A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin.
OBJECTIVE
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
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.
Medical Research Institute, University of Dundee, Ninewells Medical School, Dundee DD1 9SY, UK.
A D
AD
McNeilly
R
R
Williamson
D J K
DJ
Balfour
C A
CA
Stewart
C
C
Sutherland
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D006728:Hormones / Q000097:blood; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017211:Treatment Failure
D004041:Dietary Fats; D006728:Hormones; D007004:Hypoglycemic Agents; D020738:Leptin; D009419:Nerve Tissue Proteins; D008687:Metformin