Mechanistic Investigation Of Pulmonary Surfactant Protein D On High Fat Diet-induced Insulin Resistance

Objective:The aim of this study was to investigate whether pulmonary surfactant protein D（SPD）was involved in insulin resistance in mice induced by high fat diet and to explore its role in adipose and liver tissues with the relevant mechanisms.Methods:Healthy C57BL/6 mice and SPD-knockout mice(SPD^-/-)mice of 8 per group were fed normal diet（ND）or high fat diet（HFD）for 12 weeks.The body weight and food intake were measured weekly and the fasting blood glucose was measured at week4,8 and 12.After 12 weeks of HFD feeding,insulin tolerance test（ITT）and insulin sensitivity were tested.Hematoxylin and eosin（HE）staining,quantitative real-time RCR were used to assess the changes in morphology,function and inflammation in visceral adipose tissue（VAT）.The morphological and lipid deposition of the liver was detected by HE staining.Quantitative real-time RCR and Western blotting were used to assess the levels at mRNA and protein involved in insulin signaling and lipid metabolism in the liver.Results:（1）In addition to the lung,SPD is also expressed in the VAT and liver.（2）Body weight was not statistically significant prior to the HFD feeding but showed a timely dependent increase during the feeding.After 12 weeks of HFD feeding,the body weight and fasting blood glucose were significantly increased and the insulin sensitivity significantly decreased compared to the ND group.Deletion of SPD ameliorated the weight gain and insulin sensitivity change,but showed no effect on the fasting blood glucose of mice fed HFD.（3）In VAT,HFD caused significant increase in adipose tissue mass and adipocyte area,inhibited the expression of hormone-sensitive lipase（HSL）and adipose triglyceride lipase（ATGL）at mRNA level,and increased the expression of F4/80 and TNFαin adipose tissue,dysregulation of expression in adipokines including adiponectin,resistin,peroxisome proliferator activated receptor-γ（PPARγ）and leptin.SPD deficiency slightly ameliorated adipose accumulation and adipocyte hypertrophy,decreased expression of ATGL,but failed to correct the other pathologic indexes.（4）In the liver,HFD induced lipid deposition,enhanced expression of enzymes for lipid synthesis（FAS,ACC1,ACC2,ACL,SREBP1,GPAT）,inhibited phosphorylated levels of Akt and AMPK,which were ameliorated by SPD deletion.Conclusion:（1）SPD expressed in both VAT and liver.（2）SPD was involved in obesity and insulin resistance induced by HFD.（3）SPD led to adipose accumulation via regulating the expression of ATGL in adipose tissue.（4）SPD modulated lipid metabolism through inhibiting Akt-AMPKαsignaling pathway,which enhanced adipose synthesis and hepatic lipid accumulation.