cholecystokinin and Cachexia

The physiological control of appetite regulation involves circulating hormones with orexigenic (ghrelin) and anorexigenic (cholecystokinin) properties that induce alterations in energy intake via perceptions of hunger and satiety. We sought to investigate the relationship between appetite-regulating hormones and the cachexia associated with chronic heart failure.We randomized male Sprague-Dawley rats into myocardial infarction (MI) or sham operation (SO) groups. The levels of brain natriuretic peptide (BNP), cholecystokinin (CCK) and ghrelin in the plasma of all rats were detected by enzyme-linked immunosorbent assay (ELISA); the expression of BNP, CCK, and ghrelin in the myocardial tissue of all rats were detected by western blotting, immunohistochemistry, real-time polymerase chain reaction (PCR); myocardial morphology was assessed by microscopy.Plasma BNP and CCK levels in the cardiac cachexia (CC) groups and the heart failure non-cachexia (HF-nc) groups were significantly higher than those in the control groups (P < 0.01), and the expression of BNP and CCK in the myocardial tissue of rats: in CC groups and HF-nc groups were increased compared with the corresponding control groups (P < 0.01). In contrast, Plasma and cardiac expression of ghrelin decreased compared with the sham group (P < 0.01). Furthermore, plasma CCK levels were positively correlated with BNP concentrations (P < 0.001) and significantly negatively correlated with the ejection fraction (P < 0.001) in model animals; plasma ghrelin levels were negatively associated with BNP levels (P = 0.0023) and positively associated with ejection fraction (P = 0.0042).The appetite-regulating hormones (ghrelin and CCK) may present as a potential significant biomarker for cachexia associated with chronic heart failure.

Topics: Animals; Appetite; Biomarkers; Cachexia; Cholecystokinin; Correlation of Data; Ghrelin; Heart Failure; Male; Myocardial Infarction; Natriuretic Peptide, Brain; Rats; Rats, Sprague-Dawley; Stroke Volume

Angiotensin II (Ang II), which is elevated in many chronic disease states such as end-stage renal disease and congestive heart failure, induces cachexia and skeletal muscle wasting by increasing muscle protein breakdown and reducing food intake. Neurohormonal mechanisms that mediate Ang II-induced appetite suppression are unknown. Consequently, we examined the effect of Ang II on expression of genes regulating appetite. Systemic Ang II (1 μg/kg · min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels. These effects were completely blocked by the Ang II type I receptor antagonist candesartan or deletion of Ang II type 1a receptor. Ang II markedly reduced phosphorylation of AMP-activated protein kinase (AMPK), an enzyme that is known to regulate Npy expression. Intracerebroventricular Ang II infusion (50 ng/kg · min) caused a reduction of food intake, and Ang II dose dependently reduced Npy and orexin expression in the hypothalamus cultured ex vivo. The reduction of Npy and orexin in hypothalamic cultures was completely prevented by candesartan or the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside. Thus, Ang II type 1a receptor-dependent Ang II signaling reduces food intake by suppressing the hypothalamic expression of Npy and orexin, likely via AMPK dephosphorylation. These findings have major implications for understanding mechanisms of cachexia in chronic disease states such as congestive heart failure and end-stage renal disease, in which the renin-angiotensin system is activated.

Topics: Angiotensin II; Animals; Cachexia; Cholecystokinin; Eating; Feeding Behavior; Gene Expression Regulation; Hypothalamus; Infusions, Intraventricular; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuropeptide Y; Neuropeptides; Orexins; Phosphorylation; Time Factors

The aims of the present study were to measure the satiety neuropeptide cholecystokinin (CCK) in humans at terrestrial high altitude to investigate its possible role in the pathophysiology of anorexia, cachexia, and acute mountain sickness (AMS). Nineteen male mountaineers aged 38 +/- 12 years participated in a 20 +/- 5 day trek to Mt. Kanchenjunga basecamp (BC) located at 5,100 m, where they remained for 7 +/- 5 days. Subjects were examined at rest and during a maximal exercise test at sea-level before/after the expedition (SL1/SL2) and during the BC sojourn. There was a mild increase in Lake Louise AMS score from 1.1 +/- 1.2 points at SL1 to 2.3 +/- 2.3 points by the end of the first day at BC (P < 0.05). A marked increase in resting plasma CCK was observed on the morning of the second day at BC relative to sea-level control values (62.9 +/- 42.2 pmol/L(-1) vs. SL1: 4.3 +/- 8.3 pmol/L(-1), P < 0.05 vs. SL2: 26.5 +/- 25.2 pmol/L(-1), P < 0.05). Maximal exercise increased CCK by 78.5 +/- 24.8 pmol/L(-1), (P < 0.05 vs. resting value) during the SL1 test and increased the plasma concentration of non-esterified fatty acids and glycerol at BC (P < 0.05 vs. SL1/SL2). The CCK response was not different in five subjects who presented with anorexia on Day 2 compared with those with a normal appetite. While there was no relationship between the increase in CCK and AMS score at BC, a more pronounced increase in resting CCK was observed in subjects with AMS (> or =3 points at the end of Day 1 at BC) compared with those without (+98.9 +/- 1.4 pmol/L(-1) vs. +67.6 +/- 37.2 pmol/L(-1), P < 0.05). Caloric intake remained remarkably low during the stay at BC (8.9 +/- 1.4 MJ.d(-1)) despite a progressive decrease in total body mass (-4.5 +/- 2.1 kg after 31 +/- 13 h at BC, P < 0.05 vs. SL1/SL2), which appeared to be due to a selective loss of torso adipose tissue. These findings suggest that the satiogenic effects of CCK may have contributed to the observed caloric deficit and subsequent cachexia at high altitude despite adequate availability of palatable foods. The metabolic implications of elevated CCK in AMS remain to be elucidated.

Topics: Adult; Altitude Sickness; Analysis of Variance; Anorexia; Anthropometry; Appetite; Blood Glucose; Cachexia; Cholecystokinin; Energy Intake; Exercise; Fatty Acids, Nonesterified; Glycerol; Hand Strength; Humans; Male; Mountaineering