Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats.
OBJECTIVE
It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity--and therefore might be involved in the pathophysiology--is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this.


METHODS
Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin.


RESULTS
It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1+/-3.4 pmol/l in pre-obese Zucker rats vs 6.9+/-1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3+/-0.2 mmol/l vs 5.1+/-0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8+/-0.3 mmol/l vs 8.6+/-0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver.


CONCLUSIONS
We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.
Gram
Dorte X
DX
Novo Nordisk A/S, Måløv, Denmark. dxg@novonordisk.com
Hansen
Anker J
AJ
Wilken
Michael
M
Elm
Torben
T
Svendsen
Ove
O
Carr
Richard D
RD
Ahrén
Bo
B
Brand
Christian L
CL
D000818:Animals; D001835:Body Weight; D015740:Calcitonin Gene-Related Peptide / Q000097:blood*; D002211:Capsaicin / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects*; D009765:Obesity / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker
D002784:Cholesterol; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin