Acute and Repeated Treatment with 5-PAHSA or 9-PAHSA Isomers Does Not Improve Glucose Control in Mice

Cell Metab. 2018 Aug 7;28(2):217-227.e13. doi: 10.1016/j.cmet.2018.05.028. Epub 2018 Jun 21.


Fatty acid esters of hydroxylated fatty acids (FAHFAs) were discovered as a novel class of endogenous mammalian lipids whose profound effects on metabolism have been shown. In the current study, in vitro and in vivo the metabolic effects of two of these FAHFAs, namely palmitic acid-5- (or -9) -hydroxy-stearic acid (5- or 9-PAHSA, respectively) were profiled. In DIO mice fed with differentially composed low- or high-fat diets, acute and subchronic treatment with 5-PAHSA and 9-PAHSA alone, or in combination, did not significantly improve the deranged metabolic status. Neither racemic 5- or 9-PAHSA, nor the enantiomers were able to: (1) increase basal or insulin-stimulated glucose uptake in vitro, (2) stimulate GLP-1 release from GLUTag cells, or (3) induce GSIS in rat, mouse, or human islets or in a human pancreatic β cell line. Therefore, our data do not support the further development of PAHSAs or their derivatives for the control of insulin resistance and hyperglycemia.

Keywords: PAHSA synthesis; diet-induced obesity (DIO); hydroxylated fatty acids (FAHFAs); insulin resistance; insulin sensitizer; type 2 diabetes (T2D).

MeSH terms

  • Animals
  • Diet, Fat-Restricted
  • Diet, High-Fat
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose / metabolism
  • HEK293 Cells
  • Humans
  • Hyperglycemia / drug therapy*
  • Insulin Resistance*
  • Islets of Langerhans* / drug effects
  • Islets of Langerhans* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Obesity* / drug therapy
  • Obesity* / metabolism
  • Palmitic Acid* / administration & dosage
  • Palmitic Acid* / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Stearic Acids* / administration & dosage
  • Stearic Acids* / pharmacology


  • 5-PAHSA
  • 9-PAHSA
  • Stearic Acids
  • Palmitic Acid
  • Glucagon-Like Peptide 1
  • Glucose