Effects of chromium supplementation on physiology, feed intake, and insulin related metabolism in growing pigs subjected to heat stress.

Improving insulin sensitivity may reduce impacts of heat stress (HS) in pigs by facilitating heat dissipation. Chromium (Cr) has been reported to improve insulin sensitivity in pigs. Therefore, the aim of this experiment was to investigate whether Cr supplementation can mitigate HS in growing pigs. Thirty-six gilts were randomly assigned to 2 diets containing 0 (control) or 400 ppb Cr. After 14 d the supplemented pigs were allocated to either 8 d thermoneutral (20°C constant; TN) or cyclic HS (35°C, 0900 h to 1700 h) conditions and continued their respective diet (n = 9 per group). Growth performance was recorded during the 14-d supplementation period. The physiological responses to HS were monitored by measuring respiration rate, rectal temperature, blood gas chemistry, and feed intake during thermal exposure. Kinetics of plasma glucose, insulin and NEFA were studied by intravenous glucose tolerance test (IVGTT) on d 8 of thermal treatment. Results showed Cr alleviated the HS-increased rectal temperature (P < 0.05) and respiration rate (P < 0.01) at 1300 h and 1600 h during thermal exposure. However, Cr did not mitigate the reduction in average daily feed intake which was reduced by 35% during HS or the HS-induced respiratory alkalosis. Chromium tended to increase average daily gain (0.86 vs. 0.95 kg, P = 0.070) during the 14-d supplementation under TN conditions before thermal exposure, which might be associated with the potential of Cr in improving overall insulin sensitivity, as evidenced by a reduced insulin resistance index calculated by Homeostatic Model Assessment (HOMA-IR; 0.65 vs. 0.51, P = 0.013) and a tendency of reduced fasting plasma insulin concentration (1.97 vs. 1.67 µU/mL, P = 0.094). Heat stress decreased the acute insulin releasing rate (P = 0.012) and consequently slowed glucose clearance rate (P = 0.035) during IVGTT. Besides, HS enlarged the values of area under the curve of NEFA during IVGTT (P < 0.01), indicating a reduced lipid mobilization. In conclusion, HS reduced insulin response to IVGTT. Chromium supplementation exhibited a potential in improving insulin sensitivity and mitigating HS symptoms in growing pigs.

Site and mechanism of the colokinetic action of the ghrelin receptor agonist, HM01.

BACKGROUND: It has been recently demonstrated that the ghrelin receptor agonist, HM01, caused defecation in rats that were treated to provide a model for the constipation of Parkinson's disease. HM01 significantly increased fecal output and increased Fos activity in neurons of the hypothalamus and hindbrain, but not in the spinal defecation center. Other ghrelin agonists act on the defecation center. METHODS: Receptor pharmacology was examined in ghrelin receptor (GHSR1a) transfected cells. Anesthetized rats were used to investigate sites and mechanisms of action. KEY RESULTS: HM01 activated rat GHSR1a at nanomolar concentrations and was antagonized by the GHSR1a antagonist, YIL781. HM01, intravenous, was potent to activate propulsive colorectal contractions. This was prevented by pelvic nerve section and by intravenous YIL781, but not by spinal cord section rostral to the defecation centers. Direct intrathecal application of HM01 to the defecation center at spinal level L6-S1 initiated propulsive contractions of the colorectum. CONCLUSIONS & INFERENCES: HM01 stimulates GHSR1a receptors on neurons in the lumbosacral defecation centers to cause propulsive contractions and emptying of the colorectum. It has greater potency when given systemically, compared with other GHSR1a agonists.

A ghrelin receptor agonist is an effective colokinetic in rats with diet-induced constipation.

BACKGROUND: Despite constipation being a common problem, the treatments that are available have side effects and are only partly effective. Recent studies show that centrally penetrant ghrelin receptor agonists cause defecation in humans and other species. Here, we describe some features of a rat model of low fiber-induced constipation, and investigate the effectiveness of the ghrelin agonist, capromorelin. METHODS: Rats were given low-fiber diets for 5 weeks. Their colorectal responsiveness to distension and to a behavioral test, water avoidance and colon histology were compared to those of rats on a standard diet. KEY RESULTS: After the low-fiber diet, distension of the colon produced fewer propulsive contractions, behaviorally induced defecation was reduced, and the lining of the colorectum was inflamed. However, capromorelin was similarly effective in causing defecation in constipated and non-constipated rats. CONCLUSIONS & INFERENCES: Low-fiber diet in rats produces a constipation phenotype, characterized by reduced responsiveness of the colorectum to distension and to a behavioral stimulus of defecation, water avoidance. The effectiveness of capromorelin suggests that centrally penetrant ghrelin receptor stimulants may be effective in treating constipation.

Damage to enteric neurons occurs in mice that develop fatty liver disease but not diabetes in response to a high-fat diet.

BACKGROUND: Disorders of gastrointestinal functions that are controlled by enteric neurons commonly accompany fatty liver disease. Established fatty liver disease is associated with diabetes, which itself induces enteric neuron damage. Here, we investigate the relationship between fatty liver disease and enteric neuropathy, in animals fed a high-fat, high-cholesterol diet in the absence of diabetes. METHODS: Mice were fed a high-fat, high-cholesterol diet (21% fat, 2% cholesterol) or normal chow for 33 weeks. Liver injury was assessed by hematoxylin and eosin, picrosirius red staining, and measurement of plasma alanine aminotransaminase (ALT). Quantitative immunohistochemistry was performed for different types of enteric neurons. KEY RESULTS: The mice developed steatosis, steatohepatitis, fibrosis, and a 10-fold increase in plasma ALT, indicative of liver disease. Oral glucose tolerance was unchanged. Loss and damage to enteric neurons occurred in the myenteric plexus of ileum, cecum, and colon. Total numbers of neurons were reduced by 15-30% and neurons expressing nitric oxide synthase were reduced by 20-40%. The RNA regulating protein, Hu, became more concentrated in the nuclei of enteric neurons after high-fat feeding, which is an indication of stress on the enteric nervous system. There was also disruption of the neuronal cytoskeletal protein, neurofilament medium. CONCLUSIONS & INFERENCES: Enteric neuron loss and damage occurs in animals with fatty liver disease in the absence of glucose intolerance. The enteric neuron damage may contribute to the gastrointestinal complications of fatty liver disease.

The mechanism of enhanced defecation caused by the ghrelin receptor agonist, ulimorelin.

BACKGROUND: Discovery of adequate pharmacological treatments for constipation has proven elusive. Increased numbers of bowel movements were reported as a side-effect of ulimorelin treatment of gastroparesis, but there has been no investigation of the site of action. METHODS: Anesthetized rats were used to investigate sites and mechanisms of action of ulimorelin. KEY RESULTS: Intravenous ulimorelin (1-5 mg/kg) caused a substantial and prolonged (~1 h) increase in colorectal propulsive activity and expulsion of colonic contents. This was prevented by cutting the nerves emerging from the lumbosacral cord, by the nicotinic receptor antagonist hexamethonium and by antagonists of the ghrelin receptor. The effect of intravenous ulimorelin was mimicked by direct application of ulimorelin (5 µg) to the lumbosacral spinal cord. CONCLUSIONS & INFERENCES: Ulimorelin is a potent prokinetic that causes propulsive contractions of the colorectum by activating ghrelin receptors of the lumbosacral defecation centers. Its effects are long-lasting, in contrast with other colokinetics that target ghrelin receptors.