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

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    Publication date
    2012
    Author
    McNeilly, A.D.
    Williamson, Ritchie
    Balfour, D.J.
    Stewart, C.A.
    Sutherland, C.
    Keyword
    Alzheimer Disease; Drug therapy; Metabolism
    Animals
    ; Behavior; Drug effects; Physiology
    ; Body weight
    ; Brain
    ; Cognition disorders
    ; Conditioning; Operant
    ; Dietary fats; Pharmacology
    ; Disease models
    ; Hormones; Blood
    ; Hypoglycemic agents
    ; Insulin resistance
    ; Leptin
    ; Male
    ; Metformin
    ; Nerve tissue proteins
    ; Rats
    ; Wistar
    ; Signal transduction
    ; Treatment failure
    ; REF 2014
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    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-feeding-evoked 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; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) 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.
    URI
    http://hdl.handle.net/10454/6095
    Citation
    McNeilly AD, Williamson R, Balfour DJ, Stewart CA and Sutherland C (2012) A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin. Diabetologia. 55(11): 3061-3070.
    Link to publisher’s version
    http://dx.doi.org/10.1007/s00125-012-2686-y
    Type
    Article
    Collections
    Life Sciences Publications

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