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Aims/Introduction  Uncoupling protein 2 ( UCP 2), which was an important mitochondrial inner membrane protein associated with glucose and lipid metabolism, widely expresses in all kinds of tissues including hepatocytes. The present study aimed to explore the impact of  UCP 2 deficiency on glucose and lipid metabolism, insulin sensitivity and its effect on the liver‐associated signaling pathway by expression profiling analysis.    Materials and Methods  Four‐week‐old male  UCP 2−/− mice and  UCP 2+/+ mice were randomly assigned to four groups:  UCP 2−/− on a high‐fat diet,  UCP 2−/− on a normal chow diet,  UCP 2+/+ on a high‐fat diet and  UCP 2+/+ on a normal chow diet. The differentially expressed genes in the four groups on the 16th week were identified by Affymetrix gene array.    Results  The results of intraperitoneal glucose tolerance test and insulin tolerance showed that blood glucose and β‐cell function were improved in the  UCP 2−/− group on high‐fat diet. Enhanced insulin sensitivity was observed in the  UCP 2−/− group. The differentially expressed genes were mapped to 23 pathways ( P  < 0.05). We concentrated on the ‘peroxisome proliferator‐activated receptor ( PPAR ) signaling pathway’ ( P  = 3.19 × 10 −11 ), because it is closely associated with the regulation of glucose and lipid profiles. In the  PPAR  signaling pathway, seven genes (  PPAR γ ,  Dbi ,  Acsl3 ,  Lpl ,  Me1 ,  Scd1 ,  Fads2 ) in the  UCP 2−/− mice were significantly upregulated.    Conclusions  The present study used gene arrays to show that activity of the  PPAR  signaling pathway involved in the improvement of glucose and lipid metabolism in the liver of  UCP 2‐deficient mice on a long‐term high‐fat diet. The upregulation of genes in the  PPAR  signaling pathway could explain our finding that  UCP 2 deficiency ameliorated insulin sensitivity. The manipulation of  UCP 2 protein expression could represent a new strategy for the prevention and treatment of diabetes.

journal of diabetes investigation

Expression profiling analysis: Uncoupling protein 2 deficiency improves hepatic glucose, lipid profiles and insulin sensitivity in high‐fat diet‐fed mice by modulating expression of genes in peroxisome proliferator‐activated receptor signaling pathway