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

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

Author information

1
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Center for Life Sciences, Room 747, 330 Brookline Avenue, Boston, MA 02215, USA.
2
Clayton Foundation Laboratories for Peptide Biology, Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
3
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
4
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
5
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Center for Life Sciences, Room 747, 330 Brookline Avenue, Boston, MA 02215, USA. Electronic address: bkahn@bidmc.harvard.edu.

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.

KEYWORDS:

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

PMID:
29414687
PMCID:
PMC5807007
[Available on 2019-02-06]
DOI:
10.1016/j.cmet.2018.01.001

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