Gallbladder myocytes are short and cholecystokinin-resistant in obese diabetic mice

Background. Obesity is associated with diabetes and gallstone formation. Obese leptin-deficient (Lep(ob)) and leptin-resistant (Lep(db)) mice are hyperglycemic and have enlarged gallbladders with diminished response in vitro to cholecystokinin (CCK) and acetylcholine (ACh). Whether this Phenomenon is secondary to hyperosmolar myocytes and/or decreased neuromuscular transmission remains unclear. We ob hypothesize that myocytes from Lep(ob) and Lep(db) obese mice would not respond normally to neurotransmitters. Methods. Cholecystectomy was performed on 39 lean, 19 Lep(ob), and 20 Lep(db) 12-week-old female mice. The gallbladder was divided and enzymatically digested. Half of each gallbladder's myocytes had contraction induced by CCK (10(-8) mol/L, n = 38) or ACh (10(-5) mol/L, n = 40). Results. Body weights, gallbladder volumes, and serum glucoses were greater for Lep(ob) and Lep(db) mice compared to controls (P < .001). Resting myocyte lengths from Lep(ob) and Lep(db) mice were 93% and 91% of the length of controls (P < .001). In response to CCK, lean myocytes shortened 6% (P < .01), while myocytes from obese mice demonstrated no shortening. None of the myocytes demonstrated significant shortening with ACh. Conclusions. These data suggest that gallbladder myocytes from obese mice are (1)foreshortened and (2) have a diminished response to cholecystokinin. We conclude that altered leptin and/or increased glucose may foreshorten myocytes and decrease response to cholecystokinin.