Adipokine expression in brown and white adipocytes in response to hypoxia.

BACKGROUND: Adipose tissue has emerged as an important endocrine regulator by secreting hormones referred to as adipokines. Recent studies showed that adipose tissue considerably responds to hypoxia. Although the impact of white adipose tissue on regulative processes is established, the importance of brown adipose tissue in adults has emerged just recently. METHODS: Brown (BA) and white adipocytes (WA) were cultured either in the presence of chemical hypoxia-mimetics or under hypoxic atmosphere of 1% oxygen. Expression of hypoxia-inducible factor 1α (HIF- 1α) was assessed by western blot. The expression levels of several known HIF-1α-regulated proteins [vascular endothelial growth factor (VEGF), leptin, adiponectin, and angiotensinogen (AGT)] were quantified. RESULTS: Both chemical hypoxia-mimetics and physical hypoxia led to increased nuclear HIF-1α expression and to decreased cytoplasmatic adiponectin in both cell types. In contrast, VEGF and AGT expression did not change upon hypoxic stimulation. Leptin was exclusively detectable in WA, while uncoupling-protein 1 (UCP-1) was expressed in BA only. CONCLUSIONS: WA and BA are sensitive to hypoxia, in which HIF-1α expression is induced. Protein expression of adiponectin is hypoxia-dependent, whereas AGT, VEGF, leptin, and UCP-1 expression do not change secondary to hypoxia.

Screening for colorectal lesions with high-resolution video colonoscopes in a German male average-risk population at 40 to 59 years of age.

BACKGROUND: Prevalence data for colorectal neoplastic lesions obtained from screening colonoscopies have recently been reported for a U. S. American and a Polish average-risk population. However, prevalence data for a German average-risk population have not been published. METHODS: From 1998 until 2003 a screening colonoscopy was offered to all male participants of a health assessment program. In a total of 618 volunteers with an average risk for colorectal cancer, polypoid lesions were identified and removed using high-resolution video colonoscopes. The histological features of the lesions were categorised according to those of the most advanced one. An advanced lesion was defined as an adenoma of at least 1 cm in diameter, a polyp with villous histological features or high-grade intraepithelial neoplasms or a cancer. Data were analysed in two groups: age 40 - 49 years (group A) and age 50 - 59 years (group B). RESULTS: In group A (age 40 - 49 years, n = 285), 133 subjects (47 %) had polypoid lesions. Histological findings revealed that 57 subjects (20 %) had non-neoplastic and 76 subjects (27 %) had neoplastic lesions. In nine cases (3.2 %) polyps were classified as advanced lesions with a maximal diameter of 35 mm. In group B (age 50 - 59, n = 333), 183 subjects (55 %) had polypoid lesions. Histological findings revealed that 64 subjects (19 %) had non-neoplastic and 119 subjects (36 %) had neoplastic lesions. Among those, 34 (10.2 %) had advanced lesions with a maximal diameter of 55 mm. In neither group was an invasive cancer detected. The difference in the prevalence of neoplastic lesions between the two age groups was statistically significant (chi (2) = 5.85). An exceptionally high rate of 27 % neoplastic lesions was detected in subjects at 40 to 49 years of age. The rate of detected lesions in the group of older subjects was 36 %. CONCLUSION: By using high-resolution endoscopes we found an unexpectedly large number of neoplastic lesions in the colon even in a relatively young average-risk population. The question whether screening colonoscopy should therefore not only aim at detecting early colorectal cancer but also at identifying and removing precursor adenomas at younger ages clearly deserves further attention.

Xenin--a novel suppressor of food intake in rats.

Peptides related to the amphibian octapeptide xenopsin are present in various locations in mammalians, such as the gastrointestinal mucosa or brain tissue. In the gastrointestinal tract, xenopsin-related peptides induce partially neurogenic contractions of the colon in humans. In brain, however, their function is not known. Structural similarities of xenopsin-related peptides with neurotensin, a known modulator of ingestive behavior, suggest a possible role in feeding regulation. Therefore, we examined the effect of xenin, a recently identified xenopsin-related pentacosa peptide, on feeding behavior of fasted rats. Male Wistar rats (n=12) were intracerebroventricularly (i.c.v.) injected with either saline (10 microl) or xenin at 0.5, 1.5, 5 or 15 microg dissolved in an identical volume of 10 microl, respectively. In further experiments, xenin 15 microg/0.5 microl or 0.5 microl saline were injected into the lateral hypothalamus (LH). After injections, food intake (g), percentage of time spent with feeding (%) and prandial water intake (ml) were subsequently recorded for 2 h. After i.c.v. injection of 15 microg of xenin 1-h food intake was significantly reduced by 42% and 2-h food intake was diminished by 25%, respectively, compared to saline injection (p<0.01). This reduction of food intake was paralleled by a significant decrease of time spent with feeding by 41% (after 1 h) or 23% (after 2 h). The xenin-induced suppression of feeding behavior was dose-dependent. Thus, the minimal effective dose of xenin was 1.5 microg, while the dose of 0.5 microg was ineffective. Prandial water intake was significantly reduced only by the highest dose of xenin. Following injection of 15 microg of xenin into the lateral hypothalamus food intake was not different from control experiments. These data demonstrate a potent feeding suppressive action of xenin following intracerebroventricularly injection but not injection into the lateral hypothalamus suggesting a possible role of xenin in the central control of feeding termination and satiety.

[Occlusion of an esophagobronchial fistula by implantation of a Montgomery esophageal and a dynamic tracheal stent after failure of conventional endoprosthesis]. / Verschluss einer ösophagobronchialen Fistel durch Implantation eines ösophagealen Montgomery- und eines trachealen Dynamic-Stents nach Versagen konventioneller Endoprothetik.

Esophagorespiratory fistulas were frequently caused by malignant tumors, bougienage, laser therapy or radiochemotherapy. We here report the case of a patient with inoperable bronchial cancer, who developed a symptomatic esophagorespiratory fistula during combined radiochemotherapy with Cisplatin. A sufficient occlusion of the fistula could not be achieved with conventional plastic tubes or novel self-expanding silicone-coated Gianturco Song stents. After extraction of two Gianturco Song stents we inserted a Montgomery Salivary Bypass Stent into the esophagus and Dynamic stent into the trachea. This resulted in a total occlusion of the fistula. This present case suggests that the Montgomery stent may have little tendency to migrate due to its characteristic configuration and fixation and further demonstrates that the novel self-expanding silicone-coated Gianturco Song stents can be removed, if necessary.

Role of vagal fibers and bombesin/gastrin-releasing peptide-neurons in distention-induced gastrin release in rats.

In the rat the exact role of vagal fibers and the interaction between the extrinsic and intrinsic neural system in distention-induced gastrin release are still a matter of debate. Accordingly, the aim of the present study was to examine the contribution of afferent and efferent vagal fibers as well as intrinsic neurons on gastrin response to gastric distention. In anesthetized rats graded gastric distention by 5, 10 and 15 ml saline for 20 min caused a significant volume-dependent increase of plasma gastrin levels by 12+/-6 pg/ml (5 ml saline, n = 8, P =0.05), 26+/-7 pg/ml (10 ml saline, n = 10, P < 0.05) and 37+/-7 pg/ml (15 ml saline, n = 8, P < 0.01 ), respectively. To examine the role of the extrinsic vagal innervation, gastrin response to distention was studied in anesthetized rats after bilateral truncal vagotomy (n = 9) or selective afferent vagotomy following pretreatment with capsaicin (n = 6). Stimulation of gastrin release by 10 ml distention in sham-operated control rats was reversed to an inhibition after truncal vagotomy (26+/-7 vs. -11+/-4 pg/ml; P<0.05) and capsaicin-treatment (37+/-18 vs. -34+/-11 pg/ml; P<0.05). A contribution of cholinergic mechanisms to this vagovagal-mediated stimulation of distention-induced gastrin release was excluded, since atropine (100 microg/kg/h; n = 8) further augmented distention-stimulated gastrin release. Since bombesin/gastrin-releasing peptide (GRP)-neurons contribute to vagally stimulated gastrin secretion, we have examined gastrin response to distention in the presence of the specific bombesin-receptor antagonist D-Phe6-BN(6-13)OMe (400 microg/kg/h: n = 10). This bombesin-antagonist completely reduced distention-stimulated gastrin release in vivo. In contrast, distention of the isolated, extrinsically denervated stomach significantly decreased gastrin release by 13+/-5 pg/min (5 ml saline, n = 8, P < 0.05), 28+/-8 pg/min (10 ml saline, n = 11, P < 0.05) and 35+/-10 pg/min (15 ml saline, n = 8, P < 0.01), respectively, without changing the activity of bombesin/GRP-neurons. Distention-induced decrease of gastrin release was attenuated to 50 percent by atropine (10(-7) M: n = 10) or tetrodotoxin (TTX) (10(-6) M; n = 10), respectively. These data demonstrate, that in anesthetized rats distention-stimulated gastrin secretion depends on the activation of a vagovagal reflex and intrinsic bombesin/GRP-neurons. In contrast distention of the isolated rat stomach inhibits gastrin release in part via intrinsic cholinergic pathways and other as yet unknown mechanisms.

Brain regions where cholecystokinin exerts its effect on satiety.

The neuropeptide cholecystokinin (CCK), which is localized within the hypothalamus in integrative centers of feeding regulation, can suppress feeding behavior when exogenously applied into the lateral hypothalamus. Moreover, the endogenous peptide can be released from the same brain locus by stimuli that physiologically are associated with satiety (i.e., gastric meal loads). This endogenously released CCK contributes to the inhibition of feeding behavior during meal intake. These data strongly suggest that hypothalamic CCK may play a physiological role in the termination of feeding behavior. The presence of additional sites sensitive to CCK in extrahypothalamic regions (e.g., medial pons and lateral medulla) argue that the CCK receptor systems may functionally (1) have several links in a linear chain or (2) exist as several parallel systems. The relevance of these extrahypothalamic loci for feeding regulation will require further studies which need to be directed towards the physiological role of the endogenously released CCK in these particular areas, by use of selective CCK antagonists.

Effect of galanin on food intake in rats: involvement of lateral and ventromedial hypothalamic sites.

Galanin has previously been reported to elicit feeding in satiated animals when injected into the hypothalamic paraventricular nucleus. It is not known, however, 1) whether this action is due to activation of feeding signals or suppression of satiety signals or both or 2) whether other hypothalamic regions such as the lateral hypothalamus (LH) or the ventromedial hypothalamus (VMH) are involved in this action. The effects of galanin on food intake were therefore examined in satiated and in fasted rats both after intracerebroventricular injection (0.1, 1, and 10 micrograms/10 microliters) and after microinjection (1 and 5 micrograms/0.5 microliters) into the LH and VMH. Twenty minutes after intracerebroventricular injection, galanin significantly and dose dependently augmented food intake by up to sevenfold in freely feeding rats and by up to 79% in fasted animals. The galanin-induced augmentation of cumulative food intake up to 2 h after injection was due to the initial increase in food consumption during the 0 to 20-min interval. This suggests that galanin acts by activation of feeding behavior and not by suppression of satiety signals in these fasted animals, in which satiety signals are presumably not initially operative. Twenty minutes after intrahypothalamic injections into both the LH and VMH, galanin (5 micrograms) significantly increased food consumption, fivefold in freely feeding rats and 30-35% in fasted rats. Thus stimulation of feeding by centrally injected galanin also involves loci within the LH and VMH.

Effect of intraduodenal or intragastric nutrient infusion on food intake in man.

In man, only little is known about the site of origin of satiety signals within the gastrointestinal tract. Therefore, it was the aim of this study to examine the role of the stomach and the small intestine as a source of satiety signals. 8 overnight fasted healthy volunteers received intraduodenal (100 or 200 ml/h) or intragastric (100 ml/h) infusions of a mixed liquid diet (Biosorb) or iso-osmolar saline, respectively. 20 minutes after start of the infusion, standardized mini-sandwiches and water were presented and food intake was recorded for the ensuing 90 minutes. During both rates of intraduodenal nutrient infusion, cumulative food intake was identical to that during saline infusion. However, during intragastric nutrient infusion, cumulative food intake was significantly reduced compared to saline infusion (30 +/- 1 vs. 36 +/- 2 sandwiches; p less than 0.05). These data indicate that food consumption in man is reduced, if initiation of eating is preceded by nutrient administration into the stomach, but not into the duodenum. This effect does not appear to be mediated by gastrin, since plasma gastrin levels were not different during gastric and duodenal nutrient administration. In conclusion, the results of this study suggest that the generation of satiety signals in man is dependent on the presence of food in the stomach. Food only in the duodenum has no effect, although synergistic gastric and intestinal mechanisms can as yet not be excluded.

Neuropeptide Y and food intake in fasted rats: effect of naloxone and site of action.

Central administration of neuropeptide Y (NPY) induces food intake in freely feeding animals and this effect is mediated by hypothalamic sites. Little is known, however, about the effect of NPY on food intake and site of action in food-deprived animals. To examine this further, 24-h fasted rats received injections of saline or NPY into the lateral cerebral ventricle (10 micrograms/10 microliters; n = 8) or into the lateral (LH) or ventromedial hypothalamus (VMH) (1 microgram/0.5 microliters; n = 44). In addition, intracerebroventricular (i.c.v.) injections of NPY were carried out with or without i.c.v. naloxone (25 micrograms), a specific opioid receptor antagonist. During the first 40 min food intake was not different with or without NPY. After 60 and 120 min, food intake was 5.9 +/- 0.4 g and 8.3 +/- 0.6 g with i.c.v. saline which was significantly augmented by i.c.v. NPY to 8.7 +/- 0.9 g and 14.4 +/- 1.5 g, respectively (P less than 0.05). This increase in food consumption was due to a prolongation of feeding time. The opioid receptor antagonist naloxone significantly augmented latency to feed, both in the absence and presence of NPY (8.0 vs 1.7 min or 14.7 vs 2.8 min, respectively) and abolished the NPY-induced increase in food intake. Following intrahypothalamic injection of NPY, an increase in food intake (greater than 20%) was observed in 50% of the histologically identified LH and VMH sites, but only in 15% of the injection sites outside the LH/VMH.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of CCK on food intake in man: physiological or pharmacological effect?

The present study was designed to determine in humans the dose of CCK which suppresses food intake. 18 male subjects received in randomized order either i.v. saline or Thr28 Nle31 CCK 25-33 (CCK-9) at 100 or 500 pmol/kgh, respectively. In addition, 7 subjects received CCK together with the opiate receptor antagonist naloxone to examine if activation of endogenous opioids might interfere with the potential satiating effect of CCK. Food intake during saline was 32 +/- 2 sandwiches (mean +/- SEM), during CCK-9 100 pmol/kgh 28 +/- 2 (n.s.) and only 12 +/- 3 during CCK-9 500 pmol/kgh (p less than 0.01). The respective water intake was 730 +/- 70 ml, 590 +/- 60 ml (n.s.) and 320 +/- 50 ml (p less than 0.01). Naloxone further reduced food and water intake during high but not low dose CCK or saline. During saline postprandial insulin levels rose by 49 +/- 6 microU/ml within 45 min which was attenuated during low dose (23 +/- 6 microU/ml; p less than 0.01) and high dose CCK-9 (1 +/- 1 microU/ml; p less than 0.001). Plasma glucagon did not change in control or CCK experiments. The postprandial rise of pancreatic polypeptide was attenuated during high dose CCK. Naloxone had no effect on the hormonal response except for a prolonged reduction of insulin and glucose levels following high dose CCK + naloxone. Plasma CCK levels rose by 5.4 pmol/l in controls but by 55 and 255 pmol/l during the low and high dose CCK infusion, respectively. These data demonstrate that suppression of food intake in man by i.v. CCK is a pharmacological rather than a physiological effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Sites in the brain at which cholecystokinin octapeptide (CCK-8) acts to suppress feeding in rats: a mapping study.

In this study, an examination was made of the sites in the brain of the rat at which the injection of cholecystokinin octapeptide (CCK-8) would alter food intake. Rats fasted for 24 hr received intracerebral injections of CCK-8 (1 nmol) or an equal volume of saline (0.5 microliters), into various sites in the brain through permanently implanted stainless steel cannulae. After prior acclimatisation to individual plexiglass compartments, latency to feed, as well as consumption of food and water during 0-20, 20-40 and 40-60 min after the injection, were recorded. The available food was the standard rat pellets, to which the animal otherwise had constant daily access. With this paradigm, active sites at which CCK-8 suppressed feeding were defined as sites at which consumption of food for 0-20 min was reduced by 25% or more, or the latency to feed was increased by 3 min or more after the injection of CCK-8, as compared to the effect of the injection of saline, made at the same site. Such active sites were most densely distributed in the rostral diencephalon, e.g. hypothalamus, the medial pontine area and lateral medulla, in the vicinity of the nucleus tractus solitarii (NTS). By grouping data for injections according to histologically identified sites, statistical analysis of groups of injections confirmed that these three major areas of the brain were active with regard to the suppression of feeding by CCK-8. These data suggest that CCK may not only initiate satiety messages, as a circulating hormone at peripheral sites, but also participate in the conduction of such information to the target in the brain by serving as a neurotransmitter in the lateral medulla (e.g. NTS), medial pontine area (e.g. relay station between the NTS and hypothalamus) and the lateral hypothalamus, where local release of CCK-8 after stomach loading has been observed.

Release of hypothalamic cholecystokinin in cats: effects of nutrient and volume loading.

Systemic cholecystokinin (CCK) suppresses food intake in various species and has therefore been proposed to act as a satiety factor. Because CCK is also present in the hypothalamus and furthermore meets neurotransmitter criteria, the hypothesis was tested whether CCK participates in the transmission of satiety messages at the lateral hypothalamic (LH) level. The results of this study demonstrate that in halothane-anesthetized cats, neurons located in the LH will indeed release CCK-like material after a carbohydrate-protein meal in a time-dependent fashion. This release, as water loads demonstrate, is most likely due to volumetric distension rather than to the nutrient content. The releasable CCK does not originate from peripheral sources, since intravenously infused CCK octapeptide (CCK-8) does not appear in the perfusate. The release occurs only in discrete neurons and is not universal to CCK-releasing systems within the LH, and also, CCK-releasing systems are not present at all locations. The molecular form of CCK in feline hypothalamus is the COOH-terminal octapeptide (CCK-8) as shown by high-performance liquid chromatography. No gastrin-17 is present. CCK-8 is also the predominant form found in meal-induced as well as in KCl-induced CCK released from hypothalamic neurons. These results suggest a correlated role for hypothalamic CCK in the termination of food intake.

Chronic intraventricular administration of cholecystokinin octapeptide (CCK-8) suppresses feeding in rats.

Cholecystokinin octapeptide (CCK-8) is known to suppress feeding in sheep, pigs, golden hamsters and rats following acute intracerebroventricular (i.c.v.) injection. In this study, we report the effects of chronically administered i.c.v. CCK-8 on long-term food intake in rats. After baseline food intake was established over a period of 3 days, rats were implanted with Alzet osmotic minipumps, which delivered 1.0 microliter/h. Three groups of animals were prepared which received saline (vehicle) or CCK-8 at 12.25 micrograms/day (low dose) or CCK-8 at 122.5 micrograms/day (high dose). Surgical preparation of the animals with the intraventricular cannula and the osmotic minipump resulted in an initial reduction in food consumption in all groups. In the saline group daily food consumption returned to presurgery values by day 4. Similar results were observed with the low dose of CCK-8. In contrast, in animals receiving the high concentrations of CCK-8, the initial fall in feeding was more prominent and though it rose during the 7-day infusion interval, it remained statistically below control during this period. After termination of the infusion, daily food consumption rose to normal levels during the next 3 days. For comparison, the cumulative difference between daily food consumption over the period of 8 days during infusion and pre-infusion control was 39.9 +/- 10.0 g/24 h in the saline group. In CCK-8-infused animals, food consumption after pump implantation was reduced by an integrated value of 35.5 +/- 5.0 g/24 h at low dose and 117.4 +/- 20.2 g/24 h at high dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuronal cholecystokinin-like immunoreactivity is postprandially released from primate hypothalamus.

By use of the push-pull perfusion technique, release of neuronal cholecystokinin-like immunoreactivity (CCK-LI) from hypothalamus of owl monkeys was investigated in relation to an intragastric meal. In overnight fasted, halothane-anesthetized owl monkeys, levels of CCK-LI in the hypothalamic push-pull perfusate were below assay sensitivity (less than 4 pg/30 min). After intragastric administration of a carbohydrate/amino acid meal, however, a 10-fold increase in CCK-LI release (51 +/- 7 pg/30 min) was observed in 5 out of 15 perfusion sites during the first postprandial 30 min. During the subsequent two 30-min intervals, release of CCK-LI was still increased with 32 +/- 5 pg/30 min and 15 +/- 6 pg/30 min, respectively. Thereafter, CCK-LI release was below assay sensitivity again. Addition of 40 mM potassium chloride (KCl) to the perfusion solution, which causes neuronal depolarization, resulted in a second increase in CCK-LI release of 56 +/- 7 pg/30 min which was comparable to the meal-induced release. All sites that exhibited an increase in CCK-LI were located in the anterolateral aspect of the hypothalamus. In experiments without meal-induced release, KCl did not have any effect on CCK-LI in perfusate, suggesting that these particular sites did not contain CCK-releasing terminals. High performance liquid chromatography (HPLC) identified the C-terminal octapeptide of CCK (CCK-8) as the predominant molecular form of CCK within the owl monkey hypothalamus. No gastrin-17 was present.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracerebroventricular injections of cholecystokinin octapeptide suppress feeding in rats--pharmacological characterization of this action.

Cholecystokinin octapeptide (CCK-8), administered intracerebroventricularly (i.c.v.), will suppress feeding. The aim of the present study was to determine the pharmacological characteristics of this satiety inducing effect in rats. For this purpose, we employed a feeding bioassay model in 24 h fasted rats and examined the effects of CCK-8 and a variety of structurally related analogs on latency to feed after i.c.v. injection and on the amount of food and water consumed as measured after the initiation of feeding in sequential 20-min epochs for 1 h. CCK-8, given in doses of 0.1, 1 and 10 nmol, produced a dose-dependent increase in feeding latency and a reduction of food intake during the first 20 min after initiation of feeding. Food intake during the next 40 min and water consumption were not altered. Plasma levels of CCK-like immunoreactivity after an i.c.v. injection of a dose of CCK-8 which blocked feeding (10 nmol) rose insignificantly from 117 to 125 pg/ml. In contrast, at the minimally effective dose of CCK-8 after i.v. administration (10 nmol), which also produced an inhibition of feeding, the plasma level was 1430 pg/ml. This difference indicates that plasma levels of CCK after i.c.v. CCK-8 are not adequate to produce the observed feeding suppression and suggests that the effects of i.c.v. CCK-8 are not mediated by a peripheral redistribution. Systematic dose response studies revealed the following rank order of potencies: CCK-8 greater than or equal to G-17 II much greater than CCK-8 NS = G-17 I greater than or equal to CCK-4 = CCK 26-29 = 0. Only gastrin-17 II (sulfated) produced an effect comparably significant to CCK-8. I.c.v. proglumide at 2500 nmol failed to modify the effects of CCK-8 at 10 nmol after i.c.v. injection. These data demonstrate that the structural requirements for feeding suppressive activity in rat brain are the carboxyterminus with a sulfated tyrosine residue, located 6 to 7 residues from the carboxyterminus, as present in CCK-8 and gastrin-17 II.

An intragastric meal releases the putative satiety factor cholecystokinin from hypothalamic neurons in cats.

The release of cholecystokinin-like immunoreactivity (CCK-LI) from feline hypothalamus was studied in relation to a meal by use of the push-pull perfusion technique. While levels of CCK-LI in the perfusate of overnight-fasted anesthetized cats were below assay sensitivity (less than 7 pg/30 min), intragastric administration of a carbohydrate-amino acid meal elicited a 3-fold increase in CCK-LI, identified by high-performance liquid chromatography as the C-terminal octapeptide of CCK (CCK-8). Examination of an extrahypothalamic site showed no comparable release in CCK-LI. Intravenous infusions of CCK-8 at doses imitating physiological blood levels up to 400 times higher than those seen after physiological stimulation demonstrated the existence of a CCK blood-brain barrier in the lateral hypothalamus. These observations provide support that CCK may play a physiological role in termination of feeding behavior.