Jeon, Byeong Tak

Diabetes may adversely affect cognitive function, although the specific underlying mechanisms are unknown. On the other hand, caloric restriction (CR) increases longevity and improves memory. We examined the effects of CR on serum metabolic parameters and hippocampal protein expression in ob/ob mice, a model of obesity‐induced diabetes. We found that CR reduced hepatic steatosis and insulin resistance in ob/ob mice. In the hippocampus of these mice, CR increased the expression of O‐linked‐N‐acetylglucosamine (O‐GlcNAc) and GlcNAc transferase and decreased the expression of calcium/calmodulin‐dependent protein kinase P. It also decreased hippocampal lipocalin‐2 and phosphorylated tau. Furthermore, CR lessened the learning deficits that are typically seen in ob/ob mice. These findings indicate that CR may reverse obesity‐related brain glucose impairment and intracellular Ca 2+ dysfunction and relieve learning impairment in diabetes.

Diabetes-induced cognitive decline has been recognized in human patients of type 2 diabetes mellitus and mouse model of obesity, but the underlying mechanisms or therapeutic targets are not clearly identified. We investigated the effect of caloric restriction on diabetes-induced memory deficits and searched a molecular mechanism of caloric restriction-mediated neuroprotection. C57BL/6 mice were fed a high-fat diet for 40 weeks and RNA-seq analysis was performed in the hippocampus of high-fat diet-fed mice. To investigate caloric restriction effect on differential expression of genes, mice were fed high-fat diet for 20 weeks and continued on high-fat diet or subjected to caloric restriction (2 g/day) for 12 weeks. High-fat diet-fed mice exhibited insulin resistance, glial activation, blood–brain barrier leakage, and memory deficits, in that we identified neurogranin, a down-regulated gene in high-fat diet-fed mice using RNA-seq analysis; neurogranin regulates Ca 2+ /calmodulin-dependent synaptic function. Caloric restriction increased insulin sensitivity, reduced high-fat diet-induced blood–brain barrier leakage and glial activation, and improved memory deficit. Furthermore, caloric restriction reversed high-fat diet-induced expression of neurogranin and the activation of Ca 2+ /calmodulin-dependent protein kinase II and calpain as well as the downstream effectors. Our results suggest that neurogranin is an important factor of high-fat diet-induced memory deficits on which caloric restriction has a therapeutic effect by regulating neurogranin-associated calcium signaling.