A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin

Abstract

Aims/hypothesis We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feedingevoked cognitive deficit by improving insulin sensitivity. Methods Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n024), standard chow (SC; n016), HF + metformin (144 mg/kg in diet; n020) or SC + metformin (144 mg/kg in diet; n016) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins. Results HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex. Conclusions/interpretation Metformin prevented the metabolic but not cognitive alterations associated with HF feeding.The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.

New animal models of Alzheimer’s disease that display insulin desensitization in the brain

“…In obese, leptin resistant (db/db) mice, metformin has been shown to attenuate the increase of total tau and phospho-tau, the reduction of synaptophysin, and the decreased of Aβ level; however, it does not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia (Li et al, 2012). This result is similar to that of another study, which reports that metformin prevent metabolic but not cognitive deficits Brought to you by | HEC Bibliotheque Maryriam ET J. Authenticated Download Date | 6/9/15 3:18 AM associated with high-fat feeding (McNeilly et al, 2012). However, novel drug treatments for type 2 diabetes with glucagon-like peptide-1 (GLP-1) analogs have shown superior neuroprotective effects.…”

“…It has been shown that animals receiving high-fat (HF)/low carbohydrate (LC) food could increase brain levels of soluble Aβ (Pedrini et al, 2009). Rats receiving an HF diet for 10 weeks develop both insulin resistance and cognitive deficits; however, contrary to expectation, re-sensitizing insulin signaling in the periphery with metformin does not improve the learning and memory impairment (McNeilly et al, 2012). In a transgenic animal model of AD, impaired learning and memory of mice overexpressing mutant amyloid precursor protein (APP) and presenilin-1 (PS1dE9) are exacerbated by HF diet treatment.…”

Dietary high-fat lard intake induces thyroid dysfunction and abnormal morphology in rats

“…Lard is one of the most widely consumed foods rich in saturated fatty acids, and it is often chosen to observe the deleterious effects of a high-fat diet [20,[23][24][25] . In this study, we used standard rodent chow supplemented with lard alone, independent of other hyperlipidemia-inducing components, such as cholesterol.…”

High fat feeding is associated with stimulation of the hypothalamic-pituitary-adrenal axis and reduced anxiety in the rat

“…High fat feeding can produce behavioural changes in rodents before the development of T2DM, which are also independent of increased insulin resistance (McNeilly et al, 2011(McNeilly et al, , 2012. Other studies have shown that chronic HF feeding for 6 weeks reduces 5-hydroxytryptamine (5-HT) release and turnover in the hypothalamus and hippocampus of rodents (Pissios and Maratos-Flier, 2007).…”