Ciliary neurotrophic factor restores gallbladder contractility in leptin-resistant obese diabetic mice.
BACKGROUND
Obesity and diabetes are major risk factors for cholesterol gallstones, and the majority of obese people are leptin-resistant. Our previous work has shown that both leptin-deficient (Lepob) and leptin-resistant (Lepdb) obese diabetic mice have decreased in vitro gallbladder motility. Leptin administration to leptin-deficient (Lepob) animals restores gallbladder motility and reverses obesity and hyperinsulinemia. However, additional leptin in leptin-resistant obesity would not be expected to improve obesity-related parameters. Recent studies demonstrate that ciliary neurotrophic factor (CNTF) reduces weight and hyperinsulinemia in leptin-resistant obesity. Our hypothesis is that CNFT would cause weight loss, lower blood sugars, and restore gallbladder contractility in leptin-resistant (Lepdb) mice.


METHODS
20 C57b/6J and 20 Lepdb 8-week-old female mice were injected daily with either intraperitoneal saline or 0.3 microg/g CNTFAx15 for 17 days. Gallbladders were mounted in muscle baths and stimulated with acetylcholine, neuropeptide Y, and cholecystokinin. Gallbladder volume, serum glucose, insulin, liver weight, liver fat, and gallbladder responses were measured. Data were analyzed by ANOVA.


RESULTS
Saline treated obese mice had greater body weight and obesity parameters, but decreased gallbladder contractility to neurotransmitters compared to saline treated lean mice. CNTF administration to obese mice decreased body weight and obesity parameters, and restored gallbladder contractility. CNTF treated lean animals had weight loss and decreased gallbladder contraction to acetylcholine and cholecystokinin compared to saline treated lean animals.


CONCLUSIONS
Ciliary neurotrophic factor (CNTF) causes 1) weight loss, 2) improvement of diabetes, and 3) alterations in gallbladder motility that is improved in obese mice but decreased in lean mice. We conclude that CNTF may improve gallbladder contractility in leptin-resistant obesity with diabetes.
Graewin
Shannon J
SJ
Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
Kiely
James M
JM
Svatek
Carol L
CL
Pitt
Henry A
HA
D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005704:Gallbladder / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D016473:Gallbladder Emptying / Q000187:drug effects*; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood / Q000235:genetics*; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009119:Muscle Contraction / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D009929:Organ Size; D014617:Vacuoles
D001786:Blood Glucose; D020934:Ciliary Neurotrophic Factor; D007328:Insulin; D020738:Leptin