Journal
CELL METABOLISM
Volume 27, Issue 2, Pages 419-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2018.01.001
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Funding
- BADERC Pancreatic Islet Core [NIH P30 DK57521]
- Joslin DRC Advanced Microscopy Core from the Joslin Diabetes Center [NIH P30 DK036836]
- NIH [R01 DK43051, P30 DK57521, R01 DK106210]
- JPB Foundation [T32DK07516]
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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 similar to 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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