Cholecystokinin Knockout Mice Are Resistant to High-Fat Diet-Induced Obesity

Abstract

Background & Aims Cholecystokinin (CCK) is a satiation peptide released during meals in response to lipid intake; it regulates pancreatic digestive enzymes that are required for absorption of nutrients. We proposed that mice with a disruption in the CCK gene (CCK-KO mice) that were fed a diet of 20% butter fat would have altered fat metabolism. Methods We used quantitative magnetic resonance imaging to determine body composition and monitored food intake of CCK-KO mice using an automated measurement system. Intestinal fat absorption and energy expenditure were determined using a noninvasive assessment of intestinal fat absorption and an open circuit calorimeter, respectively. Results After consuming a high-fat diet for 10 weeks, CCK-KO mice had reduced body weight gain and body fat mass and enlarged adipocytes, despite the same level of food intake as wild-type mice. CCK-KO mice also had defects in fat absorption, especially of long-chain saturated fatty acids, but pancreatic triglyceride lipase (PTL) did not appear to have a role in the fat malabsorption. Energy expenditure was higher in CCK-KO than wild-type mice and CCK-KO mice had greater oxidation of carbohydrates while on the high-fat diet. Plasma leptin levels in the CCK-KO mice fed the high-fat diet were markedly lower than in wild-type mice, although levels of insulin, gastric-inhibitory polypeptide, and glucagon-like peptide-1 were normal. Conclusion CCK is involved in regulating the metabolic rate and is important for lipid absorption and control of body weight in mice placed on a high-fat diet.

Lipid transport in cholecystokinin knockout mice

“…Male CCK-KO mice and their wild-type (WT) littermates were generated onto a C57BL/6J genetic background [39–41] and housed in an AAALAC-accredited facility under conditions of controlled illumination (12:12-h light-dark cycle, lights on from 0600 to 1800 h). All animal protocols were approved by the University of Cincinnati Institutional Animal Care and Use Committee.…”

“…Based on our published protocols [11, 39], CCK-KO and WT mice (n = 10 per group) were individually housed at 10 wk of age and received a semi-purified high-fat pelleted diet (HFD, 20% butter fat by weight; Research Diets, Inc, New Brunswick, NJ) or pelleted chow (LFD, 5% fat diet, Harlan Teklad, Madison, WI) for 10 wk. Body weights and food intake were recorded twice a week using a top-loading balance (± 0.01 g, Adenturer SL, Ohaus Corp, Pine Brook, NJ).…”

“…Fat and lean body masses were determined using an EchoMRI whole body composition analyzer (Houston, TX) [39, 41]. After 10 wk on LFD or the HFD, fat pads, liver and plasma were carefully collected and weighed from 5-h fasted mice.…”

“…It also reportedly reduces sensitivity to the satiating effect of peripheral CCK in HFD-induced obese animals [36–38]. CCK knockout (CCK-KO) mice have comparable food intake, enhanced slightly energy expenditure and malabsorption of saturated fatty acids after chronic consumption of HFD [39]. Although CCK-KO animals on HFD have enhanced insulin sensitivity, CCK has no effect on glucose uptake by white adipose tissue and skeletal muscle [39].…”

“…CCK knockout (CCK-KO) mice have comparable food intake, enhanced slightly energy expenditure and malabsorption of saturated fatty acids after chronic consumption of HFD [39]. Although CCK-KO animals on HFD have enhanced insulin sensitivity, CCK has no effect on glucose uptake by white adipose tissue and skeletal muscle [39]. Thus, lipid metabolism in CCK-KO mice might be an important regulatory mechanism to improve insulin sensitivity.…”