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Cell. 2014 Oct 9;159(2):318-32. doi: 10.1016/j.cell.2014.09.035.

Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
2
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
3
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
4
Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden.
5
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: asaghatelian@salk.edu.
6
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: bkahn@bidmc.harvard.edu.

Abstract

Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion. PAHSAs also reduce adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 to enhance insulin-stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with the potential to treat type 2 diabetes.

PMID:
25303528
PMCID:
PMC4260972
DOI:
10.1016/j.cell.2014.09.035
[Indexed for MEDLINE]
Free PMC Article

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