title: 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.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
authors.forename: Hwajin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Neurology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Heeyoung
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
authors.forename: Rok Won
authors.initials: RW
authors.lastname: Heo
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, USA.
authors.forename: Byeong Tak
authors.initials: BT
authors.lastname: Jeon
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
authors.forename: Chin-Ok
authors.initials: CO
authors.lastname: Yi
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Jeonghyun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Seon-Yong
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: C&K genomics, Seoul, Republic of Korea.
authors.forename: Woori
authors.initials: W
authors.lastname: Kwak
authors.affiliation: Division of Metabolic Diseases, Center for Biomedical Sciences, National Institute of Health, Osong, Republic of Korea.
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea anaroh@gnu.ac.kr.
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D031204:Caloric Restriction; D003072:Cognition Disorders / Q000178:diet therapy* / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D059305:Diet, High-Fat; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051579:Neurogranin / Q000235:genetics*; D017423:Sequence Analysis, RNA
chemical_list: D051579:Neurogranin
keywords: Calcium; caloric restriction; cognitive impairment; diabetes; hippocampus