Palmitic Acid Hydroxystearic Acids Activate GPR40, Which Is Involved in Their Beneficial Effects on Glucose Homeostasis

Cell Metab. 2018 Feb 6;27(2):419-427.e4. doi: 10.1016/j.cmet.2018.01.001.


Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ∼1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca+2 flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contrast, GLP-1 receptor blockade in PAHSA-treated chow-fed mice reduces PAHSA effects on glucose tolerance, but not on insulin sensitivity. Thus, PAHSAs activate GPR40, which is involved in their beneficial metabolic effects.

Keywords: FAHFA; GLP-1 receptor; GPR40; glucose-insulin homeostasis; human islets; insulin secretion; palmitic acid hydroxystearic acid; type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / drug effects
  • Animals
  • Eating / drug effects
  • Glucose / metabolism*
  • HEK293 Cells
  • Homeostasis* / drug effects
  • Humans
  • Inflammation / pathology
  • Insulin Resistance
  • Mice, Inbred C57BL
  • Palmitic Acid / pharmacology*
  • Receptors, G-Protein-Coupled / metabolism*
  • Stearic Acids / pharmacology*


  • 5-PAHSA
  • 9-PAHSA
  • FFAR1 protein, human
  • Ffar1 protein, mouse
  • Receptors, G-Protein-Coupled
  • Stearic Acids
  • Palmitic Acid
  • Glucose