High-fat diet induced neuropathy of pre-diabetes and obesity: effects of "healthy" diet and aldose reductase inhibition.
OBJECTIVE
Subjects with dietary obesity and pre-diabetes have an increased risk for developing both nerve conduction slowing and small sensory fiber neuropathy. Animal models of this type of neuropathy have not been described. This study evaluated neuropathic changes and their amenability to dietary and pharmacological interventions in mice fed a high-fat diet (HFD), a model of pre-diabetes and alimentary obesity.


METHODS
Female C57BL6/J mice were fed normal diets or HFDs for 16 weeks.


RESULTS
HFD-fed mice developed obesity, increased plasma FFA and insulin concentrations, and impaired glucose tolerance. They also had motor and sensory nerve conduction deficits, tactile allodynia, and thermal hypoalgesia in the absence of intraepidermal nerve fiber loss or axonal atrophy. Despite the absence of overt hyperglycemia, the mice displayed augmented sorbitol pathway activity in the peripheral nerve, as well as 4-hydroxynonenal adduct nitrotyrosine and poly(ADP-ribose) accumulation and 12/15-lipoxygenase overexpression in peripheral nerve and dorsal root ganglion neurons. A 6-week feeding with normal chow after 16 weeks on HFD alleviated tactile allodynia and essentially corrected thermal hypoalgesia and sensory nerve conduction deficit without affecting motor nerve conduction slowing. Normal chow containing the aldose reductase inhibitor fidarestat (16 mg x kg(-1) x day (-1)) corrected all functional changes of HFD-induced neuropathy.


CONCLUSIONS
Similar to human subjects with pre-diabetes and obesity, HFD-fed mice develop peripheral nerve functional, but not structural, abnormalities and, therefore, are a suitable model for evaluating dietary and pharmacological approaches to halt progression and reverse diabetic neuropathy at the earliest stage of the disease.
Obrosova
Irina G
IG
Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd., Baton Rouge, LA 70808, USA. obrosoig@pbrc.edu
Ilnytska
Olga
O
Lyzogubov
Valeriy V
VV
Pavlov
Ivan A
IA
Mashtalir
Nazar
N
Nadler
Jerry L
JL
Drel
Viktor R
VR
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001833:Body Temperature Regulation; D003929:Diabetic Neuropathies / Q000139:chemically induced* / Q000517:prevention & control; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D048289:Imidazolidines / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009475:Neurons, Afferent / Q000502:physiology; D009765:Obesity / Q000503:physiopathology; D011236:Prediabetic State / Q000503:physiopathology*; D011863:Radioimmunoassay; D012684:Sensory Thresholds; D014110:Touch / Q000502:physiology
D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D048289:Imidazolidines; C077139:fidarestat; D000449:Aldehyde Reductase