c-Kit mutant mouse behavioral phenotype: altered meal patterns and CCK sensitivity but normal daily food intake and body weight

Abstract

The mouse W/Wv mutation of the c-Kit receptor causes extensive loss of gastrointestinal interstitial cells of Cajal and vagal intramuscular arrays (IMAs; one of the two putative mechanoreceptors in gastrointestinal smooth muscle). To characterize the behavioral phenotype of the c-Kit mouse and to evaluate the roles of these mechanoreceptors in controlling food intake, meal patterns and daily intakes of W/Wv mice and controls were examined using solid (20-mg pellets) and liquid (Isocal) maintenance diets. After the meal pattern experiments, CCK (0.5, 1, 2, 4, 8, and 16 microg/kg ip) was administered to examine the role of the interstitial cells and vagal IMA mechanoreceptors in relaying peripheral signals of satiety activated by CCK-A receptors, whereas the specificity of the response was assessed with the antagonist devazepide (300 microg/kg ip). On both diets, the W/Wv mice ate smaller meals for shorter durations, with a compensatory increase in meal number, resulting in daily intakes and body weights similar to the controls. After CCK injections, the mutant mice consistently suppressed intake more ( approximately 2x) in 30-min tests, regardless of the test diet (12.5% glucose, chow, pellets, and Isocal). The increased sensitivity of W/Wv mice to CCK reflected an increased potency of the hormone (c-Kit mouse ED50 = 2.4 microg/kg; control ED50 = 6.4 microg/kg) and a shift of the dose-response curve to the left. Devazepide blocked the CCK suppression of ingestion. These results indicate that the selective loss of the interstitial cells and IMAs disrupts short-term feeding of the W/Wv mice by inducing an earlier satiety, possibly by altering gastric accommodation and/or emptying, without affecting the long-term mechanisms controlling overall intake or body weight. The results also suggest that the reduction of interstitial cells and IMAs augments the sensitivity to or increases the efficiency of exogenous CCK.

Food demand functions in mice

“…Tabarin et al (2007) also used a nose poke response (FR1) to deliver individual pellets to a trough, and reported ∼26 meals per day in B6/129 mice, a wild type mixed strain similar to that used in the present study. In contrast, using wild type mice of different strains but free delivery of pellets to a trough, other investigators consistently report 8-16 meals per day (Chi & Powley, 2003;Fox & Byerly, 2004;Donovan et al, 2007). Thus, meal size under free feeding or consummatory cost conditions in mice seems to be easily influenced by these types of variables, and as shown in the present study there may be substantial individual variability.…”

“…Total number of pellets consumed (pellets acquired minus pellets spilled into the tray beneath the cage) and lever presses emitted were recorded, and the daily average cost per pellet was computed. The number of meals per day was determined using a 20-min criterion: when 20 min elapsed between successive pellet deliveries, these were considered separate meals (eg Chi & Powley, 2003). For the last 4 mice, 10-and 30-min criteria were applied to the same data set.…”

“…In a previous study (Vaughan et al, 2005), we used a single step size PR and examined 3-and 20-min reset times to define a meal; the 3-min reset lead to many small or fragmented meals, so we deemed 20 min more suitable. This temporal criterion has been validated in mouse free feeding studies (Chi & Powley, 2003). However, there is a considerable literature on how criterion choice can affect meal parameters (e.g., Clifton, 2000;Demaria-Pesce & Nicolaidis, 1998;Zorrilla et al, 2005), so it is appropriate for us to examine the effect of criteria within the present protocols.…”

“…Methodologies in which discrete small food items are presented sequentially, such as in a standard operant test protocol, are particularly appealing because they minimize food spoiling behavior. A few such studies have appeared in the recent literature (e.g., Chi & Powley, 2003;Donovan, Paulino & Raybould, 2007;Fox & Byerly, 2004;Tabarin et al, 2007) but all have used a low and constant unit cost, so do not address economic considerations. We have previously reported results from operant protocols in normal and genetically obese mice (Vaughan, Moore, Haskell-Luevano, & Rowland, 2006;Vaughan & Rowland, 2003), but those studies did not examine systematic variation in cost parameters.…”

NT-4-deficient mice lack sensitivity to meal-associated preabsorptive feedback from lipids

“…After 2-3 days of exclusively consuming pellets from an open feeding jar, mice were fed with automated pellet dispensers (Coulbourn Instruments, Allentown, PA). Details concerning the apparatus were previously described (3).…”