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

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Syed, Ismail 
Lee, Jennifer 
Moraes-Vieira, Pedro M 
Donaldson, Cynthia J 
Sontheimer, Alexandra 


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.



FAHFA, GLP-1 receptor, GPR40, glucose-insulin homeostasis, human islets, insulin secretion, palmitic acid hydroxystearic acid, type 2 diabetes, Adiposity, Animals, Eating, Glucose, HEK293 Cells, Homeostasis, Humans, Inflammation, Insulin Resistance, Mice, Inbred C57BL, Palmitic Acid, Receptors, G-Protein-Coupled, Stearic Acids

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Cell Metabolism

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Cell Press
Supported by NIH grants R01 DK43051, P30 DK57521 (B.B.K.), and R01 DK106210 (B.B.K. and A. Saghatelian); a grant from the JPB Foundation (B.B.K.); and T32DK07516 (B.B.K. and J.L.).