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Neurobiol Dis. 2015 Jan;73:348-55. doi: 10.1016/j.nbd.2014.10.015. Epub 2014 Oct 30.

BTBR ob/ob mice as a novel diabetic neuropathy model: Neurological characterization and gene expression analyses.

Author information

1
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
2
A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI 48109, USA.
3
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: efeldman@umich.edu.

Abstract

Given the lack of treatments for diabetic neuropathy (DN), a common diabetic complication, accurate disease models are necessary. Characterization of the leptin-deficient BTBR ob/ob mouse, a type 2 diabetes model, demonstrated that the mice develop robust diabetes coincident with severe neuropathic features, including nerve conduction deficits and intraepidermal nerve fiber loss by 9 and 13 weeks of age, respectively, supporting its use as a DN model. To gain insight into DN mechanisms, we performed microarray analysis on sciatic nerve from BTBR ob/ob mice, identifying 1503 and 642 differentially expressed genes associated with diabetes at 5 and 13 weeks, respectively. Further analyses identified overrepresentation of inflammation and immune-related functions in BTBR ob/ob mice, which interestingly were more highly represented at 5 weeks, an observation that may suggest a contributory role in DN onset. To complement the gene expression analysis, we demonstrated that protein levels of select cytokines were significantly upregulated at 13 weeks in BTBR ob/ob mouse sciatic nerve. Furthermore, we compared our array data to that from an established DN model, the C57BKS db/db mouse, which reflected a common dysregulation of inflammatory and immune-related pathways. Together, our data demonstrate that BTBR ob/ob mice develop rapid and robust DN associated with dysregulated inflammation and immune-related processes.

KEYWORDS:

Cytokine; Diabetic neuropathy; Functional enrichment; Gene expression analysis; Inflammation; Leptin; Matrix metalloproteinase; Mouse model; Obesity; Type-2 diabetes

PMID:
25447227
PMCID:
PMC4416075
DOI:
10.1016/j.nbd.2014.10.015
[Indexed for MEDLINE]
Free PMC Article

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