title: Long-term high-fat diet induces hippocampal microvascular insulin resistance and cognitive dysfunction.
abstract: Insulin action on hippocampus improves cognitive function, and obesity and type 2 diabetes are associated with decreased cognitive function. Cerebral microvasculature plays a critical role in maintaining cerebral vitality and function by supplying nutrients, oxygen, and hormones such as insulin to cerebral parenchyma, including hippocampus. In skeletal muscle, insulin actively regulates microvascular opening and closure, and this action is impaired in the insulin-resistant states. To examine insulin's action on hippocampal microvasculature and parenchyma and the impact of diet-induced obesity, we determined cognitive function and microvascular insulin responses, parenchyma insulin responses, and capillary density in the hippocampus in 2- and 8-mo-old rats on chow diet and 8-mo-old rats on a long-term high-fat diet (6 mo). Insulin infusion increased hippocampal microvascular perfusion in rats on chow diet by ~80-90%. High-fat diet feeding completely abolished insulin-mediated microvascular responses and protein kinase B phosphorylation but did not alter the capillary density in the hippocampus. This was associated with a significantly decreased cognitive function assessed using both the two-trial spontaneous alternation behavior test and the novel object recognition test. As the microvasculature provides the needed endothelial surface area for delivery of nutrients, oxygen, and insulin to hippocampal parenchyma, we conclude that hippocampal microvascular insulin resistance may play a critical role in the development of cognitive impairment seen in obesity and diabetes. Our results suggest that improvement in hippocampal microvascular insulin sensitivity might help improve or reverse cognitive function in the insulin-resistant states.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.|Department of Endocrinology, Central South University Xiangya Hospital, Changsha, Hunan, China; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Psychiatry, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Tanseli
authors.initials: T
authors.lastname: Nesil
authors.affiliation: Department of Psychiatry, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Ming D
authors.initials: MD
authors.lastname: Li
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Aylor
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; zl3e@virginia.edu.
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D060825:Cognitive Dysfunction / Q000209:etiology* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000494:pharmacology; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors
chemical_list: D004041:Dietary Fats
keywords: blood flow; cognition; hippocampus; insulin resistance; microvasculature