bluuebunny/crossref_metadata_2025 huggingface dataset:
Leucine metabolism in chronically hypoglycemic hypoinsulinemic growth-restricted fetal sheep
Authors: Carver T. D. , Quick A. A. , Teng C. C. , Pike A. W. , Fennessey P. V. , Hay W. W.
Published: December 2017

We measured leucine flux rates during infusions of L-[1-14C]- and L-[1-1C]leucine in fetal sheep exposed to maternal insulin-induced hypoglycemia over the last 8 wk (40%) of gestation to determine effects of chronic glucose deficiency and hypoglycemia on fetal leucine metabolism. Compared with control fetuses (C, n = 5), hypoglycemic fetuses (HG, n = 8) weighed less (C, 3.43 +/- 0.07 kg; HG, 2.32 +/- 0.24 kg), had lower plasma glucose (C, 1.04 +/- 0.02 mM; HG, 0.59 +/- 0.01 mM), insulin (C, 48 +/- 6 pM; HG, 12 +/- 6 pM), and leucine concentrations (C, 195.6 +/- 8.3 microM; HG, 140.8 +/- 15.0 microM), lower rates of net leucine uptake (C, 4.2 +/- 0.6 mumol.min-1.kg-1; HG, 2.1 +/- 0.4 mumol.min-1.kg-1) and leucine flux into protein accretion (C, 2.8 +/- 0.2 mumol.min-1.kg-1; HG, 0.6 +/- 0.1 mumol.min-1.kg-1), and an increased rate of leucine release from protein breakdown (C, 1.1 +/- 0.1 mumol.min-1.kg-1; HG, 3.3 +/- 0.2 mumol.min-1.kg-1) (P < 0.05 for all). Plasma leucine disposal, flux into protein synthesis, and oxidation were not different between groups. We conclude that adaptations of fetal leucine metabolism to long-term hypoglycemia and decreased glucose apply represent diminished leucine uptake and increased leucine release from protein breakdown, which are associated with decreased incorporation of leucine into protein accretion and a slower rate of fetal growth.
Contraction-induced intracellular signals and their relationship to muscle GLUT-4 concentration
Authors: Yaspelkis B. B. , Castle A. L. , Farrar R. P. , Ivy J. L.
Published: December 2017

This investigation used a model of increased skeletal muscle contractile activity to evaluate whether the adenylate cyclase-adenosine 3',5'-cyclic monophosphate (cAMP) pathway and/or the high-energy phosphate state of the muscle might be temporally related to the contraction-induced increase in skeletal muscle GLUT-4 protein concentration. Plantaris and gastrocnemius muscles of Sprague-Dawley rats were subjected to 3, 7, 14, or 28 days of chronic low-frequency electrical stimulation (10 Hz, 24 h/day). GLUT-4 protein concentration was slightly reduced after 3 days of electrical stimulation, similar to control values at 7 days and significantly elevated above control at 14 days (53%, P < 0.05) and 28 days (338%, P < 0.05) of stimulation. ATP, creatine phosphate, creatine, and P, were inversely related to GLUT-4 protein concentration. Adenylate cyclase activity increased with electrical stimulation and was significantly related to the increased GLUT-4 protein. cAMP was significantly increased at 14 days of stimulation and remained elevated through 28 days. These results demonstrate that both the adenylate cyclase-cAMP pathway and the high-energy phosphate state of the muscle are temporally related to elevations in skeletal muscle GLUT-4 protein concentration in response to chronic low-frequency electrical stimulation and, as such, suggest that both may comprise a component of the intracellular signal that regulates the contraction-induced increase in skeletal muscle GLUT-4 protein concentration.
Effects of dihydropyridines on aldosterone secretion in adrenal capsule preparations from pregnant rats
Authors: Brochu M. , Picard S. , Jodoin S. , St-Louis J.
Published: December 2017

The primary aim of this study was to determine when sensitivity in the aldosterone response to extracellular potassium (K+) decreases during pregnancy. Second, it tested the hypothesis that calcium channel alterations occur in the adrenal cortex during pregnancy. The decreased sensitivity to K+, observed at 22 days of gestation, was not evident at 15 days and between 18 and 36 h postpartum. Increases in extracellular calcium concentration heightened sensitivity to K+ in adrenal capsule preparations derived from nonpregnant rats but had no effect in pregnant animals. The influence of nifedipine and BAY K 8644 (blocker and activator, respectively, of voltage-operated calcium channels) on the aldosterone response to K+ and to adrenocorticotropic hormone (ACTH) was studied. Sensitivity to K+ in nonpregnant rats decreased in the presence of nifedipine and became similar to that in pregnant rats. Responses to ACTH were not affected by nifedipine. BAY K 8644 produced a larger increase in sensitivity in adrenal capsule preparations from pregnant than from nonpregnant rats, leading to superposition of the two dose-response curves to K+. These results indicate that voltage-operated calcium channels involved in aldosterone secretion are functionally impaired during pregnancy.
Effect of oxidant challenge on contractile function of the aging rat diaphragm
Authors: Lawler J. M. , Cline C. C. , Hu Z. , Coast J. R.
Published: December 2017

Although controversial, growing evidence indicates that reactive oxygen species (ROS) alter contractions of skeletal muscle, including the diaphragm. However, the impact of ROS on contractility of the aging diaphragm is unknown. The xanthine oxidase (0.01 U/ml) system was used as an ROS generator, imposing an oxidant challenge. Contractile function [twitch tension; twitch time to peak tension; twitch one-half relaxation time; tension at 10 and 20 Hz; maximal tetanic tension (Po) at 100 Hz] of costal diaphragm fiber bundles from young (4 mo) and old (25 mo) Fischer 344 rats was examined in vitro before and after treatment with control Krebs solution [young control (YC) and old control (OC)], or with xanthine oxidase (XO; 0.01 U/ml) plus hypoxanthine (0.29 mg/ml) substrate [young XO treated (YXO) and old XO treated (OXO)]. Contractile function of fiber bundles was reassessed after oxidant challenge in an unfatigued state (Post-u) or 10 min after a fatiguing stimulation protocol (Post-f). Oxidant challenge in the unfatigued fiber bundles increased twitch tension and tension at 10 and 20 Hz in YXO, but not OXO, without increasing Po. Conversely, XO significantly depressed fatigued diaphragm twitch and low-frequency tension in both OXO and YXO, compared with controls. Po was depressed Post-f in OXO but not YXO. Oxidant challenge also increased twitch one-half relaxation time of the fatigued diaphragm in both age groups. Furthermore, fiber bundles from old rats suffered greater fatigue during the stimulation protocol. We conclude that the response to oxidant challenge and increased contractile demand is impaired in the aging diaphragm.
IGF-binding protein-2 is induced during development of urinary bladder hypertrophy in the diabetic rat
Authors: Chen Y. , Gustafsson B. , Arnqvist H. J.
Published: December 2017

Because the locally produced insulin-like growth factor-binding proteins (IGFBP) may influence bladder hypertrophy, either directly or by their interaction with insulin-like growth factor I (IGF-I), we studied the IGF system during the development of urinary bladder hypertrophy in rats with streptozotocin-induced diabetes. Messenger RNA for IGF-I, IGFBP-2, and IGFBP-4 was determined by solution hybridization. The bladder wet weight was elevated after 7 days. DNA synthesis was increased and peaked at 2 days, whereas DNA content per bladder wet weight was decreased by 7 days. The IGF-I mRNA did not change during the first 7 days and then decreased, and IGFBP-4 mRNA was increased transiently on day 7. On the other hand, IGFBP-2 mRNA was significantly increased after 1 day (2-fold), peaked by 7 days (6.4-fold), and then declined to approximately 50% above control at the end of experiment. This was associated with an increased IGFBP-2 protein content. Our results suggest that both stretching of the bladder due to diuresis and the diabetic state contribute to changes of the IGF system in the hypertrophying bladder.
Discordance of prolactin gene transcription, mRNA storage, and hormone release in individual mammotropes
Authors: Castano J. P. , Faught W. J. , Glave E. E. , Russell B. S. , Frawley L. S.
Published: December 2017

The mammotrope has traditionally been a favored model for studies of hormonal gene expression, biosynthesis, and release. However, the primary site(s) at which these processes are coordinated and integrated remains to be established. Because there is considerable indirect evidence to suggest that the rate of prolactin (PRL) secretion is dictated, in large part, at the level of transcription, the relative contribution of other putative regulatory foci has received less attention. The purpose of the present study was to test the primacy of transcriptional regulation at the single-cell level. To this end, we quantified within individual mammotropes the relationship between PRL gene transcription, mRNA storage, and hormone release. This was accomplished by the combined application of "real-time" measurement of gene expression, in situ hybridization cytochemistry, and reverse hemolytic plaque assay, respectively. Our results demonstrate a quantitative dissociation among these variables, suggesting that control mechanisms besides transcription play a primary role in integrating and coordinating flow through the PRL secretory pathway.
Acute exercise attenuates age-associated resistance to insulin-like growth factor I
Authors: Willis P. E. , Chadan S. , Baracos V. , Parkhouse W. S.
Published: December 2017

This study examined the influence of acute exercise on the ability of insulin-like growth factor I (IGF-I) to stimulate protein synthesis in an isolated in vitro soleus muscle preparation in female C57Bl/6 mice aged 5, 12, and 24 mo. Gastrocnemius muscles were analyzed for IGF-I receptor mRNA levels, IGF-I receptor number, and IGF-I receptor binding capacities and affinity constants. IGF-I (20 nM) was unable to stimulate rates of protein synthesis in the 12- and 24-mo-old control animals. These animals demonstrated declines in IGF-I receptor protein. After acute exercise, IGF-I receptor mRNA was elevated, IGF-I receptor protein levels were unaffected, and rates of protein synthesis were stimulated by IGF-I in the 12- and 24-mo-old animals. Acute exercise significantly increased IGF-I receptor binding capacity and affinity constants in the 24- but not the 12-mo-old animals. We conclude that acute exercise can restore the action of IGF-I in aged muscle, potentially by increasing the IGF-I receptor binding capacity and affinity or as a result of factors downstream of the IGF-I receptor.
Preclinical screening of the applicability of strontium as a marker for intestinal calcium absorption
Authors: Sips A. J. , Barto R. , Netelenbos J. C. , van der Vijgh W. J.
Published: December 2017

The applicability of stable strontium as a marker for measuring intestinal calcium absorption is mainly dependent on the validity of the assumption that calcium and strontium are absorbed with a constant ratio. Up to now, it is not clear whether this ratio is affected by intervention therapy. Therefore, preclinical screening of this ratio before and after treatment is indispensable for a clinical calcium absorption test based on the use of stable strontium as a marker. We studied the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D(3)], a potent enhancer of active intestinal calcium absorption, on the pharmacokinetics of both calcium-45 and strontium in adult male rats, in a short-term dose-finding study [0-50 ng 1,25(OH)2D(3)/100 g body weight] and also in a placebo-controlled study in which 12.5 ng 1,25(OH)2D(3)/100 g body weight were applied to assess the long-term pharmacokinetics. The mean bioavailability (true absorption) was 33% for calcium and 19% for strontium (ratio 1.7:1), whereas, after 1,25(OH)2D(3) pretreatment, it was 73 and 43% (ratio 1.7:1), respectively. These findings demonstrate that intestinal strontium absorption has, like intestinal calcium absorption, an active component. Moreover, they underscore the applicability of stable strontium as a tool for investigating calcium absorption under various conditions.
A mathematical model of diurnal variations in human plasma melatonin levels
Authors: Brown E. N. , Choe Y. , Shanahan T. L. , Czeisler C. A.
Published: December 2017

Studies in animals and humans suggest that the diurnal pattern in plasma melatonin levels is due to the hormone's rates of synthesis, circulatory infusion and clearance, circadian control of synthesis onset and offset, environmental lighting conditions, and error in the melatonin immunoassay. A two-dimensional linear differential equation model of the hormone is formulated and is used to analyze plasma melatonin levels in 18 normal healthy male subjects during a constant routine. Recently developed Bayesian statistical procedures are used to incorporate correctly the magnitude of the immunoassay error into the analysis. The estimated parameters [median (range)] were clearance half-life of 23.67 (14.79-59.93) min, synthesis onset time of 2206 (1940-0029), synthesis offset time of 0621 (0246-0817), and maximum N-acetyltransferase activity of 7.17(2.34-17.93) pmol x l(-1) x min(-1). All were in good agreement with values from previous reports. The difference between synthesis offset time and the phase of the core temperature minimum was 1 h 15 min (-4 h 38 min-2 h 43 min). The correlation between synthesis onset and the dim light melatonin onset was 0.93. Our model provides a more physiologically plausible estimate of the melatonin synthesis onset time than that given by the dim light melatonin onset and the first reliable means of estimating the phase of synthesis offset. Our analysis shows that the circadian and pharmacokinetics parameters of melatonin can be reliably estimated from a single model.
Glucose-fatty acid interactions in prepubertal and pubertal children: effects of lipid infusion
Authors: Arslanian S. , Suprasongsin C.
Published: December 2017

This investigation examined whether puberty differs from prepuberty in regard to the effects of increased free fatty acid (FFA) on in vivo glucose metabolism. Nine prepubertal and 13 pubertal healthy children were studied. Each subject was studied twice, once with 0.9% sodium chloride solution (control study) and once with 20% Intralipid infusion in the basal state and during a 3-h hyperinsulinemic-euglycemic clamp, with [6,6-2H2]glucose tracer. During control studies, prepubertal children had lower basal fat oxidation and higher insulin-mediated glucose disposal than pubertal adolescents. During Intralipid infusion, basal glucose uptake increased in prepubertal children but did not change in pubertal adolescents. Insulin-stimulated whole body glucose disposal did not change in prepubertal children (control 77.6 +/- 8.9, Intralipid 84.5 +/- 13.3 micromol x kg(-1) x min(-1)) but decreased in pubertal adolescents (control 55.0 +/- 3.6, Intralipid 46.7 +/- 3.4 micromol x kg(-1) x min(-1), P = 0.01) despite comparable decrements in glucose oxidaion. We conclude that in prepubertal children lipids exert effects in the basal state by stimulating hepatic glucose production and glucose disposal, whereas in pubertal adolescents they induce peripheral tissue insulin resistance by decreasing insulin-stimulated glucose uptake. This differential response could be due to developmental-maturational changes in tissue sensitivity and/or specificity to the glucose-FFA interaction.
Gender-dependent effects of exercise training on serum leptin levels in humans
Authors: Hickey M. S. , Houmard J. A. , Considine R. V. , Tyndall G. L. , Midgette J. B. , Gavigan K. E. , Weidner M. L. , McCammon M. R. , Israel R. G. , Caro J. F.
Published: December 2017

Leptin, the product of the ob gene, is elevated in obese humans and appears to be closely related to body fat content. The purpose of the present investigation was to determine the effect of aerobic exercise training on systemic leptin levels in humans. Eighteen sedentary middle-aged men (n = 9) and women (n = 9) who did not differ in aerobic capacity (29.4 +/- 1.2 vs. 27.5 +/- 1.2 ml x kg(-1) x min(-1)) or insulin sensitivity index (3.41 +/- 1.12 vs. 4.88 +/- 0.55) were studied. Fat mass was significantly lower in females vs. males (21.83 +/- 2.25 vs. 26.99 +/- 2.37 kg, P < 0.05). Despite this, fasting serum leptin was significantly higher in the females vs. males (18.27 +/- 2.55 vs. 9.88 +/- 1.26 ng/ml, P < 0.05). Serum leptin concentration decreased 17.5% in females (P < 0.05) after 12 wk of aerobic exercise training (4 day/wk, 30-45 min/day) but was not significantly reduced in males. Fat mass was not altered after training in either group. In contrast, both aerobic capacity (+13% males, +9.1% females) and insulin sensitivity (+35% males, +82% females) were significantly improved subsequent to training. These data suggest that 1) women have higher circulating leptin concentrations despite lower fat mass and 2) exercise training appears to have a greater effect on systemic leptin levels in females than in males.
Anti-TNF treatment does not reverse the abnormalities in lipid metabolism of the obese Zucker rat
Authors: Lopez-Soriano J. , Lopez-Soriano F. J. , Bagby G. J. , Williamson D. H. , Argiles J. M.
Published: December 2017

Because obesity, insulin resistance, and hyperlipidemia are often associated, and recent evidence suggests that the cytokine tumor necrosis factor-alpha (TNF) may influence the activity of insulin in various target tissues, the present study was designed to see whether TNF was also associated with the changes in lipid metabolism that lead to hyperlipidemia in the obese model of the Zucker rat. A polyclonal goat anti-rat TNF antibody was subcutaneously administered to Zucker rats for 4 days to block TNF actions. The results indicate that none of the alterations in lipid metabolism seen in the obese animals were reversed by the anti-TNF treatment. This was the case for the lipogenic rate in liver and adipose tissue, the disposal of an exogenous [14C]triolein load, adipose tissue lipoprotein lipase activity, and the hypertriglyceridemia. Measurements of lipolysis in adipose tissue slices from the anti-TNF-treated animals also did not show any significant effect of the treatment. In conclusion, TNF does not seem to be involved in the abnormalities of lipid metabolism observed in the obese Zucker rat.
Fetal sheep endocrine responses to sustained hypoxemic stress after chronic fetal placental embolization
Authors: Gagnon R. , Murotsuki J. , Challis J. R. , Fraher L. , Richardson B. S.
Published: December 2017

The purpose of this study was to determine the endocrine and circulatory responses of the ovine fetus, near term, to sustained hypoxemic stress superimposed on chronic hypoxemia. Fetal sheep were chronically embolized (n = 7) for 10 days between 0.84 and 0.91 of gestation via the descending aorta until arterial oxygen content was decreased by approximately 30%. Control animals (n = 8) received saline only. On experimental day 10, both groups were embolized over a 6-h period until fetal arterial pH decreased to approximately 7.00. Regional distribution of lower body blood flows was measured on day 10, before and at the end of acute embolization. On day 10, the chronically embolized group had lower arterial oxygen content (P < 0.05), Po2 (P < 0.01), and placental blood flow (P < 0.05) than controls and higher prostaglandin E2 (PGE2) and norepinephrine plasma concentrations (both P < 0.05). In response to a superimposed sustained hypoxemic stress, there was a twofold greater increase in PGE2 in the chronically embolized group than in the control group (P < 0.05). However, the increase in fetal plasma cortisol in response to superimposed hypoxemic stress was similar in both groups, despite significantly lower adrenocorticotropic hormone and adrenal cortex blood flow responses in the chronically hypoxemic group (both P < 0.05). We conclude that PGE2 response to a sustained superimposed reduction in placental blood flow, leading to metabolic acidosis, is enhanced under conditions of chronic hypoxemia and may play an important role for the maintenance of the fetal cortisol response to an episode of superimposed acute stress.
Postprandial stimulation of muscle protein synthesis is independent of changes in insulin
Authors: Svanberg E. , Jefferson L. S. , Lundholm K. , Kimball S. R.
Published: December 2017

Protein synthesis in skeletal muscle is markedly stimulated (approximately 180% of control rate) within 3 h of oral feeding in mice subjected to an overnight fast (18 h). The stimulation of protein synthesis is the result of a faster rate of translation initiation; however, neither the mediators (i.e., hormones or nutrients) nor the mechanisms responsible for the effect of feeding are well understood. Results of the present study revealed that the amount of eukaryotic initiation factor 4E (eIF-4E) present in the phosphorylated form (i.e., 70%) was not changed after overnight starvation or a subsequent 3-h refeeding period compared with muscles from freely fed mice. In contrast, the phosphorylation state of the eIF-4E binding protein 1 (4E-BP1) was changed with nutritional state. Starvation increased the proportion of the unphosphorylated form of 4E-BP1, whereas feeding promoted a shift to the more highly phosphorylated forms of the protein. Moreover, starvation increased the amount of 4E-BP1 recovered by almost threefold, indicative of an increase in the eIF-4E.4E-BP1 complex. The increased association of 4E-BP1 with eIF-4E was completely reversed within 3 h of feeding. Starvation and refeeding also altered the amount of eIF-4G that coimmunoprecipitated with eIF-4E. However, in contrast to the results obtained for 4E-BP1, starvation decreased the amount of eIF-4G recovered in the eIF-4E immunoprecipitate, suggesting that starvation causes a decrease in the formation of the active eIF-4F complex. The alterations in 4E-BP1 phosphorylation and association of 4E-BP1 and eIF-4G with eIF-4E observed in control mice in response to starvation and refeeding were also observed in diabetic mice exhibiting characteristics of type I or type II diabetes subjected to the same conditions, suggesting that insulin alone does not mediate the observed changes. Thus the integrated feeding response represents an important area of investigation for understanding the regulation of translation initiation.
Effect of GH/IGF-I deficiency on long-term renal changes and urinary albumin excretion in diabetic dwarf rats
Authors: Gronbaek H. , Volmers P. , Bjorn S. F. , Osterby R. , Orskov H. , Flyvbjerg A.
Published: December 2017

Growth hormone (GH) and insulin-like growth factor I (IGF-I) may play a role in early diabetic renal and glomerular growth and in the later development of experimental diabetic kidney disease. Rats from a genetic GH/IGF-I-deficient dwarf rat strain were made streptozotocin diabetic and were compared with nondiabetic dwarf rats. GH/IGF-I-intact rats with and without diabetes served as controls. After 6 mo of diabetes, kidney weight and total glomerular volume increased significantly in GH/IGF-I-intact diabetic rats compared with the nondiabetic GH/IGF-I-intact rats (P < 0.05), whereas the diabetic dwarf rats had insignificant changes compared with dwarf control rats. By the end of the study, urinary albumin excretion (UAE) increased from similar base levels of approximately 15-20 micrograms/24 h to 473 +/- 52 (SE) micrograms/24 h in GH/IGF-I-intact diabetic rats compared with 151 +/- 32 micrograms/24 h in diabetic dwarf rats (P < 0.01). In conclusion, isolated GH/IGF-I deficiency reduces the degree of renal and glomerular hypertrophy and the increase in UAE after 6 mo of experimental diabetes in GH/IGF-I-deficient rats.
Clenbuterol increases the expression of myogenin but not myoD in immobilized rat muscles
Authors: Delday M. I. , Maltin C. A.
Published: December 2017

Immobilization of one hindlimb of young rats in plantar flexion for 3 days led to changes in the plantaris muscles. These comprised a loss of muscle mass and a reduction in protein and RNA content, but no change in the transcript levels of the myogenic regulatory factors myogenin and myoD. Dietary administration of the beta-adrenoceptor agonist clenbuterol (2 mg/kg diet), which has been shown to ameliorate muscle wasting in a wide range of atrophic conditions, also limited muscle wasting in terms of weight, protein, and RNA in the immobilized plantaris muscles. In addition, drug treatment in immobilized plantaris muscles was associated with a marked increase in the steady-state levels of mRNA for myogenin (approximately 360% increase over control) but not myoD. These data provide the first evidence for independent changes in these two myogenic regulatory factors in immobilized muscle and suggest that the action of clenbuterol on these factors may depend on the mechanistic basis for the atrophic response.
Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults
Authors: Vahl N. , Jorgensen J. O. , Skjaerbaek C. , Veldhuis J. D. , Orskov H. , Christiansen J. S.
Published: December 2017

We tested the hypothesis that body composition is the major predictor of growth hormone (GH) secretion in nonobese adults. We measured lean and fat tissue distribution (computerized tomography and dual-energy X-ray absorptiometry scan) and physical fitness [maximal oxygen consumption (Vo2max)] in 42 healthy nonobese adults (22 women and 20 men, age range 27-59 yr, mean +/- SE body mass index = 24 +/- 0.5 kg/m2). Deconvolution analysis was used to estimate specific features of 24-h GH secretion and clearance. Approximate entropy was used to quantify the regularity of GH release. Older subjects exhibited decreased estimates of GH secretion compared with younger subjects. Females had higher estimates of GH secretion, a longer GH half-life, and displayed more irregularity in GH release than males. Mean 24-h serum GH concentrations correlated inversely with intra-abdominal fat and waist-to-hip ratio and positively with Vo2max. Multiple linear regression analysis revealed intra-abdominal fat as the dominant determinant of estimates of GH secretion. Vo2max was more important than sex and age in predicting GH secretion. We conclude that abdominal fat is the major determinant of GH secretion in healthy nonobese adults. Although the underlying mechanisms remain elusive, our findings extend the clinical implications of visceral adiposity to include hyposomatotropism.
Effect of short-term propionate infusion on feed intake and blood parameters in sheep
Authors: Leuvenink H. G. , Bleumer E. J. , Bongers L. J. , van Bruchem J. , van der Heide D.
Published: December 2017

The hypothesis that propionate is a short-term feed intake-regulating agent was studied. Mature wether sheep were infused over 20 min with Na propionate into the mesenteric vein, while feed intake and feeding pattern were monitored over 1.5 h. Feed intake was reduced by infusions at 2 mmol/min, which were associated with marked increases in jugular as well as portal concentrations of insulin, glucose, and propionate. In a second experiment, animals were infused with 2 mmol/min Na propionate into the portal vein. No decrease in feed intake was observed, although there were similar increases in insulin, glucose, and propionate as found in mesenteric vein-infused animals. It is concluded that mesenteric propionate in high doses acts as a satiety factor. Possible explanations for the difference between site of infusion may be a different distribution of the infusate over the liver and/or the presence of propionate-sensitive receptors in the mesenteric/portal vein region. It seems unlikely that insulin concentrations are involved in inducing satiety in propionate-infused animals.
Water deprivation upregulates ANG II AT1 binding and mRNA in rat subfornical organ and anterior pituitary
Authors: Sanvitto G. L. , Johren O. , Hauser W. , Saavedra J. M.
Published: December 2017

We studied angiotensin II (ANG II) receptor subtype expression in selected brain nuclei and pituitary gland after water deprivation by in vitro receptor autoradiography using 125I-labeled [Sar1]ANG II and by in situ hybridization using 35S-labeled AT1A, AT1B, and AT2 receptor-specific riboprobes. In control rats we found binding to AT1 receptors in the subfornical organ, paraventricular nucleus, median eminence, and anterior pituitary; AT1A mRNA expression in the subfornical organ and paraventricular nucleus; and AT1B mRNA expression in the anterior pituitary. No receptor mRNA was found in the median eminence. AT1 receptors and AT1A receptor mRNA levels were increased in the subfornical organ, and, in the anterior pituitary, AT1 receptors and AT1B receptor mRNA were increased, only after 5 days of water deprivation. No significant changes occurred after 1 or 3 days of water deprivation, and no regulation of ANG II receptor expression was detected in other brain areas. Our results show that prolonged water deprivation selectively regulates AT1 receptor expression and AT1A and AT1B receptor mRNA levels in the subfornical organ and anterior pituitary, respectively, supporting a role for these receptors during sustained dehydration.
Gender differences in energy expended during activities and in daily energy expenditure of elderly people
Authors: Morio B. , Beaufrere B. , Montaurier C. , Verdier E. , Ritz P. , Fellmann N. , Boirie Y. , Vermorel M.
Published: December 2017

Gender effects on energy expended during light seated activities, walking, cycling, and sleep and their consequences on daily energy expenditure (EE) were examined in 11 men and 15 women aged 66.4 +/- 7.1 yr. Two open-circuit whole body calorimeters were used for EE measurements, except for cycling, during which EE was measured separately with the use of a face mask. Lean body mass (determined using H218O dilution method), fat mass, usual physical activity level, and activity intensity (e.g., walking speed and cycling power output) were taken as covariates in the analysis of EE variations before studying gender effects. Sleeping metabolic rate (SMR) and daily EE, adjusted for differences in all covariates, were 11.2 (P = 0.005) and 8.7% (P = 0.071) lower in women than in men, respectively. No gender-related differences were found in the various physical activity EEs above SMR (e.g., gross EE-SMR) [light seated activities (P = 0.790), walking (P = 0.263), and cycling (P = 0.287)] and daily physical activity EE above SMR (P = 0.587) after adjustment for differences in all covariates. Therefore, the lower adjusted daily EE of women could be related to their lower SMR, the most reliable criterion of whole body metabolic rate.
Splanchnicotomy increases adrenal sensitivity to ACTH in nonstressed rats
Authors: Jasper M. S. , Engeland W. C.
Published: December 2017

Awake rats demonstrate an ultradian rhythm in adrenal secretion of corticosterone. Splanchnic denervation in unstressed rats increases the frequency of corticosterone pulses, revealing an inhibitory function of adrenal innervation. In contrast, one day after surgical stress, adrenal denervation reduces adrenal pulsatility, suggesting a stimulatory function of adrenal innervation. To test whether neural modulation of pulsatile secretion was due to a direct effect of the splanchnic nerve on adrenal sensitivity to adrenocorticotropic hormone (ACTH), rats treated with dexamethasone were administered repetitive pulses of ACTH, and the amplitude of corticosterone responses was determined. Intact or control (C) and splanchnicotomized (SPLNX) rats were tested at 2 or 5 days after surgery. Five days after surgery, adrenal responsiveness in C animals was reduced compared with SPLNX animals. However, no differences were seen 2 days after surgery. To determine whether the reduction in adrenal responsiveness involved a cellular or organ level mechanism, dispersed adrenal cortical cells isolated from intact or denervated adrenal glands were stimulated with ACTH, and corticosterone secretion was determined. Consistent with in vivo results, denervation increased the responsiveness of adrenal cells obtained 5, but not 1 or 2, days after surgery. These findings support a neurally mediated inhibition of adrenal sensitivity to ACTH in unstressed rats.
Serum free IGF-I during a hyperinsulinemic clamp following 3 days of administration of IGF-I vs. saline.
Authors: Frystyk J , Hussain M , Skjaerbaek C , Schmitz O , Christiansen J S , Froesch E R , Orskov H
Published: December 2017

In a randomized crossover study in eight healthy subjects, we compared the effect of 3 days of continuous subcutaneous administration of insulin-like growth factor I (IGF-I; 10 micrograms.kg-1.h-1) and saline on fasting serum levels of free IGF-I, total (extractable) IGF-I, and IGF-binding protein (IGFBP)-1 and -3. On the 3rd day a hyperinsulinemic (euglycemic and hypoglycemic) clamp was performed. When preclamp (baseline) levels were compared after 3 days, IGF-I administration had increased total IGF-I from 225 +/- 21 (means +/- SE) to 1,003 +/- 46 micrograms/l (P < 0.0001), free IGF-I from 0.5 +/- 0.2 to 10.4 +/- 1.7 micrograms/l (P < 0.001), IGFBP-3 from 2,908 +/- 148 to 3,591 +/- 179 micrograms/l (P < 0.01), and IGFBP-1 from 7.6 +/- 3.8 to 19.6 +/- 2.5 micrograms/l (P < 0.01). During the clamp, levels of free IGF-I increased gradually from baseline to 1.0 +/- 0.3 micrograms/l (saline; P < 0.01) and to 19.6 +/- 4.7 micrograms/l (IGF-I; P < 0.005). Concomitantly, levels of IGFBP-1 decreased gradually from baseline to 4.1 +/- 2.3 micrograms/l (saline; P < 0.0005) and to 4.6 +/- 1.8 micrograms/l (IGF-I; P < 0.0001). Total IGF-I exhibited minor changes only during the clamp (P < 0.05), and IGFBP-3 was unchanged. In conclusion, administration of IGF-I increased total IGF-I about fourfold, whereas free IGF-I increased 20-fold. Noteworthily, in both situations a further twofold increase in free IGF-I was observed during the hyperinsulinemic clamp, concomitant with a decrease in IGFBP-1. This supports the hypothesis that IGFBP-1 is important in the short-term regulation of free IGF-I in vivo.
Role of glycogen-lowering exercise in the change of fat oxidation in response to a high-fat diet.
Authors: Schrauwen P , van Marken Lichtenbelt W D , Saris W H , Westerterp K R
Published: December 2017

One of the candidate factors for determining the increase of fat oxidation after a switch from a reduced-fat diet to a high-fat diet is the size of the glycogen storage. Therefore, we studied the effect of low glycogen stores on fat oxidation after a switch from a reduced-fat diet to a high-fat diet. Twelve healthy, nonobese males and females (age: 22 +/- 1 yr, body mass index: 21.0 +/- 0.7, maximal power output: 254 +/- 11 W) consumed a reduced-fat (RF) diet (30, 55, and 15% of energy from fat, carbohydrate, and protein, respectively) three times a day at home for 3 days (days 1-3). On two occasions subjects came to the laboratory on day 3 at 1500 to perform an exhaustive glycogen-lowering exercise (EX), after which they went into the respiration chamber for a 36-h stay. On one occasion, subjects directly entered the respiration chamber at 1800 for a 36-h stay. In the respiration chamber they were given either a high-fat (HF) diet (60, 25, and 15% of energy from fat, carbohydrate, and protein, respectively) or a RF diet. In both cases they were fed at energy balance. All diets were consumed as breakfast, lunch, dinner, and two or more snacks per day. On the HF treatment, fat oxidation was below fat intake, indicating the slow change of oxidation to intake on a HF diet. After the HF+EX treatment, however, fat oxidation matched fat intake. In conclusion, lean subjects are capable of rapidly adjusting fat oxidation to fat intake when glycogen stores are lowered by exhaustive exercise.
Inhibition of TSH-induced hydrogen peroxide production by TNF-alpha through a sphingomyelinase signaling pathway.
Authors: Kimura T , Okajima F , Kikuchi T , Kuwabara A , Tomura H , Sho K , Kobayashi I , Kondo Y
Published: December 2017

Tumor necrosis factor-alpha (TNF-alpha) has been suggested to be related to the pathogenesis of autoimmune thyroid diseases, nonthyroid illness, and other thyroid dysfunctions induced by infectious diseases. In relation to these, in vitro studies demonstrated that TNF-alpha influences growth and/or differentiated functions mediated by thyroid-stimulating hormone (TSH), including 125I organification. In the present study, we found that TNF-alpha inhibits TSH-induced H2O2 production, which is an inevitable process for iodide organification, and hence thyroid hormone synthesis, in FRTL-5 thyroid cells. In the cells, TNF-alpha induced ceramide production and the addition of exogenous ceramide or sphingomyelinase treatment of the cells simulated TNF-alpha actions. Although TSH stimulation of H2O2 production is mediated by the phospholipase C (PLC)-Ca2+ pathway, TNF-alpha and exogenous and endogenous ceramide affected neither TSH-dependent PLC activation and Ca2+ mobilization nor TSH-induced cAMP accumulation but attenuated Ca(2+)-induced H2O2 production. We conclude that TNF-alpha, through a sphingomyelinase-ceramide pathway, regulates TSH-induced H2O2 production at steps beyond the Ca2+ mobilization step in the PLC-Ca2+ signaling pathway coupled to TSH. This suggests participation of TNF-alpha in thyroid disorder in hormone synthesis induced by thyroid disease associated with the activation of immune systems.
Regulation of glucose transporter GLUT-4 and hexokinase II gene transcription by insulin and epinephrine
Authors: Jones Jared P. , Dohm G. Lynis
Published: December 2017

Transport of glucose across the plasma membrane by GLUT-4 and subsequent phosphorylation of glucose by hexokinase II (HKII) constitute the first two steps of glucose utilization in skeletal muscle. This study was undertaken to determine whether epinephrine and/or insulin regulates in vivo GLUT-4 and HKII gene transcription in rat skeletal muscle. In the first experiment, adrenodemedullated male rats were fasted 24 h and killed in the control condition or after being infused for 1.5 h with epinephrine (30 μg/ml at 1.68 ml/h). In the second experiment, male rats were fasted 24 h and killed after being infused for 2.5 h at 1.68 ml/h with saline or glucose (625 mg/ml) or insulin (39.9 μg/ml) plus glucose (625 mg/ml). Nuclei were isolated from pooled quadriceps, tibialis anterior, and gastrocnemius muscles. Transcriptional run-on analysis indicated that epinephrine infusion decreased GLUT-4 and increased HKII transcription compared with fasted controls. Both glucose and insulin plus glucose infusion induced increases in GLUT-4 and HKII transcription of twofold and three- to fourfold, respectively, compared with saline-infused rats. In conclusion, epinephrine and insulin may regulate GLUT-4 and HKII genes at the level of transcription in rat skeletal muscle.
Differential effect of pp120 on insulin endocytosis by two variant insulin receptor isoforms
Authors: Calzi Sergio Li , Choice Curtis V. , Najjar Sonia M.
Published: December 2017

The insulin receptor is expressed as two variably spliced isoforms that differ by the absence (isoform A) or presence (isoform B) of a 12-amino acid sequence encoded by exon 11 at the carboxy terminus of the α-subunit. Coexpression of the A isoform and pp120, a substrate of the insulin receptor tyrosine kinase, in NIH 3T3 fibroblasts increased receptor A-mediated insulin endocytosis and degradation by two- to threefold compared with cells expressing receptors alone. Because B is the predominant isoform in the liver and binds insulin with lower affinity than A, we have examined the effect of pp120 on receptor B-mediated endocytosis. In contrast to isoform A, the effect of pp120 on isoform B-mediated insulin internalization and degradation in stably transfected NIH 3T3 cells was minimal.
The hot IVGTT two-compartment minimal model: indexes  of glucose effectiveness and insulin sensitivity
Authors: Vicini Paolo , Caumo Andrea , Cobelli Claudio
Published: December 2017

A two-compartment minimal model (2CMM) has been proposed [A. Caumo and C. Cobelli. Am. J. Physiol. 264 ( Endocrinol. Metab. 27): E829–E841, 1993] to describe intravenous glucose tolerance test (IVGTT) labeled (hereafter hot) glucose kinetics. This model, at variance with the one-compartment minimal model (1CMM), allows the estimation of a plausible profile of glucose production. The aim of this study is to show that the 2CMM also allows the assessment of insulin sensitivity ([Formula: see text]), glucose effectiveness ([Formula: see text]), and plasma clearance rate (PCR). The 2CMM was identified on stable-isotope IVGTTs performed in normal subjects ( n = 14). Results were (means ± SE) [Formula: see text] = 0.85 ± 0.14 ml ⋅ kg−1 ⋅ min−1, PCR = 2.02 ± 0.14 ml ⋅ kg−1 ⋅ min−1, and [Formula: see text] = 13.83 ± 2.54 × 10−2ml ⋅ kg−1 ⋅ min−1 ⋅ μU−1 ⋅ ml. The 1CMM was also identified; glucose effectiveness and insulin sensitivity indexes were [Formula: see text]V = 1.36 ± 0.08 ml ⋅ kg−1 ⋅ min−1and [Formula: see text] V = 12.98 ± 2.21 × 10−2ml ⋅ kg−1 ⋅ min−1 ⋅ μU−1 ⋅ ml, respectively, where V is the 1CMM glucose distribution volume.[Formula: see text]V was lower than PCR and higher than [Formula: see text] and did not correlate with either [ r = 0.45 (NS) and r = 0.50 (NS), respectively], whereas [Formula: see text]V was not different from and was correlated with[Formula: see text]( r = 0.95; P < 0.001).[Formula: see text] compares well ( r = 0.78; P < 0.001) with PCR normalized by the 2CMM total glucose distribution volume. In conclusion, the 2CMM is a powerful tool to assess glucose metabolism in vivo.
Structure and activity of uroguanylin and guanylin from the intestine and urine of rats
Authors: Fan Xiaohui , Hamra F. Kent , London Roslyn M. , Eber Sammy L. , Krause William J. , Freeman Ronald H. , Smith Christine E. , Currie Mark G. , Forte Leonard R.
Published: December 2017

Uroguanylin and guanylin are related peptides that activate common guanylate cyclase signaling molecules in the intestine and kidney. Uroguanylin was isolated from urine and duodenum but was not detected in extracts from the colon of rats. Guanylin was identified in extracts from small and large intestine but was not detected in urine. Uroguanylin and guanylin have distinct biochemical and chromatographic properties that facilitated the separation, purification, and identification of these peptides. Northern assays revealed that mRNA transcripts for uroguanylin were more abundant in small intestine compared with large intestine, whereas guanylin mRNA levels were greater in large intestine relative to small intestine. Synthetic rat uroguanylin and guanylin had similar potencies in the activation of receptors in T84 intestinal cells. Production of uroguanylin and guanylin in the mucosa of duodenum is consistent with the postulate that both peptides influence the activity of an intracellular guanosine 3′,5′-cyclic monophosphate signaling pathway that regulates the transepithelial secretion of chloride and bicarbonate in the intestinal epithelium.
Effect of physical activity and fasting on gut and liver proteolysis in the dog
Authors: Halseth Amy E. , Flakoll Paul J. , Reed Erica K. , Messina Allison B. , Krishna Mahesh G. , Lacy D. Brooks , Williams Phillip E. , Wasserman David H.
Published: December 2017

The aim of this study was to determine how gut and liver protein kinetics adapt to acute exercise in the 18-h-fasted dog ( n = 7) and in dogs glycogen depleted by a 42-h fast ( n = 8). For this purpose, sampling (artery and portal and hepatic veins) and infusion (vena cava) catheters and Doppler flow probes (portal vein and hepatic artery) were implanted with animals under general anesthesia. At least 16 days later, an experiment, consisting of a 120-min equilibration period, a 30-min basal sampling period, and a 150-min exercise period, was performed. At the start of the equilibration period, a constant rate infusion of [1-13C]leucine was initiated. Gut and liver leucine appearance and disappearance rates were calculated in these studies by combining a novel stable isotopic method and arteriovenous difference methods. In the determination of tissue leucine kinetics the tissue inflow of both α-[13C]ketoisocaproic acid and [13C]leucine was taken into account. The results of this study show that 1) the splanchnic bed (liver plus gut) contributes ∼40% to the whole body proteolytic rate in the basal state and during exercise in dogs fasted for either 18 or 42 h, 2) the contributions of the gut and liver to splanchnic bed proteolysis is about equal in the basal state in both 18- and 42-h-fasted dogs, and 3) exercise in the 18-h-fasted dog leads to a greater emphasis on gut proteolysis and a lesser emphasis on hepatic proteolysis. These studies highlight the important contribution of gut and hepatic proteolysis to whole body proteolysis and the ability of the gut to acutely adapt to changes in physical activity.
Transport of CRH from mouse brain directly affects peripheral production of β-endorphin by the spleen
Authors: Martins J. Martin , Banks William A. , Kastin Abba J.
Published: December 2017

The blood-brain barrier (BBB) regulates the passage of substances between the brain and the periphery. It has not been shown that the secretion from the brain of a small amount of a substance can directly affect the periphery by transport across the BBB. We found that central injection of radioactively labeled corticotropin-releasing hormone (CRH) resulted in the accumulation of intact CRH in the spleen. CRH also increased splenic β-endorphin, an effect not blocked by pretreatment with dexamethasone. Inhibition of the secretion of CRH from the brain by colchicine resulted in decreased accumulation of CRH in the spleen and also decreased splenic β-endorphin. Similar findings occurred in the pituitary gland. The results show that the passage of labeled CRH from the brain can directly affect a peripheral organ, thus emphasizing the regulatory function of the BBB.
Determination of cerebral glucose transport and metabolic kinetics by dynamic MR spectroscopy
Authors: Van Zijl P. C. M. , Davis D. , Eleff S. M. , Moonen C. T. W. , Parker R. J. , Strong J. M.
Published: December 2017

A new in vivo nuclear magnetic resonance (NMR) spectroscopy method is introduced that dynamically measures cerebral utilization of magnetically labeled [1-13C]glucose from the change in total brain glucose signals on infusion. Kinetic equations are derived using a four-compartment model incorporating glucose transport and phosphorylation. Brain extract data show that the glucose 6-phosphate concentration is negligible relative to glucose, simplifying the kinetics to three compartments and allowing direct determination of the glucose-utilization half-life time [ t½= ln2/( k2+ k3)] from the time dependence of the NMR signal. Results on isofluorane ( n = 5)- and halothane ( n = 7)- anesthetized cats give a hyperglycemic t½= 5.10 ± 0.11 min−1(SE). Using Michaelis-Menten kinetics and an assumed half-saturation constant Kt= 5 ± 1 mM, we determined a maximal transport rate Tmax= 0.83 ± 0.19 μmol ⋅ g−1⋅ min−1, a cerebral metabolic rate of glucose CMRGlc= 0.22 ± 0.03 μmol ⋅ g−1⋅ min−1, and a normoglycemic cerebral influx rate CIRGlc= 0.37 ± 0.05 μmol ⋅ g−1⋅ min−1. Possible extension of this approach to positron emission tomography and proton NMR is discussed.