tug-469 and Insulin-Resistance

The fatty acid receptor 1 (FFAR1/GPR40) mediates fatty acid-dependent augmentation of glucose-induced insulin secretion (GIIS) in pancreatic β-cells. Genetically engineered Ffar1-knockout/congenic mice univocally displayed impaired fatty acid-mediated insulin secretion, but in vivo experiments delivered controversial results regarding the function of FFAR1 in glucose homeostasis and liver steatosis. This study presents a new coisogenic mouse model carrying a point mutation in Ffar1 with functional consequence. These mice reflect the situations in humans in which point mutations can lead to protein malfunction and disease development.. The Munich N-ethyl-N-nitrosourea (ENU) mutagenesis-derived F1 archive containing over 16,800 sperms and corresponding DNA samples was screened for mutations in the coding region of Ffar1. Two missense mutations (R258W and T146S) in the extracellular domain of the protein were chosen and homozygote mice were generated. The functional consequence of these mutations was examined in vitro in isolated islets and in vivo in chow diet and high fat diet fed mice.. Palmitate, 50 μM, and the FFAR1 agonist TUG-469, 3 μM, stimulated insulin secretion in islets of Ffar1. A point mutation in Ffar1 abrogates the stimulatory effect of palmitate on GIIS, an effect that does not necessarily translate to HFD-induced glucose intolerance.

Topics: Aniline Compounds; Animals; Diet, High-Fat; Fatty Acids; Fatty Liver; Glucose; Glucose Intolerance; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Mice; Palmitates; Phenylpropionates; Point Mutation; Receptors, G-Protein-Coupled