Adipose Dysfunction in Adulthood Insulin Resistance of Low-Birth Weight Mice: A Proteomics Study

Jun Wang,1– 3 Linlin Yang,4 Linquan Yang,4 Fei Zhou,1 Hang Zhao,2 Jing Liu,2 Huijuan Ma,1,2,4,* Guangyao Song1,2,* 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Endocrinology and Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China; 3Department of Emergency, Baoding First Central Hospital, Baoding, Hebei, People’s Republic of China; 4Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huijuan Ma, Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, 050051, Hebei, People’s Republic of China, Email huijuanma76@163.com Guangyao Song, Department of Endocrinology and Metabolic Diseases, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, 050051, Hebei, People’s Republic of China, Email sguangyao2@163.comPurpose: To investigate changes in the protein expression profile of white adipose tissue in low-birth weight (LBW) mice with high-fat diets using tandem mass tag (TMT) and liquid chromatography-mass spectrometry (LC-MS/MS) and parallel reaction monitoring (PRM).Methods: Institute of Cancer Research (ICR) mice were used to establish an LBW model using malnutrition during pregnancy. Male pups were randomly selected from LBW and normal-birth weight (NBW) offspring, then all given a high-fat diet. Blood glucose, serum insulin, total cholesterol (TC) and triglyceride (TG) levels were measured. The weight ratio of liver, muscle, and adiposity index were calculated. Hematoxylin and eosin staining was used to visualize adipose tissue morphology. Oil red O staining of liver and TG content of muscle were used to determine ectopic lipid deposition. TMT combined with LC-MS/MS was used to analyze protein expression in white adipose tissue. PRM and Western blot were used to verify the expression of CD36, SCD1, PCK1 and PPARγ.Results: Compared with NBW mice, fasting blood glucose, insulin and HOMA-IR significantly increased in LBW mice, indicating insulin resistance and impaired glucose regulation; TC, TG, adipocyte size, and adiposity index were increased in LBW mice, suggesting obesity and disorder of lipid metabolism. We observed ectopic lipid deposition in liver and muscle. There were 996 differentially expressed proteins (DEPs) in the LBW/NBW groups. Peroxisome proliferator-activated receptor (PPAR) was a relatively important signaling pathway regulating metabolic process in functional enrichment analysis of DEPs. Up-regulated expression of CD36, SCD1, and PCK1 in the adipose tissue of LBW mice was observed through PPAR pathways cluster analysis. And PRM and Western blot assay validated the proteomics findings.Conclusion: When exposed to high-fat diets, LBW mice exhibited insulin resistance and disorder of lipid metabolism compared with NBW mice. The expression of PPARγ was elevated, as well as upstream CD36, downstream SCD1 and PCK1 of the PPARγ in the adipose tissue of LBW mice. It was suggested that the activation in CD36/PPARγ/SCD1 and CD36/PPARγ/PCK1 pathways may induce adipose dysfunction, thereby increasing susceptibility to insulin resistance.Keywords: low birth weight, adipose tissue, insulin resistance, lipid metabolism