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Discovery of A Novel Class of Naturally‐Occurring Lipids with Anti‐Diabetic and Anti‐inflammatory Effects
Author(s) -
Kahn Barbara,
Yore MM,
Syed I,
MoraesVieira PM,
Zhang T,
Herman MA,
Homan E,
Lee J,
Chen S,
Peroni OD,
Hammarstedt A,
Patel R,
McGraw TE,
Smith U,
Saghatelian A
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.504.3
Subject(s) - medicine , glut4 , endocrinology , lipogenesis , adipose tissue , insulin , white adipose tissue , glucose homeostasis , insulin resistance , chemistry , fatty acid , type 2 diabetes , diabetes mellitus , biology , biochemistry
Increased adipose tissue (AT) lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing Glut4 in AT (AG4OX) have elevated AT lipogenesis and increased glucose tolerance in spite of obesity and elevated circulating fatty acids. To determine if the lipid profile contributes to improved glucose homeostasis in AG4OX, we performed lipidomic analysis of AT. This revealed a 16‐18‐fold increase in a novel class of lipids in AG4OX AT vs wildtype mice. Using a targeted Mass Spec approach, we identified 16 novel lipid family members with multiple isomers based on structural variations. These lipids are branched fatty acid esters of hydroxy fatty acids or FAHFAs. We studied the biologic effects of the isomers of palmitic acid hydroxy stearic acid or PAHSAs. These are present at highest levels in brown adipose tissue followed by subcutaneous and perigonadal white AT with lower levels in many other tissues. PAHSA levels are acutely regulated by fasting. Most isomers are reduced 50–65% in serum and AT of insulin‐resistant vs insulin‐sensitive people. Nearly all isomers in humans correlate remarkably strongly with insulin sensitivity determined by euglycemic clamp. PAHSAs are also reduced in subcutaneous white AT in mice fed a High Fat Diet. Oral administration of PAHSAs lowers ambient glycemia and enhances glucose tolerance and insulin sensitivity in insulin‐resistant obese mice while stimulating GLP1 and insulin secretion. PAHSAs also augment insulin stimulated glucose uptake and Glut4 translocation to the plasma membrane in adipocytes. PAHSAs suppress inflammatory processes in immune cells. Biological effects of PAHSAs are mediated through lipid‐responsive GPCRs. In summary, we identified a novel lipid class that improves glucose‐insulin homeostasis. In conclusion, restoration of the low PAHSA levels in insulin‐resistant people may be effective to treat type‐2 diabetes.