Effect of intracerebroventricular alpha-MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a hypothalamic neuropeptide proposed to play a key role in energy homeostasis. To investigate the behavioral, metabolic, and hypothalamic responses to chronic central alpha-MSH administration, alpha-MSH was infused continuously into the third cerebral ventricle of rats for 6 days. Chronic alpha-MSH infusion reduced cumulative food intake by 10.7% (P < 0.05 vs. saline) and body weight by 4.3% (P < 0.01 vs. saline), which in turn lowered plasma insulin levels by 29.3% (P < 0.05 vs. saline). However, alpha-MSH did not cause adipose-specific wasting nor did it alter hypothalamic neuropeptide mRNA levels. Central alpha-MSH infusion acutely activated neurons in forebrain areas such as the hypothalamic paraventricular nucleus, as measured by a 254% increase in c-Fos-like immunoreactivity (P < 0.01 vs. saline), as well as satiety pathways in the hindbrain. Our findings suggest that, although an increase of central melanocortin receptor signaling acutely reduces food intake and body weight, its anorectic potency wanes during chronic infusion and causes only a modest decrease of body weight.     

α-黑色素细胞刺激素对白细胞介素-1β发热的解热机理研究

本研究观察了α－黑色素细胞刺激素（α－ＭＳＨ）对家兔白细胞介素－１β（ＩＬ－１β）发热效应及下丘脑组织腺苷环－磷酸（ｃＡＭＰ）含量的影响;同时观察了下丘本外培养过程中,α－ＭＳＨ对ＩＬ－１β刺激下丘脑释放ｃＡＭＰ的影响。结果显示：α－ＭＳＨ能显著降低ＩＬ－１β引起的体温升高（Ｐ〈０．０５）;同时抑制下丘脑组织ｃＡＭＰ含量的增高（Ｐ〈０．０１）。ＩＬ－１β与下丘脑组织培养,其上清液的ｃＡＭＰ含量明显     

Melanocortins and opioids modulate early postnatal growth in rats

This study was undertaken to investigate the effects of melanocortins and opioids on rat early postnatal body and organ growth. Among melanocortins tested desacetyl-alpha-melanocyte-stimulating hormone (alpha-MSH) at dosages of 0.3 and 3 micrograms/g/day was effective in stimulating neonatal growth with a weight gain of 7 and 5.6%, respectively, after 2 weeks of treatment. Likewise, a weight rise of 4.2 and 3% was obtained with 3 micrograms/g/day of both alpha-MSH and Nle4-D-Phe7 alpha-MSH. As far as opioids were concerned, while N-acetyl-beta-endorphin (beta-End) was ineffective, the activity of beta-End was dependent on dosage. Indeed, newborns treated with 0.03 microgram/g/day showed a slight, but significant, increase in weight, whereas a marked decrease in growth followed treatment with 0.3 and, mainly, 3 micrograms/g/day, with a final weight loss of 3.4 and 5.5%, respectively. All melanocortins exerted a positive action on muscular and brain trophism and, in addition, desacetyl-alpha-MSH also induced a rise of fat deposits. On the contrary, while the 0.03 microgram/g/day beta-End dose caused an increase in muscular and brain weight, the higher dosages of the opioid were detrimental, not only for muscle and brain, but also for both liver and spleen weight. A slight, although significant (P < 0.05), enhancement of serum dehydroepiandrosterone sulfate (DHEAS) level was found after the injection of 0.3 microgram/g desacetyl-alpha-MSH, whereas both the 0.3 and 3 micrograms/g doses of desacetyl-alpha-MSH and the 3 micrograms/g dose of alpha-MSH determined the rise of plasma androstenedione (P < 0.05). All tested melanocortins and opioids failed to modify the concentrations of corticosterone. Our results suggest that melanocortins and opioids can modulate early postnatal growth in rats either by direct or indirect mechanisms.     

Age dependent endothelin contribution to NOC/oFQ induced impairment of NMDA cerebrovasodilation after brain injury

This study was designed to characterize the role of endothelin-1 (ET-1) in nociceptin/orphanin FQ (NOC/oFQ) induced impairment of NMDA cerebrovasodilation after fluid percussion brain injury (FPI) as a function of age in newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window. Previous studies have observed that NOC/oFQ is released into CSF and contributes to impaired NMDA induced pial artery dilation following FPI to a greater extent in newborn vs juvenile pigs. Topical ET-1 (10(-10) M), a concentration approximating that observed in CSF following FPI in the newborn, increased CSF NOC/oFQ from 67 +/- 4 to 119 +/- 7 pg/ml under non FPI conditions. CSF NOC/oFQ was elevated within 60 min of FPI (70 +/- 3 to 444 +/- 51 pg/ml) but such release was attenuated by the ET-1 antagonist BQ123 in the newborn (66 +/- 3 to 145 +/- 10 pg/ml). CSF ET-1 and NOC/oFQ were not elevated as greatly in the juvenile following FPI and BQ123 correspondingly did not attenuate CSF NOC/oFQ release as much as in the newborn. Under non injury conditions, ET-1 (10(-10) M) coadministered with NMDA attenuated pial dilation to this excitatory amino acid. Following FPI in the newborn, NMDA (10(-8), 10(-6) M) induced pial artery dilation was reversed to vasoconstriction and both NOC/oFQ and ET-1 receptor antagonists partially prevented such alterations (9 +/- 1 and 16 +/- 1, sham control; -7 +/- 1 and -12 +/- 1, FPI; -2 +/- 1 and -3 +/- 1, FPI-NOC/oFQ antagonist; and 2 +/- 1 and 5 +/- 1 %, FPI-ET-1 antagonist). NMDA induced pial dilation was only attenuated following FPI in the juvenile and modestly restored by NOC/oFQ and ET-1 receptor antagonists. These data show that ET-1, in concentrations present in CSF following FPI, contributes to the release of CSF NOC/oFQ following such an insult. The greater release of such ET-1 following FPI in the newborn contributes to the corresponding greater release of NOC/oFQ in the newborn vs the juvenile. Moreover, ET-1 also contributes to the impairment of NMDA cerebrovasodilation after brain injury to a greater extent in newborns vs juveniles. These data suggest that ET-1 contributes to NOC/oFQ induced impairment of NMDA cerebrovasodilation after brain injury in an age dependent manner.     

Parathyroid hormone-related peptide improves contractile function of stunned myocardium in rats and pigs

The effect of synthetic parathyroid hormone (PTH)-related peptide [PTHrP(1-34)] on regional myocardial function was studied in 11 anesthetized pigs. Intracoronary infusion of PTHrP (cumulative dose: 14 +/- 1 microg) decreased coronary resistance to 33 +/- 2% of baseline (P < 0.05) and regional myocardial function to 90 +/- 3% of baseline (not significant). Ischemia-reperfusion alters the activity of several kinases and therefore possibly the myocardial effects of PTHrP. In stunned myocardium, induced by 20-min ischemia and 30-min reperfusion, the dose of PTHrP reducing coronary resistance to a minimum of 29 +/- 2% was decreased to 8 +/- 2 microg (P < 0.05). Regional myocardial function was no longer decreased but increased to 132 +/- 9% (P < 0.05). The increase in regional myocardial function during PTHrP was inversely related to baseline function at 30-min reperfusion in vivo (r = 0.9) as well as in myocytes isolated from stunned pig hearts (r = 0.7). In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, blockade of endogenous PTHrP by d-Trp(12)-Tyr(34)-PTH(7-34) attenuated the recovery of left ventricular developed pressure by 30 +/- 14% (P < 0.05). Thus endogenous and exogenous PTHrP impact on the function of stunned myocardium.     

Growth hormone gene polymorphisms and growth performance traits in Duroc, Landrace and Tao-Yuan pigs

This study investigated the restriction fragment length polymorphism (RFLP) of the porcine growth hormone (pGH) gene in Duroc, Landrace, and Tao-Yuan pigs and its effects on growth performance and levels of plasma growth hormone in peripheral circulation. Genomic DNA extracted from 81 Tao-Yuan, 60 Landrace and 48 Duroc pigs were subjected to Southern blot hybridization with a pGH cDNA probe. Polymorphism was detected with the restriction enzymes TaqI and DraI. A comparison of these three breeds showed significant differences in allelic frequencies. Blood samples for radioimmunoassay (RIA) of GH were collected biweekly during the experimental period from pigs 12 to 40 weeks of age. Tao-Yuan pigs showed a mean plasma GH level (2.51 +/- 1.23 ng/mL) that was much lower than that of the Landrace (3.80 +/- 1.52 ng/mL) and Duroc (4.20 +/- 1.03 ng/mL) pigs (P < 0.05). Moreover, the Tao-Yuan pigs also showed poorer growth performance than the Landrace and the Duroc pigs both in the daily weight gain (0.37 +/- 0.06 vs. 0.67 +/- 0.05 and 0.70 +/- 0.05 kg/day, P < 0.01) and feed efficiency (3.12 +/- 0.28 vs. 2.60 +/- 0.14 and 2.52 +/- 0.12, P < 0.05). These results suggest that the growth performance trait in these pigs is highly correlated with their growth hormone genotype.     

Growth hormone secretion, serum, and cerebral spinal fluid insulin and insulin-like growth factor-I concentrations in pigs with streptozotocin-induced diabetes mellitus.

Diabetes mellitus was induced using streptozotocin in five gilts between 8 and 12 weeks of age. Gilts were maintained with exogenous insulin (INS) except during experimental periods. Four litter-mate gilts served as controls. At 9 months of age, all gilts were ovariectomized, and 30 days after ovariectomy, Experiment (Exp) 1 was conducted. Jugular vein catheters were inserted and blood samples were collected every 10 min for 8 hr. Experiment 2 was conducted when gilts were 11 months of age. Venous blood and cerebrospinal fluid (CSF) samples were collected in the absence (Phase I) or presence (Phase II) of INS therapy. In Experiment 1, plasma glucose concentrations were greater (P < 0.05) in diabetic (465 +/- 17 mg/100 ml) than in control (82 mg +/- 17 mg/100 ml) gilts, whereas serum INS was lower (P < 0.0001) in diabetic gilts (0.3 +/- 0.02 vs 0.9 +/- 0.05 ng/ml) and insulin-like growth factor-I was similar in diabetic and control gilts (32 +/- 3 vs 43 +/- 4 ng/ml, respectively). Mean serum GH concentration was 2-fold greater (P < 0.02) in diabetics (2.8 +/- 0.4 ng/ml) than in control gilts (1.2 +/- 0.2 ng/ml). Diabetic gilts exhibited a greater (P < 0.05) number of GH pulses than control gilts (3.2 +/- 0.4 vs 1.5 +/- 0.3/8 hr, respectively). In addition, GH pulse magnitude was markedly elevated (P < 0.02) in diabetic (5.8 +/- 0.4 ng/ml) compared with control gilts (3.3 +/- 0.6 ng/ml). Mean basal serum GH concentrations were greater (P < 0.07) in diabetic (2.2 +/- 0.5 ng/ml) compared with control gilts (1.0 +/- .1 ng/ml). In Experiment 2, CSF concentrations of insulin-like growth factor-I, INS, GH, and protein were similar for diabetic and control gilts in both phases. Serum GH levels were similar for diabetics and controls in Phase I, but were greater (P < 0.05) in diabetics than in controls in Phase II. CSF glucose levels were greater in diabetic than in control gilts in both the presence (P < 0.003) and absence (P < 0.0002) of INS therapy, whereas plasma glucose was greater (P < 0.003) in diabetic than in control gilts in the absence of INS, but returned to control concentrations in the presence of INS. However, serum GH levels were unchanged after INS therapy in the diabetic gilts. In conclusion, altered GH secretion in the diabetic gilt may, in part, be due to elevated CSF glucose concentrations, which may alter GH-releasing hormone and/or somatostatin secretion from the hypothalamus.     

A moderate inflammation caused by the deterioration of housing conditions modifies Trp metabolism but not Trp requirement for growth of post-weaned piglets

Deterioration of the environment in which piglets are housed after weaning induces a moderate inflammatory response and modifies tryptophan (Trp) metabolism that can, in turn, decrease Trp availability for growth. We hypothesised that a Trp supply above the current recommendations may be required to preserve Trp availability and to maximise the growth of pigs suffering from moderate inflammation. The aim of this experiment was to compare growth performance and plasma concentrations of Trp and some of its metabolites in piglets, suffering or not from moderate inflammation, when they were fed diets containing graded levels of standardised ileal digestible (SID) Trp, obtained with the addition of crystalline l-Trp to the same basal diet (15%, 18%, 21% or 24%, relative to SID lysine). Differences in inflammatory status were obtained by housing the pigs under different sanitary conditions. Forty blocks of four littermate piglets each were selected and weaned at 4 weeks of age. The experimental design consisted of a split plot where the housing conditions (moderate inflammation v. control) were used as the main plot and dietary Trp content as the subplot. Body weight gain and feed intake were recorded 3, 5 and 7 weeks after weaning. Blood was sampled 13, 36 and 43 days after weaning to measure plasma concentrations of Trp, kynurenine and nicotinamide (i.e. two metabolites of Trp catabolism) and haptoglobin, a major acute phase protein in pigs. There was no interaction between dietary Trp and inflammatory status, irrespective of the response criterion. Compared with control pigs, pigs housed in poor housing conditions consumed less feed (P < 0.0001), had a lower growth rate (P < 0.001), higher plasma concentrations of haptoglobin (P < 0.05) and lower concentrations of plasma Trp irrespective of the Trp content in the diet. Increasing the Trp content in the diet improved feed intake (P < 0.05), growth rate and feed/gain (P < 0.05), but did not prevent the deterioration of performance induced by moderate inflammation because of poor housing conditions. The results of this study suggest that an inflammatory response caused by poor housing sanitary conditions altered Trp metabolism and growth performance, but this was not prevented by additional dietary crystalline l-Trp.     

Central action of insulin regulates pulsatile luteinizing hormone secretion in the diabetic sheep model

This study tested the hypothesis that central mechanisms regulating luteinizing hormone (LH) secretion are responsive to insulin. Our approach was to infuse insulin into the lateral ventricle of six streptozotocin-induced diabetic sheep in an amount that is normally present in the CSF when LH secretion is maintained by peripheral insulin administration. In the first experiment, we monitored cerebrospinal fluid (CSF) insulin concentrations every 3-5 h in four diabetic sheep given insulin by peripheral injection (30 IU). The insulin concentration in the CSF was increased after insulin injection, and there was a positive relationship between CSF and plasma concentrations of insulin (r = 0.80, P < 0.01). In the second experiment, peripheral insulin administration was discontinued, and the sheep received either an intracerebroventricular (i.c.v.) infusion of insulin (12 mU/day in 2.4 ml saline) or saline (2.4 ml/day) for 5 days (n = 6) in a crossover design. The dose of insulin (i.c.v.) was calculated to approximate the increase in CSF insulin concentration found after peripheral insulin treatment. To monitor LH secretory patterns, blood samples were collected by jugular venipuncture at 10-min intervals for 4 h on the day before and 5 days after the start of i.c.v. insulin infusion. To monitor the increase in CSF insulin concentrations, a single CSF sample was collected one and four days after the start of the central infusion. The i.c.v. insulin infusion increased CSF insulin concentrations above those in saline-treated animals (P < 0.05) and maintained them at or above the peak levels achieved after peripheral insulin treatment. Central insulin infusion did not affect peripheral (plasma) insulin or glucose concentrations. LH pulse frequency in insulin-treated animals was greater than that in saline-treated animals (3.5 +/- 0.2 vs. 2.3 +/- 0.3 pulses/4 h, P < 0.01), but it was less than that during peripheral insulin treatment (4.8 +/- 0.2 pulses/4 h, P < 0.01). Our findings suggest that physiologic levels of central insulin supplementation are able to increase pulsatile LH secretion in diabetic sheep with low peripheral insulin. These results are consistent with the notion that central insulin plays a role in regulating pulsatile GnRH secretion.     

Quantification of the permeability of the blood-CSF barrier to alpha-MSH in the rat

The ability of alpha-MSH to cross the blood-CSF barrier of the rat was assessed by measurement of the rate of appearance of immunoreactive alpha-MSH in a cerebrospinal fluid (CSF) perfusate following intravenous injection of peptide. Comparisons were made with the rate of appearance of a simultaneously administered dose of 14C-inulin which is poorly permeable at the blood-CSF barrier. Concentrations of drugs measured in plasma were fitted to two-compartment pharmacokinetic models, and those measured in the CSF perfusate to one-compartment open systems receiving an input from the plasma compartment. The rate constant for entry of alpha-MSH into CSF was 0.00087 min-1, which was not significantly different from that for inulin of 0.00055 min-1. As alpha-MSH penetrated into CSF at a rate comparable to inulin, it was concluded that the limited entry of peptide was by aqueous diffusion along with other water-soluble macromolecules.     

Independent changes of thyroid hormones in blood plasma and cerebrospinal fluid after melatonin treatment in ewes

The authors measured the effects of exogenous melatonin treatment on the concentrations of total (T) and free (f) fractions of thyroxine (T4) and triiodothyronine (T3) in cerebrospinal fluid (CSF) and blood plasma as well as the expression of their binding/transporter protein, transthyretin (TTR), in the choroid plexus of ewes from May to August. Melatonin implantation in May and July mainly prevented the decrease in plasma for fT3 and TT3 exhibited in untreated group, and induced a limited decrease in TT4 in June. By contrast, melatonin implantation prevented the decrease in CSF fT3 observed in the untreated group. No effect of melatonin was found on the expression of TTR mRNA in the choroid plexus There were a correlations between blood fT4 and CSF TT4 concentrations in both control and melatonin treated group (r²−0.4; P < 0.01 vs. r²−0.14; P < 0.05), as well as between blood fT3 and CSF TT3 concentrations but only in the melatonin-treated group (r²−0.26; P < 0.02). We conclude that T3, the active form of the hormone within the brain, is regulated by melatonin independently of the peripheral changes within the blood. The lack of correlation between plasma fT3 and CSF TT3 in the control group suggests that an increase in local T3 conversion could contribute as an additional source of T3 in the CSF during the period of increasing day length. These data seem to confirm a local nature for recently discovered connections between the pineal melatonin signal and thyroid-dependent seasonal biology in mammals.     

Indomethacin reversal of ethanol-induced suppression of ovine fetal breathing movements and relationship to prostaglandin E2

The effects of indomethacin on the ethanol-induced suppression of fetal breathing movements and fetal arterial plasma and cerebrospinal fluid (CSF) PGE2 concentrations and maternal arterial plasma PGE2 concentration were determined in the near-term fetal lamb. Eight conscious instrumented pregnant ewes (between 130 and 133 days of gestation; term, 147 days) received 1-h maternal intravenous infusion of 1 g ethanol/kg total body weight, and the fetus received 6-h intravenous infusion of indomethacin (1 mg/h per kg fetal body weight) commencing 30 min later. Serial fetal and maternal arterial blood samples (n = 8) and fetal CSF samples (n = 5) were collected at selected times throughout the 12-h study for the determination of PGE2 concentration. Fetal breathing movements were monitored continuously throughout the experimental period. Maternal ethanol infusion resulted in initial suppression (P less than 0.05) of fetal breathing movements for 2 h below pretreatment value, followed by a rapid increase in the incidence of fetal breathing movements after the onset of fetal indomethacin treatment. Fetal and maternal plasma PGE2 concentrations and fetal CSF PGE2 concentration were increased (P less than 0.05) above the pre-infusion value during the administration of ethanol and 1 h thereafter. Fetal indomethacin treatment suppressed (P less than 0.05) to undetectable levels fetal plasma and CSF PGE2 concentrations, which then became similar (P greater than 0.05) to pretreatment by 12 h. There was a positive correlation between fetal plasma and CSF PGE2 concentrations. There was an inverse correlation between the incidence of fetal breathing movements and fetal CSF PGE2 concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is tryptophan catabolism increased under indoleamine 2,3 dioxygenase activity during chronic lung inflammation in pigs?

In a preliminary study we observed that piglets suffering from chronic lung inflammation induced by an intravenous injection of complete Freund adjuvant showed a marked decrease in plasma tryptophan (Trp) concentration suggesting increased Trp utilisation. During the inflammatory process, a cytokine-induced enzyme called indoleamine 2,3-dioxygenase (IDO) has been shown to catabolise Trp into kynurenine (Kyn). Yet, during inflammation, increased Trp catabolism may decrease Trp availability for other functions such as growth. This metabolic pathway has never been studied in pigs. So, the objectives of this study were to measure IDO activity in pigs and to determine if the decrease in plasma Trp concentrations previously observed in piglets suffering from chronic lung inflammation could be explained by the induction of IDO activity. In order to do so, we compared IDO activity measured in the tracheo-bronchial lymph nodes and in the lungs of 7 piglets, injected with complete Freund adjuvant (CFA), to 7 pair-fed littermate healthy controls. Blood samples were taken at 0, 2, 5, 7 and 10 days following CFA injection in order to measure plasma Trp, Kyn and haptoglobin concentrations. Indoleamine 2,3-dioygenase activity in the tracheo-bronchial lymph nodes (P < 0.05), in the lungs (P < 0.07) and plasma haptoglobin (P < 0.01) were higher in pigs with lung inflammation than in the controls. Plasma Trp and Kyn were not significantly affected by CFA injection. Our data showed that IDO is activated under chronic lung inflammation in pigs. The impact of IDO activation on plasma Trp concentration and its availability is discussed according to the amount of Trp provided by the diet.     

The obese Göttingen minipig as a model of the metabolic syndrome: dietary effects on obesity, insulin sensitivity, and growth hormone profile

The objective of the study reported here was to induce obesity in the female G?ttingen minipig to establish a model of the human metabolic syndrome. Nine- to ten-month-old female G?ttingen minipigs received a high-fat high-energy (HFE) diet or a low-fat, low-energy (LFE) diet. The energy contents derived from fat were 55 and 13 %, respectively. After 5 weeks, animals were subjected to dual energy x-ray absorptiometry (DEXA) scanning, intravenous glucose tolerance testing (IVGTT), and 6-h growth hormone profile recording. After treatment, mean body weight of pigs of the LFE group was 21.0 +/- 0.4 kg, and was 26.8 +/- 0.2 kg in pigs of the HFE group (P < 0.0001). The DEXA scanning indicated that the fat content of the LFE group was 10.0 +/- 1.2 % versus 15.2 +/- 0.7 % in the HFE group (P < 0.003). Triglycerides concentration was significantly (P < 0.05) increased in pigs of the HFE group (0.24 +/- 0.03 mM), compared with that in pigs of the LFE group (0.13 +/- 0.04 mM). Preprandial plasma glucose and insulin concentrations were not affected, but insulin area under the curve during IVGTT was significantly high in the obese animals. Growth hormone (GH) secretion was low in both groups of pigs. The obese minipig shares some of the metabolic impairments seen in obese humans, and may thus serve as a model of the metabolic syndrome.     

Thymic regulation of primate fetal ovarian-adrenal differentiation

We report that fetal thymectomy inhibits oogenesis and induces abnormal ovarian differentiation in rhesus monkeys. In utero thymectomy (n = 5) elevated plasma follicle-stimulating hormone (7.8 +/- 1.1 microgram/ml vs. 4.2 +/- 0.5 microgram/ml; P less than 0.05) and decreased plasma prolactin (24.5 +/- 3.3 ng/ml vs. 76.3 +/- 11.2 ng/ml; P less than 0.05) concentrations compared with intact controls (n = 12), but did not change plasma luteinizing hormone, estradiol, cortisol, dehydroepiandrosterone sulfate, or thymosin-alpha 1 concentrations. In utero thymectomy reduced the weight of neonatal ovaries and adrenal glands, but not hepatic, renal, splenic, or total body weights. After fetal thymectomy, newborn ovaries (n = 8) contained a reduced total number of germ cells (123,926 +/- 11,651 vs. 432,034 +/- 40,311; P less than 0.001). The percentages of individual germ cell types were similar between thymectomized and intact groups (n = 11) except for an increased percentage of preantral-antral follicles in the thymectomy group (P less than 0.01). Our results indicate that the primate fetal thymus regulates antenatal ovarian follicular development, perhaps by interactions between the nascent immunologic and pituitary-ovarian systems.     

Changes in hypothalamic agouti-related protein (AGRP), but not alpha-MSH or pro-opiomelanocortin concentrations in dietary-obese and food-restricted rats.

Melanocortin-4 receptor (MC4-R) density is thought to be regulated by synaptic availability of endogenous agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), and also by agouti-related protein (AGRP), which acts as a competitive antagonist. As hypothalamic MC4-R have been implicated in the regulation of energy balance, we examined concentrations of alpha-MSH and AGRP in hypothalami of dietary-obese and food-restricted rats. In dietary-obese rats, AGRP concentrations were significantly increased by 43% (p < 0.01) above lean controls, whereas a 91% (p < 0.01) reduction was observed in food-restricted rats. Surprisingly, hypothalamic concentrations of alpha-MSH and its precursor peptide, pro-opiomelanocortin (POMC), did not differ significantly from controls in either model. In conclusion, we suggest that MC4-R activity may not be regulated by changes in agonist (alpha-MSH) but by changes in the antagonist (AGRP) availability, which may modulate background activation of the receptor by tonic alpha-MSH release. AGRP may be an important modulator of feeding behaviour.     

Pituitary-adrenocortical and lymphocyte responses to bromocriptine-induced hypoprolactinemia, adrenocorticotropic hormone, and restraint in swine

A study was conducted with castrated male pigs (barrows) to evaluate effects of bromocriptine-induced hypoprolactinemia (6 days) on basal and adrenocorticotropic hormone (ACTH)-altered (single injection) pituitary-adrenocortical function, on lymphocyte proliferative responses, and on interleukin 2 production. In addition, the study was designed to measure the short time course of pituitary-adrenocortical and lymphocyte responses to ACTH and to a 30-min restraint stressor. Blood samples were taken via indwelling jugular catheters at -0.5, +0.5, +2, and +5 hr (with reference to time of acute treatment exposure) on Day 6 of the study. Lymphocyte responses were measured only at the 2-hr interval. Exposure (6 days) to bromocriptine (CB154) was associated with 53% reductions (P less than 0.05) in plasma prolactin (1.37 +/- 0.13 vs 0.60 +/- 0.04 vs 0.68 +/- 0.08 ng/ml) when averaged across all time intervals in control, CB154-treated, and CB154 + ACTH-treated pigs, respectively. The reductions in plasma prolactin were associated with a reduction (P less than 0.05) in basal plasma cortisol at only one time interval (+0.5 hr) when CB154-treated pigs were compared with controls (17.7 +/- 4.2 vs 26.9 +/- 3.2 ng/ml). CB154 had no effect on plasma ACTH or growth hormone concentrations for the time periods at which they were measured. CB154 treatment produced numerical, but not statistically significant, 38% reductions in interleukin 2 production (6.31 +/- 1.8 vs 3.91 +/- 1.47 units/ml). Lymphocyte proliferative responses to the mitogen concanavalin A and interleukin 2 production decreased 65 and 75% (P less than 0.05), respectively, 2 hr subsequent to ACTH administration when compared with control animals. Hence, under the conditions of this study, only a modest association between lowered plasma prolactin concentrations and basal cortisol concentrations was evident. The data suggest the absence of dopamine regulation of basal plasma ACTH in pigs and provide evidence for a rapidly occurring inhibitory effect of ACTH administration on specific lymphocyte activities.     

Evaluation of chronic immune system stimulation models in growing pigs

Two experiments (EXPs) were conducted to evaluate models of immune system stimulation (ISS) that can be used in nutrient metabolism studies in growing pigs. In EXP I, the pig's immune response to three non-pathogenic immunogens was evaluated, whereas in EXP II the pig's more general response to one of the immunogens was contrasted with observations on non-ISS pigs. In EXP I, nine growing barrows were fitted with a jugular catheter, and after recovery assigned to one of three treatments. Three immunogens were tested during a 10-day ISS period: (i) repeated injection of increasing amounts of Escherichia coli lipopolysaccharide (LPS); (ii) repeated subcutaneous injection of turpentine (TURP); and (iii) feeding grains naturally contaminated with mycotoxins (MYCO). In EXP II, 36 growing barrows were injected repeatedly with either saline (n = 12) or increasing amounts of LPS (n = 24) for 7 days (initial dose 60 μg/kg body weight). Treating pigs with TURP and LPS reduced feed intake (P < 0.02), whereas feed intake was not reduced in pigs on MYCO. Average daily gain (ADG; kg/day) of pigs on LPS (0.50) was higher than that of pigs on TURP (0.19), but lower than that of pigs on MYCO (0.61; P < 0.01). Body temperature was elevated in pigs on LPS and TURP, by 0.8°C and 0.7°C, respectively, relative to pre-ISS challenge values (39.3°C; P < 0.02), but remained unchanged in pigs on MYCO. Plasma concentrations of interleukin-1β were increased in pigs treated with LPS and TURP (56% and 55%, respectively, relative to 22.3 pg/ml for pre-ISS; P < 0.01), but not in MYCO-treated pigs. Plasma cortisol concentrations remained unchanged for pigs on MYCO and TURP, but were reduced in LPS-treated pigs (30% relative to 29.8 ng/ml for pre-ISS; P < 0.05). Red blood cell glutathione concentrations were lower in TURP-treated pigs (13% relative to 1.38 μM for pre-ISS; P < 0.05), but were unaffected in pigs on LPS and MYCO. In EXP I, TURP caused severe responses including skin ulceration and substantial reductions in feed intake and ADG, whereas MYCO did not induce effective ISS. In EXP II, ISS increased relative organ weights, eye temperature, white blood cell count and plasma acute-phase proteins (P < 0.05), confirming that repeated injection with increasing amounts of LPS induced chronic and relatively mild ISS. Repeated injection with increasing amounts of LPS is a suitable model for studying nutrient metabolism and evaluating the efficacy of nutritional intervention during chronic ISS in growing pigs.     

Alpha-melanocyte stimulating hormone increases plasma levels of glucagon and insulin in rabbits

Intravenous injections of 25 and 2.5 micrograms alpha-melanocyte stimulating hormone (alpha-MSH) increased plasma levels of glucagon, insulin and free fatty acids in fasted and fed rabbits. 45 micrograms beta-melanocyte stimulating hormone (beta-MSH) had similar effects, whereas 22 micrograms gamma-2-melanocyte stimulating hormone (gamma-MSH) was inactive. The alpha-MSH-induced increases in the plasma levels of glucagon, insulin and free fatty acids were not inhibited by alpha- or beta-adrenergic blocking drugs. The alpha-MSH-induced increases in the plasma levels of insulin were, however, augmented by phentolamine (an alpha-adrenergic receptor blocking drug). The plasma levels of glucose were increased by 25 micrograms alpha-MSH in fed rabbits, only, and were decreased by alpha-MSH during alpha-receptor blockade. The acute in vivo effects of alpha-MSH and beta-MSH on the plasma levels of glucagon, insulin and free fatty acids were rather similar to those previously reported for corticotropin (ACTH). It is possible that the 4-10 ACTH sequence, present in alpha-MSH, beta-MSH and ACTH, but not in gamma-MSH, is a message sequence for the observed effects. However, ORG 2766, a 4-9 ACTH analogue, was inactive. The mechanism by which alpha-MSH increased the plasma levels of glucagon and insulin in rabbits remains to be determined. It is possible, that the effects were mediated by both a central nervous action and a direct action on the endocrine pancreas.