as potential therapeutic agents for the treatment of type 2 diabetes [9], [10], [11], [12]. In contrast to short-term effects, long-term exposure of beta cells to FFAs impairs insulin secretion and triggers apoptosis [13]. The deleterious effects of FFAs have been linked to altered glucose/fatty acid oxidation cycle [13], decreased NADPH content [14], endoplasmic reticulum (ER) stress [15] and partitioning towards formation of toxic ceramide species [16]. Also, FFAR1 signaling has been implicated in the long-term deleterious effects of FFAs [17], [18], [19], [20]. We have recently demonstrated that fatty acid metabolism and FFAR1 signaling act synergistically on insulin secretion [17]. Reduced β-oxidation of fatty acids in the presence of a FFAR1 antagonist pointed out mitochondria as a site where the two pathways may converge [17]. It is known that this organelle is pivotal in beta-cell function. Uncoupling of respiration from ATP synthesis is essential for the regulation of ATP/ADP ratio and insulin secretion [21]; and beta cells depleted of mitochondria are unable to properly change insulin secretion in response to metabolic changes [22], [23]. Taking into account the aforementioned, we decided to investigate the effects of fatty acid metabolism and FFAR1 signaling on mitochondrial function.
Materials and methods
Results and discussion
Conclusions In summary, during palmitate exposure, integrated action of intracellular metabolism of the fatty acid and Gαq-coupled FFAR1 signaling on mitochondrial respiration underlies the synergistic action of the two pathways on insulin secretion.