A β-geo fusion cassette was inserted into exon 2 of the cholecystokinin (Cck) gene, abolishing gene function. Cholecystokinin is a gastrointestinal satiety hormone secreted by enteroendocrine intestinal I cells in response to fat and protein. Its release stimulates pancreatic enzyme secretion, modulates intestinal motility, and regulates meal size in the central nervous system. CCK is also a neurotransmitter released by subpopulations of neurons in the central nervous system, where it influences both memory and exploratory behaviors. Homozygous CCK-/- mice are viable, fertile, and normal in size, with lacZ staining visible in the gut and brain. Specifically, lacZ expression is evident in the neural tube, neural crest, mid- and hindbrain, and heart (E8.5-9.5), from the proximal stomach into the colon (E10.5-15.5), and persists in scattered endocrine cells in the upper intestine in adults. Expression is also evident in the cortex, hippocampus, and thalamus of adult mice. On a high fat diet, these mice gain less weight, have less fat mass, and absorb less total fat than wildtype mice. They have higher energy expenditure, enhanced insulin sensitivity, and decreased glucose tolerance than control mice, with no change to triglyceride, cholesterol, glucose and insulin levels. These CCK-/- mice exhibit impaired glucose-stimulated insulin secretion with no change in islet size, number, or morphology. Pancreatic amylase levels are 60% higher in these mice and they have a higher frequency of gall stones than wildtype mice. They also display spatial learning and memory defects, with reduced exploratory and increased anxiety-related behaviors.
