Cholecystokinin responsiveness varies across the population dependent on metabolic phenotype

Abstract

Cholecystokinin (CCK) is an important satiety factor, acting at type 1 receptors (CCK1Rs) on vagal afferent neurons; however, CCK agonists have failed clinical trials for obesity. We postulated that CCK1R function might be defective in such patients due to abnormal membrane composition, such as that observed in cholesterol gallstone disease. Due to the challenges in directly studying CCK1Rs relevant to appetite control, our goal was to develop and apply a method to determine the impact of a patient's own cellular environment on CCK stimulus-activity coupling and to determine whether CCK sensitivity correlated with the metabolic phenotype of a high-risk population. Wild-type CCK1Rs were expressed on leukocytes from 112 Hispanic patients by using adenoviral transduction and 24-h culture, with quantitation of cholesterol composition and intracellular calcium responses to CCK. Results were correlated with clinical, biochemical, and morphometric characteristics. Broad ranges of cellular cholesterol and CCK responsiveness were observed, with elevated cholesterol correlated with reduced CCK sensitivity. This was prominent with increasing degrees of obesity and the presence of diabetes, particularly when poorly controlled. No single standard clinical metric correlated directly with CCK responsiveness. Reduced CCK sensitivity best correlated with elevated serum triglycerides in normal-weight participants and with low HDL concentrations and elevated glycated hemoglobin in obese and diabetic patients. CCK responsiveness varies widely across the population, with reduced signaling in patients with obesity and diabetes. This could explain the failure of CCK agonists in previous clinical trials and supports the rationale to develop corrective modulators to reverse this defective servomechanism for appetite control. This trial was registered at www.clinicaltrials.gov as NCT03121755.

Changes in eating behavior, taste and food preferences and the effects of gastrointestinal hormones

“…Cholecystokinin (CCK) is a satiety factor, acting at type 1 receptors (CCK1Rs) on vagal afferent neurons [19]. Therefore, its role in the treatment of obesity has been studied in trials with negative results.…”

Changes in the plasma membrane in metabolic disease: impact of the membrane environment on G protein‐coupled receptor structure and function

“…However, in this study (Desai et al, ), no standard clinical, biochemical or morphometric parameters, alone or in combination, were found to be adequate to identify those subjects exhibiting this defect in CCK responsiveness. Another key finding was that the CCK sensitivity was best correlated with different types of lipids in patients with different BMIs.…”

“…In a recent study (Desai et al, ), we have developed a technique that enables the study of CCK 1 receptor function in a patient's own cell membrane micro‐environment. In this work, the CCK 1 receptor was expressed ex vivo in leukocytes collected from patients using an adenoviral construct, in order to measure its function.…”

“…In this work, the CCK 1 receptor was expressed ex vivo in leukocytes collected from patients using an adenoviral construct, in order to measure its function. This was achieved within 24 h of sample collection without any changes occurring in the natural membrane micro‐environment (Desai et al, ). Applying this technique to samples collected from 112 patients with a high incidence of obesity and metabolic disease revealed a wide variation in CCK responsiveness.…”

Plasma bile acid changes in type 2 diabetes correlated with insulin secretion in two‐step hyperglycemic clamp

“…It has been reported that insulin can suppress hepatic bile acid biosynthesis through the forkhead transcription factor O1 (FoxO1)/small heterodimer partner (Shp)/cholesterol 7α‐hydroxylase (Cyp7a1) axis or by targeting Cyp8b1 expression . The inverse correlation between BA levels and insulin secretion may result from the inhibitory effect of insulin on hepatic BA synthesis and transport or, alternatively, from the effects of BAs on β‐cell function directly or indirectly via its effects on islet α‐cells, enteroendocrine cells, or other BA‐target organs, such as the liver or adipose tissue …”