Caloric restriction improves diabetes-induced cognitive deficits by attenuating neurogranin-associated calcium signaling in high-fat diet-fed mice.

Abstract

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.

• Authors: Hwajin Kim, Heeyoung Kang, Rok Won Heo, Byeong Tak Jeon, Chin-Ok Yi, Hyun Joo Shin, Jeonghyun Kim, Seon-Yong Jeong, Woori Kwak, Won-Ho Kim, Sang Soo Kang, Gu Seob Roh
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 36 Issue 6 Pg. 1098-110 (06 2016) ISSN: 1559-7016 [Electronic] United States
• PMID: 26661177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015.

Chemical References

• Neurogranin

Topics

• Animals
• Calcium Signaling
• Caloric Restriction
• Cognition Disorders (diet therapy, etiology)
• Diabetes Mellitus, Type 2 (complications)
• Diet, High-Fat
• Gene Expression Profiling
• Hippocampus (metabolism)
• Mice
• Mice, Inbred C57BL
• Neurogranin (genetics)
• Sequence Analysis, RNA