Alterations in activity and energy expenditure contribute to lean phenotype in Fischer 344 rats lacking the cholecystokinin-1 receptor gene

Abstract

CCK is hypothesized to inhibit meal size by acting at CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. Earlier studies have shown that obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic and obese. Recent findings show that rats with CCK1R-null gene on a Fischer 344 background (Cck1r(-/-)) are lean and normophagic. In this study, the metabolic phenotype of this rat strain was further characterized. As expected, the CCK1R antagonist, devazepide, failed to stimulate food intake in the Cck1r(-/-) rats. Both Cck1r(+/+) and Cck1r(-/-) rats became diet-induced obese (DIO) when maintained on a high-fat diet relative to chow-fed controls. Cck1r(-/-) rats consumed larger meals than controls during the dark cycle and smaller meals during the light cycle. These effects were accompanied by increased food intake, total spontaneous activity, and energy expenditure during the dark cycle and an apparent reduction in respiratory quotient during the light cycle. To assess whether enhanced responsiveness to anorexigenic factors may contribute to the lean phenotype, we examined the effects of melanotan II (MTII) on food intake and body weight. We found an enhanced effect of MTII in Cck1r(-/-) rats to suppress food intake and body weight following both central and peripheral administration. These results suggest that the lean phenotype is potentially driven by increases in total spontaneous activity and energy expenditure.

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

“…Blood was collected for glucose measurements by tail vein nick and measured by the glucometer using the AlphaTRAK 2 blood glucose monitoring system (Abbott Laboratories, Abbott Park, IL) (11). Total cholesterol, triglycerides (TGs), and free fatty acids (FFAs) were measured using an enzymatic-based kit (Wako Chemicals, Richmond, VA).…”

Mapping Molecular Datasets Back to the Brain Regions They are Extracted from: Remembering the Native Countries of Hypothalamic Expatriates and Refugees

“…We have found that this approach was suitable for measuring differences in NTS expression of OT receptor mRNA. In addition, we have used the Arcturus AutoPix Fluorescent LCM System to confirm the “expected” reduction in cholecystokinin-1 receptor (CCK1R) mRNA in both the ARH (–3.48 mm to –2.04 mm from Bregma; [334]) and dorsomedial hypothalamic nucleus (DMH) (–3.60 mm to –2.80 mm from Bregma; [334]) in rats that lack CCK1Rs relative to wild-type rats [36]. As before, slide-mounted cryostat sections (10 μm) of ARH and DMH were selected at 200 μm intervals, dehydrated in ethanol and xylene, and then air-dried (n=6 slides/brain).…”

“…Slide-mounted cryostat sections (10 μm-thick) were generated through the ARH from ad libitum fed or 48-h fasted wild-type or cholecystokinin-1 receptor (CCK1R) knockout (KO) Fischer 344 rats ( left panel ) or ad libitum fed or 48-h fasted wild-type Sprague-Dawley rats ( right panel ). Sections were thawed briefly prior to dehydration in ethanol and xylene and allowed to air dry as described previously [29, 35, 36]. LCM was used to collect bilateral sections (10 μm-thick) from the ARH (200 μm intervals) from six anatomically matched levels and sections were mounted onto slides.…”

Intracellular interplay between cholecystokinin and leptin signalling for satiety control in rats

“…However, intraperitoneal (i.p.) injection of CCK-1 receptor antagonist stimulates food intake 10,[12][13][14][15][16][17][18][19] and thus i.p. injection of LGM will influence intrinsic CCK and leptin release due to the size of meal or energy intake.…”

“…The dominant receptor subtypes, CCK-1 and CCK-2 receptors, are both G q -coupled seven-transmembrane receptors 8 , 9 . CCK-1 receptors influence satiety, as CCK-1 agonists reduce food intake 10 , 11 whereas pharmacological blockage of CCK-1 receptors stimulate food intake 10 , 12 – 19 . CCK-1 receptors are localized in peripheral and central machinery known to control satiety, and their dense expression has been found in the pylorus, nodose ganglion, nucleus tractus solitarius, and hypothalamic satiety-controlling centres 20 .…”