title: Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.
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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Yore
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ismail
authors.initials: I
authors.lastname: Syed
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Moraes-Vieira
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Tejia
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Herman
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Homan
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Rajesh T
authors.initials: RT
authors.lastname: Patel
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Shili
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Odile D
authors.initials: OD
authors.lastname: Peroni
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Abha S
authors.initials: AS
authors.lastname: Dhaneshwar
authors.affiliation: Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Hammarstedt
authors.affiliation: Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: McGraw
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: asaghatelian@salk.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.affiliation: 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.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000378:metabolism*; D004032:Diet; D004952:Esters / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D005227:Fatty Acids / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000178:diet therapy; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050155:Lipogenesis; D008297:Male; D013058:Mass Spectrometry; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D004952:Esters; C498007:FFAR4 protein, mouse; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; C495693:Slc2a4 protein, mouse; D052216:Glucagon-Like Peptide 1