301-OR: Lipin 1–Mediated Phosphatidic Acid Phosphatase Activity in Adipocytes Regulates Systemic Insulin Sensitivity on High-Fat Diet

Emerging evidence suggests that the capacity of adipocytes to appropriately store lipids and prevent their ectopic accumulation in liver and skeletal muscle may be an important regulator of systemic insulin sensitivity. Lipin 1 is a lipid phosphatase that is highly expressed in adipocytes and catalyzes the conversion of phosphatidic acid (PA) to diacylglycerol (DAG); the penultimate step in triglyceride synthesis. Adipose tissue lipin 1 expression positively correlates with insulin sensitivity in obese humans and mouse models. To test the role of adipose tissue lipin 1 in systemic insulin sensitivity, we generated mice lacking lipin 1 in adipocytes (Adn-Lpin1-/- mice). On normal chow, loss of lipin 1 in adipocytes modestly reduced white and brown adipose tissue mass, but did not affect glucose tolerance or insulin sensitivity. However, in response to 2 weeks high fat diet (HFD; 60% fat) feeding, Adn-Lpin1-/- mice remained lean, but developed hyperglycemia compared to littermate wild type (WT) mice. Lipidomic analyses demonstrated an increase in liver lipids (PA, DAG, and triglyceride) in HFD-fed Adn-Lpin1-/- mice compared to WT controls, whereas only PA accumulated in skeletal muscle. Plasma triglyceride concentration was not different, but free fatty acids and glycerol were significantly reduced in Adn-Lpin1-/- vs. WT mice fed HFD, suggesting that lipolysis may be decreased. Plasma adiponectin and resistin were significantly reduced in HFD-fed Adn-Lpin1-/- vs. WT control mice while leptin concentrations were not different. Lastly, with 5 weeks of HFD feeding, despite being leaner, Adn-Lpin1-/- mice became markedly hyperglycemic and glucose intolerant compared to littermate WT controls. Collectively, these data suggest that loss of lipin 1 in adipocytes leads to insulin resistance on HFD, likely due to an impaired capacity to store lipids appropriately in adipose tissue. Disclosure A.J. Lutkewitte: None. B.N. Finck: Advisory Panel; Self; Cirius Therapeutics. Stock/Shareholder; Self; Cirius Therapeutics.