CNTF restores gallbladder contractility in leptin-resistant obese diabetic mice

Background. Obesity and diabetes are major risk factors for the development of cholesterol gallstones, and the majority of obese people have leptin-resistant obesity. Previous studies from our laboratory have demonstrated that both leptin-deficient (Lep^ob) and leptin-resistant (Lep^db) obese diabetic mice have decreased in vitro gallbladder motility. We have also shown that leptin administration to leptin-deficient (Lep^ob) animals restores gallbladder motility and reverses obesity and hyperinsulinemia. However, the administration of additional leptin to leptin-resistant (Lep^db) mice would not be expected to ameliorate their physiologic parameters. In contrast, recent studies have demonstrated that ciliary neurotrophic factor (CNTF) can reduce weight and hyperinsulinemia in leptin-resistant obesity. Hypothesis. CNTF would cause weight loss, lower blood sugars, and restore gallbladder contractility in leptin-resistant (Lep^db) mice. Methods. To test this hypothesis, 20 C57b/6J and 20 Lep^db 8-week-old mice were injected intraperitoneally daily with either saline or 0.3 μg/g CNTF_Ax15 for 17 days. At 11 weeks, mice were weighed and underwent cholecystectomy. Intact gallbladders were mounted in 3 mL muscle baths and stimulated with acetylcholine (ACh) and cholecystokinin (CCK). Serum glucose levels were measured. Data were analyzed by two-way ANOVA. Results are shown in the table. Conclusions. These data suggest that daily administration of ciliary neurotrophic factor (CNTF) causes (1) significant weight loss, (2) improvement of diabetes, and (3) significant alterations in gallbladder motility which is decreased in lean nondiabetic mice and improved in obese diabetic mice. We conclude that ciliary neurotrophic factor may improve gallbladder contractility in leptin-resistant obese diabetes.

TABLE—ABSTRACT 48.

Strain	Wt (g)	Glucose (mg/dL)	ACh 10−5 M (N/cm2)	CCK 10−8 M (N/cm2)
Saline C57	17 ± 0	110 ± 12	.39 ± .04	1.14 ± .13
CNTF C57	13 ± 0∗	101 ± 7	.20 ± .04∗	0.59 ± .08∗
Saline Lepdb	41 ± 2†	440 ± 26†	.13 ± .03∗	0.46 ± .08∗
CNTF Lepdb	22 ± 1‡	200 ± 33†	.54 ± .10‡	1.02 ± .09‡

∗

P < 0.05 versus Saline C57;

†

P < 0.01 versus other groups;

Ddagger;

P < 0.001 versus Saline lep^db.

Full-size table