Abstract: Objective To investigate the effects of phosphatidic acid phosphatase(Lipin1)on the metabolomics of PC12 cells in high glucose environment. Methods PC12 cells infected with lentivirus were constructed. PC12 cells infected with empty capsid lentivirus(WT group)and underexpression Lipin1 lentivirus(D-WT group)were incubated with 25 mmol/L glucose. PC12 cells infected with empty capsid lentivirus(HG group)and overexpression Lipin1 lentivirus(G-HG group)were incubated with 100 mmol/L glucose. The expression of Lipin1 was determined with Western blotting after 48 h(n≥6). WT group, HG group and G-HG group were treated for 48h and the cells were collected and subjected to LC-MS/MS to compare the metabolomic differences(n=6). Results The Lipin1 expression was significantly higher in the WT group than in D-WT and HG groups(P<0.05), significantly higher in G-HG group than in HG group(P<0.01). When the screening criteria for differential metabolites were VIP>1, P<0.05, fold change(FC)>1.5 or <0.65, glutamic acid significantly decreased in HG group than in WT group; diacylglycerol(DAG)and 2-arachidacylglycerol(2-AG)significantly increased in G-HG group than in HG group. Cognitive-related pathway after high glucose incubation and regulation of Lipin1 involved the retrograde endocannabinoid signaling(ECS), glutamatergic synapse, long term enhancement(LTP)and long term inhibition(LTD). Conclusion Decreased glutamic acid in high glucose environment may explain the pathogenesis of diabetic encephalopathy. Overexpression of Lipin1 can improve neuro-related metabolites DAG and 2-AG and related pathway ECS to alleviate cognitive impairment. Lipin1 may be one of the key therapeutic targets for diabetic encephalopathy.

Key words: Lipin1, Diabetic encephalopathy, Cognitive function, Metabolomics