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

Abstract

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.

• Authors: Ismail Syed, Jennifer Lee, Pedro M Moraes-Vieira, Cynthia J Donaldson, Alexandra Sontheimer, Pratik Aryal, Kerry Wellenstein, Matthew J Kolar, Andrew T Nelson, Dionicio Siegel, Jacek Mokrosinski, I Sadaf Farooqi, Juan Juan Zhao, Mark M Yore, Odile D Peroni, Alan Saghatelian, Barbara B Kahn
• Journal: Cell metabolism (Cell Metab) Vol. 27 Issue 2 Pg. 419-427.e4 (02 06 2018) ISSN: 1932-7420 [Electronic] United States
• PMID: 29414687 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• 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)