Abstract
Obesity and cognitive decline can occur in association. Brain dysmetabolism and insulin resistance might be common underlying traits. We aimed to examine the effect of high-fat diet (HFD) on cognitive decline, and of cognitive impairment on food intake and body-weight, and explore efficacy of chronic intranasal insulin (INI) therapy. We used control (C) and triple transgenic mice (3×Tg, a model of Alzheimer’s pathology) to measure cerebral mass, glucose metabolism, and the metabolic response to acute INI administration (cerebral insulin sensitivity). Y-Maze, positron emission-computed tomography, and histology were employed in 8 and 14-month-old mice, receiving normal diet (ND) or HFD. Chronic INI therapy was tested in an additional 3×Tg-HFD group. The 3×Tg groups overate, and had lower body-weight, but similar BMI, than diet-matched controls. Cognitive decline was progressive from HFD to 3×Tg-ND to 3×Tg-HFD. At 8 months, brain fasting glucose uptake (GU) was increased by C-HFD, and this effect was blunted in 3×Tg-HFD mice, also showing brain insulin resistance. Brain mass was reduced in 3×Tg mice at 14 months. Dentate gyrus dimensions paralleled cognitive findings. Chronic INI preserved cognition, dentate gyrus and metabolism, reducing food intake, and body weight in 3×Tg-HFD mice. Peripherally, leptin was suppressed and PAI-1 elevated in 3×Tg mice, correlating inversely with cerebral GU. In conclusion, 3×Tg background and HFD exert additive (genes*lifestyle) detriment to the brain, and cognitive dysfunction is accompanied by increased food intake in 3×Tg mice. PAI-1 levels and leptin deficiency were identified as potential peripheral contributors. Chronic INI improved peripheral and central outcomes.
Highlights
MATERIALS AND METHODSObesity and neurodegenerative diseases are growing in prevalence
PAI-1 levels and leptin deficiency were identified as potential peripheral contributors
MCP1 and IL6 were reduced in Triple transgenic (3×Tg) models at 8 and 14 months, and tumor necrosis factor-α (TNF-α) and resistin levels tended to be deficient in 3×Tg-normal diet (ND) (Figures 4A,B)
Summary
MATERIALS AND METHODSObesity and neurodegenerative diseases are growing in prevalence. Obesity was shown to predict cognitive impairment (Elias et al, 2005; Whitmer et al, 2005; Hassing et al, 2010), associating with cerebral matter losses (Driscoll et al, 2012), which were reversed by dieting (Haltia et al, 2007). In obese rodents, these abnormalities were related to, e.g., reduced hippocampal plasticity (Wu et al, 2003). INI treatment has shown promise as therapy to overcome cerebral insulin resistance in dementia and in obesity (Benedict et al, 2004; Craft et al, 2012; Jauch-Chara et al, 2012; Ott et al, 2012; Heni et al, 2017; Nedelcovych et al, 2018). The current evidence suggests that short-term intra-cerebral insulin therapy results in cognitive improvements (Park et al, 2000; Marks et al, 2009; Vandal et al, 2014; Salameh et al, 2015), but efficacy of protracted insulin regimens has been less explored and not confirmed in most of the existing studies, in which phenomena of desensitization due to overdosing have been advocated (Kamal et al, 2012; Nazarians-Armavil et al, 2013; Bell and Fadool, 2017)
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