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

Publication date: 6 February 2018
Source:Cell Metabolism, Volume 27, Issue 2
Author(s): 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
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.

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Teaser

PAHSA levels are reduced in serum and subcutaneous WAT of insulin-resistant people and HFD-fed mice. Restoring PAHSA levels has high therapeutic potential to treat patients with type 2 diabetes. Syed, Lee et al. show that chronic PAHSA treatment improves glucose homeostasis in chow- and HFD-fed mice, and identify GPR40 as a novel PAHSA target.


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