TY - JOUR
T1 - BTBR ob/ob mice as a novel diabetic neuropathy model
T2 - Neurological characterization and gene expression analyses
AU - O'Brien, Phillipe D.
AU - Hur, Junguk
AU - Hayes, John M.
AU - Backus, Carey
AU - Sakowski, Stacey A.
AU - Feldman, Eva L.
N1 - Funding Information:
Funding was provided by the National Institutes of Health ( 1DP3DK094292 , 1R24082841 to E.L.F.), the Juvenile Diabetes Research Foundation International (post-doctoral fellowship to J.H.), the American Diabetes Association ( 7-12-BS-045 ), the Program for Neurology Research & Discovery , and the A. Alfred Taubman Medical Research Institute .
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - Cytokine
KW - Diabetic neuropathy
KW - Functional enrichment
KW - Gene expression analysis
KW - Inflammation
KW - Leptin
KW - Matrix metalloproteinase
KW - Mouse model
KW - Obesity
KW - Type-2 diabetes
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U2 - 10.1016/j.nbd.2014.10.015
DO - 10.1016/j.nbd.2014.10.015
M3 - Article
C2 - 25447227
AN - SCOPUS:84909979541
SN - 0969-9961
VL - 73
SP - 348
EP - 355
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -