Showing papers in "American Journal of Physiology-regulatory Integrative and Comparative Physiology in 1997"
TL;DR: This review will consider whether nitric oxide contributes to maternal systemic vasodilation during pregnancy, regulates uterine and fetoplacental blood flow, and is involved in uterine quiescence prior to parturition, and whether a deficiency of NO contributes to the hypertensive disorder of pregnancy, preeclampsia.
Abstract: This review will consider whether nitric oxide (NO) contributes to maternal systemic vasodilation during pregnancy, regulates uterine and fetoplacental blood flow, and is involved in uterine quiescence prior to parturition. Also, whether a deficiency of NO contributes to the hypertensive disorder of pregnancy, preeclampsia, will be considered. The biosynthesis of NO increases in gravid rats and sheep, but the status in normal human pregnancy and preeclampsia is controversial. NO contributes to maternal systemic vasodilation and reduced vascular reactivity during normal pregnancy; however, the relative contribution of NO is variable depending on the animal species, vascular bed, and vessel size. Impaired relaxation responses to acetylcholine, but not bradykinin or NO donors, are observed in small arteries from women with preeclampsia, suggesting a receptor or signal transduction defect, although NO may play little, if any, role here. Uterine arteries have increased endothelial nitric oxide synthase (NOS) activity, protein expression, and guanosine 3',5'-cyclic monophosphate production during pregnancy; however, whether these mediate uterine vasodilation during pregnancy remains to be established. NOS is expressed in the human placental syncytiotrophoblast and in the fetoplacental and umbilical vascular endothelium where basal production of NO contributes to low fetoplacental vascular resistance. Controversy exists over the status of placental NOS in preeclampsia, although an abnormality of umbilical NOS activity is likely. Finally, the uterus has NOS activity, which decreases at the end of gestation, and exogenous NO relaxes the myometrium, but whether endogenous NO contributes to uterine quiescence during pregnancy has yet to be confirmed.
715 citations
TL;DR: The DIO and DR traits in the outbred Sprague-Dawley population appear to be due to a polygenic pattern of inheritance.
Abstract: In outbred Sprague-Dawley rats, about one-half develop diet-induced obesity (DIO) on a diet relatively high in fat and energy (HE diet). The rest are diet resistant (DR), gaining weight and fat at the same rate as chow-fed controls. Here we selectively bred for high (DIO) and low (DR) weight gainers after 2 wk on HE diet. By the F5 generation, both male and female inbred DIO rats gained > 90% more weight than inbred DR rats on HE diets. Even on low-fat chow diet, DIO males were 31% and females were 22% heavier than their respective DR rats. Full metabolic characterization in male rats showed that weight-matched, chow-fed DIO-prone rats had similar energy intakes and feed efficiency [body weight (kg0.75)/energy intake (kcal)] but 44% more carcass fat than comparable DR-prone rats. Their basal plasma insulin and glucose levels in the fed state were 70 and 14% higher, respectively. But, when fasted, DIO-prone oral glucose tolerance results were comparable to DR-prone rats. Chow-fed DIO-prone males also had 42% greater 24-h urine norepinephrine levels than DR-prone males. During 2 wk on HE diet, DIO rats ate 25% more, gained 115% more weight, had 36% more carcass fat, and were 42% more feed efficient than comparable DR rats. Fasted HE diet-fed DIO rats developed frank glucose intolerance during a glucose tolerance test with 55 and 158% greater insulin and glucose areas under the curve, respectively. Thus the DIO and DR traits in the outbred Sprague-Dawley population appear to be due to a polygenic pattern of inheritance.
518 citations
TL;DR: The results suggest that mounting an immune response requires significant energy and therefore requires using resources that could otherwise be allocated to other physiological processes.
Abstract: Animals must balance their energy budget despite seasonal changes in both energy availability and physiological expenditures. Immunity, in addition to growth, thermoregulation, and cellular maintenance, requires substantial energy to maintain function, although few studies have directly tested the energetic cost of immunity. The present study assessed the metabolic costs of an antibody response. Adult and aged male C5BL/6J mice were implanted with either empty Silastic capsules or capsules filled with melatonin and injected with either saline or keyhole limpet hemocyanin (KLH). O2 consumption was monitored periodically throughout antibody production using indirect calorimetry. KLH-injected mice mounted significant immunoglobulin G (IgG) responses and consumed more O2 compared with animals injected with saline. Melatonin treatment increased O2 consumption in mice injected with saline but suppressed the increased metabolic rate associated with an immune response in KLH-injected animals. Melatonin had no effect on immune response to KLH. Adult and aged mice did not differ in antibody response or metabolic activity. Aged mice appear unable to maintain sufficient heat production despite comparable O2 production to adult mice. These results suggest that mounting an immune response requires significant energy and therefore requires using resources that could otherwise be allocated to other physiological processes. Energetic trade-offs are likely when energy demands are high (e.g., during winter, pregnancy, or lactation). Melatonin appears to play an adaptive role in coordinating reproductive, immunologic, and energetic processes.
333 citations
TL;DR: It is concluded that aging is associated with diminished desire to eat and hunger, slowing of solid and liquid gastric emptying, no change in orocecal and total gut transit, and 4) autonomic nerve dysfunction.
Abstract: Animal studies suggest that aging is associated with anorexia and disordered gastrointestinal transit. To determine whether there is a relationship between the effects of aging on appetite and gastrointestinal transit in humans, 19 young (age 23-50 yr) and 14 elderly (age 70-84 yr) normal volunteers underwent measurements of 1) desire to eat, hunger, and fullness (visual analog scales); 2) gastric emptying (scintigraphy); 3) orocecal transit (breath hydrogen); 4) total gut transit (radiopaque markers); and 5) autonomic nerve function (cardiovascular reflexes). We found that, postprandially, elderly subjects had less desire to eat (P < 0.05) and less hunger (P < 0.05), but not a significantly greater fullness than younger subjects. Gastric emptying (50% emptying time) for solid (182 +/- 26 vs. 127 +/- 13 min, P < 0.05) and liquid (47 +/- 4 vs. 35 +/- 3 min, P < 0.05) meal components was slower in elderly subjects. Postprandial hunger was inversely related (r = -0.39, P < 0.05) to solid gastric emptying. There were no significant differences in orocecal and total gut transit times between the two groups. Autonomic nerve function was abnormal in 11 elderly but none of the young subjects (P < 0.01). We conclude that aging is associated with 1) diminished desire to eat and hunger, 2) slowing of solid and liquid gastric emptying, 3 no change in orocecal and total gut transit, and 4) autonomic nerve dysfunction. The slowing of gastric emptying may contribute to anorexia in aging subjects.
296 citations
TL;DR: Plasma leptin in C57BL/6J mice increases with age or a high-fat diet; correlates with body weight, fat content, and plasma insulin; and is reduced during fasting by an action inhibited by high-Fat diet and related to changes of plasma insulin.
Abstract: Mechanisms regulating circulating leptin are incompletely understood. We developed a radioimmunoassay for mouse leptin to examine the influence of age, dietary fat content, and fasting on plasma concentrations of leptin in the background strain for the ob/ob mouse, the C57BL/6J mouse. Plasma leptin increased with age [5.3 +/- 0.6 ng/ml at 2 mo (n = 23) vs. 14.2 +/- 1.6 ng/ml at 11 mo (n = 15), P < 0.001]. Across all age groups (2-11 mo, n = 160), log plasma leptin correlated with body weight (r = 0.68, P < 0.0001), plasma insulin (r = 0.38, P < 0.001), and amount of intra-abdominal fat (r = 0.90, P < 0.001), as revealed by magnetic resonance imaging. Plasma leptin was increased by a high-fat diet (58% fat for 10 mo) and reduced by fasting for 48 h. The reduction of plasma leptin was correlated with the reduction of plasma insulin (r = 0.43, P = 0.012) but not with the initial body weight or the change in body weight. Moreover, the reduction in plasma leptin by fasting was impaired by high-fat diet. Thus plasma leptin in C57BL/6J mice 1) increases with age or a high-fat diet; 2) correlates with body weight, fat content, and plasma insulin; and 3) is reduced during fasting by an action inhibited by high-fat diet and related to changes of plasma insulin.
290 citations
TL;DR: The results indicate that GLP-2 is able to induce trafficking of SGLT-1 from an intracellular pool into the BBM within 60 min and that phosphoinositol 3-kinase may well be involved in the intrACEllular signaling pathway in this response.
Abstract: The effect of in vivo infusion of the peptide hormone glucagon-like peptide 2 (GLP-2) on glucose transport across the rat jejunal brush-border membrane (BBM) was assessed using isolated membrane ve...
257 citations
TL;DR: The present results provide a basis at the phenotypic level to begin to apply genetic methods to the analysis of circadian rhythms and aging in mammals.
Abstract: The effects of age on the circadian clock system have been extensively studied, mainly in two rodent species, the laboratory rat and the golden hamster. However, less information is available on ho...
257 citations
TL;DR: The data indicate that endurance training can cause tissue- and muscle fiber-specific adaptation of antioxidant systems and that GSH homeostasis in extrahepatic tissues may be determined by utilization and uptake of GSH via the gamma-glutamyl cycle.
Abstract: The effect of endurance training on glutathione (GSH) status and antioxidant enzyme system was investigated in skeletal muscle, heart, and liver of female Sprague-Dawley rats pair fed an isocaloric diet. Ten weeks of treadmill training (25 m/min, 10% grade for 2 h/day, 5 days/wk) increased citrate synthase activity in the deep vastus lateralis (DVL) and soleus muscles by 79 and 39%, respectively (P < 0.01), but not in the heart or liver. In DVL, GSH content was increased 33% (P < 0.05) with training, accompanied by a 64% (P < 0.05) increase in glutamate content but no change in cysteine. Trained rats showed a 62 and 27% higher GSH peroxidase (GPX) and superoxide dismutase (SOD) activity, respectively (P < 0.05), in DVL compared with control rats. In contrast, GSH content and glutathione reductase (GR) activity in soleus declined with training (P < 0.05), whereas activities of GPX and SOD remained unchanged. Training did not alter GSH status in the liver or plasma but significantly decreased the GSH-to glutathione disulfide ratio in the heart. In addition, GR activity in the liver and GSH sulfur-transferase activity in the heart and DVL were significantly lower in the trained vs control rats DVL muscle had threefold higher gamma-glutamyl transpeptidase activity compared with other tissues; however no significant alteration was observed in the activity of gamma-glutamyltranspeptidase or gamma-glutamylcysteine synthetase in the liver, heart, or skeletal muscle. These data indicate that endurance training can cause tissue- and muscle fiber-specific adaptation of antioxidant systems and that GSH homeostasis in extrahepatic tissues may be determined by utilization and uptake of GSH via the gamma-glutamyl cycle.
238 citations
TL;DR: It is concluded that vagal afferentation may be important in the mediation of the response to minor amounts of circulating LPS, whereas theresponse to larger amounts is brought about mostly (if not exclusively) by nonvagal mechanisms.
Abstract: Experimentally, systemic inflammation induced by a bolus intravenous injection of lipopolysaccharide (LPS) may be accompanied by three different thermoregulatory responses: monophasic fever (the typical response to low doses of LPS), biphasic fever (medium doses), and hypothermia (high doses). In our recent study [Romanovsky, A. A., V. A. Kulchitsky, C. T. Simons, N. Sugimoto, and M. Szekely. Am. J. Physiol. (Regulatory Integrative Comp. Physiol.). In press], monophasic fever did not occur in subdiaphragmatically vagotomized rats. In the present work, we asked whether vagotomy affects the two other types of thermoregulatory response. Adult Wistar rats were vagotomized (or sham operated) and had an intravenous catheter implanted. On day 28 postvagotomy, the thermal responses to the intravenous injection of Escherichia coli LPS (0, 1, 10, 100, or 1,000 micrograms/kg) were tested in either a neutral (30 degrees C) or slightly cool (25 degrees C) environment. Three major results were obtained. 1) In the sham-operated rats, the 1 microgram/kg dose of LPS caused at 30 degrees C a monophasic fever with a maximal colonic temperature (Tc) rise of approximately 0.6 degree C; this response was abated (no Tc changes) in the vagotomized rats. 2) At 30 degrees C, all responses to higher doses of LPS (10-1,000 micrograms/kg) were represented by biphasic fevers (the higher the dose, the less pronounced the first and the more pronounced the second phase was); none of these biphasic fevers was altered in the vagotomized animals. 3) In response to the 1,000 micrograms/kg dose at 25 degrees C, hypothermia occurred: Tc changed by -0.5 +/- 0.1 degree C (nadir); this hypothermia was exaggerated (-1.1 +/- 0.1 degrees C) in the vagotomized rats. It is concluded that vagal afferentation may be important in the mediation of the response to minor amounts of circulating LPS, whereas the response to larger amounts is brought about mostly (if not exclusively) by nonvagal mechanisms. This difference may be explained by the dose-dependent mechanisms of the processing of exogenous pyrogens. Vagotomized animals also appear to be more sensitive to the hypothermizing action of LPS in a cool environment; the mechanisms of this phenomenon remain speculative.
236 citations
TL;DR: Data demonstrate that CCK's suppression of intake depends on actions of both vagal afferent and efferent fibers, and suggests that the greater efficacy of higher CCK doses is the result of the potentiation of these vagal Afferent actions due to local physiological gastrointestinal effects of the peptide that rely on vagal efferent input.
Abstract: To assess the role of subdiaphragmatic vagal afferent and efferent fibers in the mediation of the inhibition of food intake by cholecystokinin (CCK), we compared the ability of a dose range (1-16 microg/kg), of CCK to affect 30-min liquid glucose (0.125 g/ml) intake in rats with either total subdiaphragmatic vagotomy, selective subdiaphragmatic vagal deafferentation, selective subdiaphragmatic vagal deefferentation, or sham surgery. Selective vagal deafferentation and deefferentations were produced by combinations of unilateral subdiaphragmatic vagotomy and contralateral afferent or efferent rootlet transection as fibers enter the caudal medulla. CCK produced a dose-related suppression of glucose intake in sham animals, and this action was eliminated in rats with total subdiaphragmatic vagotomy. CCK suppression of intake was attenuated in rats with vagal deafferentation, such that there was a loss of sensitivity to CCK. Vagal deefferentation resulted in lower levels of baseline intake and a truncation of the feeding-inhibitory actions of CCK. These data demonstrate that CCK's suppression of intake depends on actions of both vagal afferent and efferent fibers. We interpret these data as suggesting that 1) the actions of low doses of CCK depend on activation of vagal afferent CCK receptors and 2) the greater efficacy of higher CCK doses is the result of the potentiation of these vagal afferent actions due to local physiological gastrointestinal effects of the peptide that rely on vagal efferent input.
232 citations
TL;DR: It appears that the medullary blood flow is a potent determinant of both sodium and water excretion and signals changes in blood volume and arterial pressure to the tubules via the physical forces that Professor Starling so clearly defined 100 years ago.
Abstract: The original fascination with the medullary circulation of the kidney was driven by the unique structure of vasa recta capillary circulation, which Berliner and colleagues (Berliner, R. W., N. G. Levinsky, D. G. Davidson, and M. Eden. Am. J. Med. 24: 730-744, 1958) demonstrated could provide the economy of countercurrent exchange to concentrate large volumes of blood filtrate and produce small volumes of concentrated urine. We now believe we have found another equally important function of the renal medullary circulation. The data show that it is indeed the forces defined by Starling 100 years ago that are responsible for the pressure-natriuresis mechanisms through the transmission of changes of renal perfusion pressure to the vasa recta circulation. Despite receiving only 5-10% of the total renal blood flow, increases of blood flow to this region of the kidney cause a washout of the medullary urea gradient and a rise of the renal interstitial fluid pressure. These forces reduce tubular reabsorption of sodium and water, leading to a natriuresis and diuresis. Many of Starling's intrinsic chemicals, which he named "hormones," importantly modulate this pressure-natriuresis response by altering both the sensitivity and range of arterial pressure around which these responses occur. The vasculature of the renal medulla is uniquely sensitive to many of these vasoactive agents. Finally, we have found that the renal medullary circulation can play an important role in determining the level of arterial pressure required to achieve long-term fluid and electrolyte homeostasis by establishing the slope and set point of the pressure-natriuresis relationship. Measurable decreases of blood flow to the renal medulla with imperceptible changes of total renal blood flow can lead to the development of hypertension. Many questions remain, and it is now evident that this is a very complex regulatory system. It appears, however, that the medullary blood flow is a potent determinant of both sodium and water excretion and signals changes in blood volume and arterial pressure to the tubules via the physical forces that Professor Starling so clearly defined 100 years ago.
TL;DR: It is found that REM sleep is accompanied by a selective increase in GABA release, but not by a change in glutamate or glycine release in the dorsal raphe nucleus, which implicate GABA release as a critical element in the production of the REM sleep state.
Abstract: The cessation of firing of serotonergic dorsal raphe neurons is a key controlling event of rapid eye movement (REM) sleep. We tested the hypothesis that this cessation of activity is due to gamma-aminobutyric acid (GABA) release using the in vivo microdialysis technique. We found that REM sleep is accompanied by a selective increase in GABA release, but not by a change in glutamate or glycine release in the dorsal raphe nucleus. Microinjection of the GABA agonist muscimol into the dorsal raphe increased REM sleep, although microperfusion of the GABA antagonist picrotoxin blocked REM sleep. These results implicate GABA release as a critical element in the production of the REM sleep state and in the control of discharge in serotonergic neurons across the sleep/wake cycle.
TL;DR: The data suggest that, in addition to immediate thermoregulatory changes, a phase advance of the circadian system had occurred and that the phase advance could still be measured on the posttreatment day.
Abstract: The phase-shifting capacity and thermoregulatory effects of a single oral administration at 18 h of melatonin (5 mg) or S-20098, a melatonin agonist (5 or 100 mg), was investigated in eight healthy young men in a double-blind placebo crossover design. The unmasking conditions of a shortened constant-routine protocol (mini-CR) were used to collect evening phase markers of physiological parameters. In comparison to placebo, all three drug administrations induced an earlier dim-light melatonin onset (DLMO), an earlier increase in distal skin temperature, and an earlier decrease in core body temperature (CBT), heart rate, and proximal skin temperature. This indicates that administration at 18 h of both melatonin and S-20098 (more pronounced with 100 than 5 mg) induced an earlier regulation of the endogenous circadian nocturnal decline in CBT. On the posttreatment day a second mini-CR revealed persistent significantly phase-advanced circadian rhythms as estimated by DLMO, as well as by the midrange crossing time of CBT and heart rate decline. There were no significant differences between the two doses of S-20098. The data suggest that, in addition to immediate thermoregulatory changes, a phase advance of the circadian system had occurred and that the phase advance could still be measured on the posttreatment day.
TL;DR: The results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLp-1.
Abstract: Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogenous regulatory agents, central administration of these peptides may have aversive side effects, which could explain the anorexia. In the present experiment, exposure to a saccharine taste was immediately followed by central administration of leptin or GLP-1 to determine if these drugs could produce a conditioned taste aversion (CTA) in rats. At doses equated for producing comparable reductions in short-term food intake, GLP-1, but not leptin, generated a robust CTA. Although leptin caused no aversion, this peptide was the only drug to cause relatively long-term reductions in food consumption (16 h) and body weight (24 h). Hence, the results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLP-1.
TL;DR: Analysis of oxygen consumption in ob/ob mice demonstrated a reduction in energy expenditure compared with lean controls; this reduction showed a diurnal fluctuation and was most evident during the light cycle, suggesting that increased energy utilization plays an important role in the anti-obese actions of leptin.
Abstract: Obesity occurs whenever energy intake exceeds energy expenditure. The ob gene product leptin is a potent anorectic agent when administered to ob/ob mice, but its effects on energy expenditure have not been investigated in detail. The present study was designed to analyze the acute metabolic effects of leptin in vivo. Analysis of oxygen consumption in ob/ob mice demonstrated a reduction in energy expenditure compared with lean controls; this reduction showed a diurnal fluctuation and was most evident during the light cycle. A single intraperitoneal dose of leptin increased oxygen consumption during the light cycle in ob/ob mice, ablating the circadian fluctuation in this parameter. In addition, leptin had a profound effect on fuel selection: the respiratory quotient was markedly reduced, indicating a reduction in carbohydrate oxidation and an increase in fat oxidation. These acute effects of leptin on metabolic parameters are consistent with the selective loss of body fat observed on chronic leptin treatment and suggest that increased energy utilization plays an important role in the anti-obese actions of leptin.
TL;DR: Results suggest that COX-2 induced in brain blood vessels/leptomeninges is involved in the molecular mechanism of LPS-induced fever.
Abstract: We previously showed that a febrile dose of lipopolysaccharide (LPS) in rats resulted in induction of cyclooxygenase-2 (COX-2) mRNA in brain blood vessels/leptomeninges and telencephalic neurons. To elucidate the causal link between fever and LPS-induced COX-2 mRNA, we experimentally modified one or the other of these parameters and examined their relation. 1) LPS-induced fever was suppressed by pretreatment with a COX-2-specific inhibitor. 2) Levels of COX-2 mRNA in the neurons and blood vessels 2.5 h after LPS administration were even higher in the inhibitor-pretreated rats (afebrile) than in vehicle-pretreated ones (febrile). 3) After repeated administration of LPS, rats became tolerant to LPS, in which state LPS induced neither fever nor COX-2 mRNA in blood vessels/leptomeninges. When rats had not completely established LPS tolerance, they showed various degrees of fever that were closely correlated with the level of COX-2 mRNA in blood vessels but not with that in neurons. 4) Urethan anesthesia reduced basal as well as LPS-induced COX-2 mRNA in telencephalic neurons, but the rats still responded to LPS with fever and induction of COX-2 mRNA in the blood vessels/leptomeninges. These results suggest that COX-2 induced in brain blood vessels/leptomeninges is involved in the molecular mechanism of LPS-induced fever.
TL;DR: The data indicate that endogenous nitric oxide within the PVN regulates sympathetic outflow via some inhibitory mechanisms, which may contribute to elevated sympathetic nerve activity observed during various diseases states such as heart failure and hypertension.
Abstract: The paraventricular nucleus (PVN) of the hypothalamus is known to be involved in the control of sympathetic outflow. The goal of the present study was to examine the role of nitric oxide within the PVN in the regulation of renal sympathetic nerve activity. Renal sympathetic nerve discharge (RSND), arterial blood pressure, and heart rate in response to the microinjection of nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 50, 100, and 200 pmol) into the PVN were measured in male Sprague-Dawley rats. Microinjection of L-NMMA elicited an increase in RSND, arterial blood pressure, and heart rate. Administration of NG-monomethyl-D-arginine (D-NMMA, 50-200 pmol) into the PVN did not change RSND, arterial pressure, or heart rate. Similarly, microinjection of another nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 nmol) also elicited an increase in RSND, arterial blood pressure, and heart rate. L-Arginine (100 nmol) reversed the effects of L-NAME in the PVN. Furthermore, microinjection of sodium nitroprusside (SNP; 50, 100, and 200 nmol) into the PVN elicited a significant decrease in RSND, arterial blood pressure, and heart rate. These effects of L-NMMA, L-NAME, and SNP on RSND and arterial blood pressure were not mediated by their vasoactive action because microinjection of phenylephrine and hydralazine did not elicit similar respective changes. In conclusion, our data indicate that endogenous nitric oxide within the PVN regulates sympathetic outflow via some inhibitory mechanisms. Altered nitric oxide mechanisms within the PVN may contribute to elevated sympathetic nerve activity observed during various diseases states such as heart failure and hypertension.
TL;DR: Analysis of AGT mRNA levels in adipose tissue of obese Zucker rats, viable yellow (Avy) mice, and humans and by treating 3T3-L1 adipocytes with insulin, glucose, and a beta-adrenergic agonist shows that AGT RNA is upregulated by insulin and downregulated by beta- adrenergic stimulation in adipocytes.
Abstract: Synthesis of angiotensin II (ANG II) has recently been described in adipose cells and has been linked to regulation of adiposity. Angiotensinogen (AGT), the substrate from which ANG II is formed, was previously shown to be elevated in adipose tissue of obese (ob/ob and db/db) mice and regulated by nutritional manipulation. It is unknown, however, whether overexpression of adipose AGT can be extended to other models of obesity and whether hormonal and/or nutritional factors directly regulate AGT expression in adipocytes. We investigated these possibilities by analyzing AGT mRNA levels in adipose tissue of obese Zucker rats, viable yellow (Avy) mice, and humans and by treating 3T3-L1 adipocytes with insulin, glucose, and a beta-adrenergic agonist. We demonstrate that AGT mRNA is decreased by approximately 50 and 80%, respectively, in adipose tissue of obese vs. lean Zucker rats and Avy mice. We also report that AGT is expressed at variable levels in human adipose tissue. Finally, we show that AGT mRNA is upregulated by insulin and downregulated by beta-adrenergic stimulation in adipocytes.
TL;DR: It is found that bright light induces phase shifts throughout subjective day with no apparent dead zone, and there is no evidence of transients in constant routine assessments of the fitted temperature minimum 1-2 days after completion of the resetting stimulus.
Abstract: Fifty-six resetting trials were conducted across the subjective day in 43 young men using a three-cycle bright-light (approximately 10,000 lx). The phase-response curve (PRC) to these trials was assessed for the presence of a "dead zone" of photic insensitivity and was compared with another three-cycle PRC that had used a background of approximately 150 lx. To assess possible transients after the light stimulus, the trials were divided into 43 steady-state trials, which occurred after several baseline days, and 13 consecutive trials, which occurred immediately after a previous resetting trial. We found that 1) bright light induces phase shifts throughout subjective day with no apparent dead zone; 2) there is no evidence of transients in constant routine assessments of the fitted temperature minimum 1-2 days after completion of the resetting stimulus; and 3) the timing of background room light modulates the resetting response to bright light. These data indicate that the human circadian pacemaker is sensitive to light at virtually all circadian phases, implying that the entire 24-h pattern of light exposure contributes to entrainment.
TL;DR: It was showed that milk stasis during early established lactation induces tight junctions to switch to a leaky state after approximately 18 h and to revert to the closed state shortly after milking and the suitability of plasma alpha-lactalbumin as an indicator of tight junction status in vivo was indicated.
Abstract: Eight cows in early lactation were used to study the effect of milk accumulation on the state of mammary tight junctions and to examine alpha-lactalbumin as an indicator of tight junction permeabil...
TL;DR: Results show that restraint stress has a greater effect on metabolism and energy balance when it is applied in the morning, and mechanisms involved in the suppression of food intake 9 h after restraint are still unclear.
Abstract: Three experiments were conducted to investigate the effect of restraint stress applied at different times of the light-dark cycle on feeding behavior and body weight of rats. Sprague-Dawley rats were restrained for 3 h in restraining tubes either at the start or the end of the light cycle. There was a significant reduction in food intake on the day of restraint and no change in food intake during a 10-day recovery period in either experiment. Reductions of food intake on the day of restraint were about the same for both restrained groups compared with their controls. When stress was applied in the evening, eating was inhibited during the first 2 h after restraint, whereas in rats restrained in the morning, feeding was suppressed twice: during the 4 h after restraint and during the first 2 h of the dark cycle. Restraint induced a significant weight loss that was greater in the rats stressed in the morning. Neuropeptide Y (NPY) levels determined at the time of food suppression for both experiments (beginning of the dark cycle) revealed an elevation of NPY in the paraventricular nucleus of rats stressed in the morning compared with other groups, but no difference in hypothalamic NPY mRNA expression. Expression of uncoupling protein mRNA in brown adipose tissue and leptin mRNA in epididymal fat, measured at the start of the dark period, was not altered by stress. There was an elevation of dopamine turnover in the hypothalami of rats restrained at the end of light cycle, but not those restrained in the morning. These results show that restraint stress has a greater effect on metabolism and energy balance when it is applied in the morning. Additional studies are needed to elucidate mechanisms involved in the suppression of food intake 9 h after restraint.
TL;DR: It is suggested that mild hypothermia induced by isolated core cooling is associated with an adrenergic response characterized by peripheral sympathetic nervous system activation without a significant adrenocortical or adrenomedullary response.
Abstract: The adrenergic, respiratory, and cardiovascular responses to isolated core cooling were assessed in awake human subjects. Mild core hypothermia was induced by intravenous infusion of 30 or 40 ml/kg of cold saline (4 degrees C) on 2 separate days. A warm intravenous infusion (30 ml/kg, 37 degrees C) was given on a third day as a control treatment. Mean norepinephrine concentration increased 400% and total body oxygen consumption increased 30% when core temperature decreased 0.7 degrees C. Mean norepinephrine concentration increased 700% and total body oxygen consumption increased 112% when core temperature decreased 1.3 degrees C. Core cooling was associated with peripheral vasoconstriction and increased mean arterial blood pressure, whereas heart rate was unchanged. Plasma epinephrine and cortisol concentrations were unchanged during core cooling. There were no changes in any measured parameter with the warm infusion. These findings suggest that mild hypothermia induced by isolated core cooling is associated with an adrenergic response characterized by peripheral sympathetic nervous system activation without a significant adrenocortical or adrenomedullary response. The respiratory and cardiovascular responses to core cooling are characterized by a shivering-induced increase in metabolic rate, norepinephrine-mediated peripheral vasoconstriction, and increased arterial blood pressure.
TL;DR: The data suggest that Type 1 and Type 2 GVA terminals may provide afferent neural signals, which, in turn, will be involved in body weight and food intake control systems, respectively.
Abstract: In vitro gastric vagal afferents' (GVAs) unit activities were recorded from the ventral GVA nerve strands in rats. The responsiveness of 16 GVA terminals to close intra-arterial injection of vehicle (0.1 ml), leptin (350 pmol), and cholecystokinin (CCK)-8 (10 pmol) was analyzed to generate a spike count-versus-time histogram. Data of 5-min spike counts before and after each treatment were normalized by dividing the latter by the former. A quotient (Q) > 1 indicates an excitatory effect, Q 1; CCK-8 pretreatment did not consistently alter leptin sensitivity. In contrast, Type 2 (n = 8) responded to leptin with Q 1. These data suggest that Type 1 and Type 2 GVA terminals may provide afferent neural signals, which, in turn, will be involved in body weight and food intake control systems, respectively.
TL;DR: Until recently, the major site of erythropoietin (Epo) production in the fetus was thought to be the liver, but studies have shown now that the Epo gene is expressed strongly in the fetal kidney, even in the temporary mesonephros.
Abstract: It is well established that erythropoiesis occurs first in the yolk sac, then in the liver, subsequently moving to the bone marrow and, in rodents, the spleen during development. The origin of the erythropoietic precursors and some factors suggested to be important for the changing location of erythropoiesis are discussed in this review. Until recently, the major site of erythropoietin (Epo) production in the fetus was thought to be the liver, but studies have shown now that the Epo gene is expressed strongly in the fetal kidney, even in the temporary mesonephros. The metanephric Epo mRNA is upregulated by anemia, downregulated by glucocorticoids, and contributes substantially to circulating hormone levels in hemorrhaged ovine fetuses. Other sites of Epo and Epo receptor production, likely to have important actions during development, are the placenta and the brain.
TL;DR: Findings provide the first evidence demonstrating that estrogen is protective against hypertension, possibly by amplifying the vasodilator contributions of ANG-(1-7), while reducing the formation and vasoconstrictor actions of ANG II.
Abstract: In pursuit of the hypothesis that estrogen shifts the vasoconstrictor-vasodilator balance of the renin-angiotensin system, we investigated the cardiovascular responses to administration of angiotensin-(1-7) [ANG-(1-7)] and angiotensin II (ANG II) in female transgenic (mRen2)27-positive [Tg(+)] and -negative [Tg(-)] rats in the presence and absence of 3 wk of estrogen replacement therapy. Fifty-three female Tg(-) and Tg(+) rats were oophorectomized and received either 17 beta-estradiol (1.5 mg/rat s.c. for 3 wk) or vehicle. At the end of 3 wk of estrogen treatment, mean blood pressure was lowered in freely moving chronically cannulated Tg(+) (159 +/- 4 vs. 145 +/- 5 mmHg, P < 0.05) and Tg(-) (119 +/- 4 vs. 108 +/- 2 mmHg, P < 0.05) rats. Moreover, the magnitude of the depressor component of the biphasic response to ANG-(1-7) was significantly enhanced in estrogen-treated Tg(+) rats, whereas the pressor component to ANG-(1-7) was attenuated in both Tg(+) and Tg(-) rats. Estrogen replacement significantly attenuated the pressor response to ANG II in both Tg(+) and Tg(-) rats. In addition, estrogen replacement therapy significantly reduced plasma ANG-converting enzyme activity in association with a reduction in circulating levels of ANG II. Tissue levels (kidney and aorta) of ANG-converting enzyme were also reduced with chronic estrogen replacement therapy. On the other hand, estrogen augmented the levels of plasma ANG-(1-7) in Tg(+) animals. Plasma renin activity was unchanged with estrogen treatment. These findings provide the first evidence demonstrating that estrogen is protective against hypertension, possibly by amplifying the vasodilator contributions of ANG-(1-7), while reducing the formation and vasoconstrictor actions of ANG II.
TL;DR: The present study supports the concept that NO has a role in hypercapnia-induced vasodilation in humans by studying the effect of NO synthase inhibition by N G-monomethyl-l-arginine on the changes of cerebral and ocular hemodynamic parameters elicited byhypercapnia and hyperoxia in healthy young subjects.
Abstract: It is well known that changes in P CO 2 or P O 2 strongly influence cerebral and ocular blood flow. However, the mediators of these changes have not yet been completely identified. There is evidenc...
TL;DR: This work suggests that neonatal QS is not an immature form of SWS and that AS is best considered as an undifferentiated behavioral state from which bothSWS and REM sleep develop.
Abstract: Active sleep (AS) in the neonate has been considered to be an immature form of rapid eye movement (REM) sleep. Quiet sleep (QS) has been thought to represent an immature form of slow wave sleep (SWS). To determine the relationship between the behaviorally determined states of AS and QS and electrographically determined REM sleep and SWS, we examined sleep ontogeny in the developing rat using an experimental routine that permitted long-term recordings and minimized the effects of maternal separation. Under these conditions, a transient state that included electroencephalographic slow wave activity and phasic motor activity was eventually replaced with the mature SWS pattern. Our work suggests that neonatal QS is not an immature form of SWS and that AS is best considered as an undifferentiated behavioral state from which both SWS and REM sleep develop.
TL;DR: The data suggest that jump training is associated with elevated activities of SOD and the coupled enzymes GPX and GR in muscle tissue, but other antioxidants remain unchanged.
Abstract: The purpose of this study was to measure resting muscle and blood antioxidant status in untrained (n = 8) and jump-trained (n = 8) humans and to evaluate free radical-mediated muscle damage after a strenuous jump test consisting of six bouts of 30-s continuous jumping separated by 2 min of rest. Resting muscle antioxidant activities [superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GR), and manganese SOD] were significantly higher in jump-trained compared with untrained subjects. Blood antioxidant enzyme activities and muscle catalase, however, were not different between the two groups. Creatine kinase activities increased significantly (P < 0.0001) after the jump test in untrained individuals, but remained unchanged in the jump trained. Plasma and muscle malonaldehyde (MDA) after the jump test were not significantly different from rest. These data suggest that jump training is associated with elevated activities of SOD and the coupled enzymes GPX and GR in muscle tissue, but other antioxidants remain unchanged. High-intensity jump exercise induces muscle enzyme leakage in untrained humans, but muscle lipid peroxidation, measured as changes in MDA, was not different in the two groups despite the varied muscle antioxidant enzyme levels.
TL;DR: DIO-prone rats overexpress and fail to regulate ARC NPY mRNA to energy restriction or hyperinsulinemia, possibly secondary to reduced inhibition because of defective ARC/ME dopamine turnover.
Abstract: Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) produce metabolic and physiological effects that promote the development and maintenance of obesity. In turn, NPY metabolism in these neurons is inhibited by dopamine release. In this study, ARC prepro-NPY mRNA and ARC/median eminence (ME) dopamine turnover were assessed in chow-fed male Sprague-Dawley rats prone to develop diet-induced obesity (DIO) or to be diet resistant (DR) when fed a high-energy (HE) diet. By in situ hybridization, DIO-prone rats had 39% more ARC NPY mRNA expression than DR-prone rats under chow-fed conditions. DIO-prone rat ARC/ME dopamine levels were 14% higher, but dopamine half-life was 176% longer and turnover was 59% less than DR-prone rats. Neither a 48-h fast nor 50% energy intake restriction for 5 days affected the already increased ARC NPY mRNA levels in DIO-prone rats. Both manipulations increased NPY expression to the level of DIO-prone rats in DR-prone rats by 23 and 35%, respectively. Finally, when fed HE diet for 2 wk, neither DIO- nor DR-prone rats altered their ARC NPY expression despite the development of obesity and hyperinsulinemia in DIO rats. Thus DIO-prone rats overexpress and fail to regulate ARC NPY mRNA to energy restriction or hyperinsulinemia. This dysregulation is possibly secondary to reduced inhibition because of defective ARC/ME dopamine turnover. Both may be important predisposing factors in the development of DIO.
TL;DR: Daily ESLC sessions during a 2-mo period resulted in increased LBM, decreased BF content, and increased muscular endurance in tetraplegic subjects without any noticeable adverse effects.
Abstract: The practical aspects of utilizing electrically stimulated leg cycling (ESLC) to counteract alterations in body composition were investigated in five tetraplegic subjects with long-standing complete spinal cord injuries (C5-C7). After a 2-wk adaptation period, the subjects performed seven ESLC sessions per week for 8 wk. No adverse reactions were noted in response to the ESLC program. The ESLC sessions were accompanied by higher lactate concentrations compared with arm exercise. Heart rate and blood pressure response revealed clear, but not serious, signs of autonomic dysreflexia in the beginning of the ESLC sessions. Body temperature increased moderately during the ESLC sessions. Peak oxygen uptake (Vo2) during an ESLC session increased by 70% (P < 0.05) after 8 wk of training. Body composition, evaluated by dual-energy X-ray absorptiometry (DEXA), demonstrated an increase in lean body mass (LBM) from 66.2 +/- 2.6 to 68.2 +/- 2.1% (P < 0.05), with a concomitant decrease in whole body fat (BF) content from 29.7 +/- 2.6 to 27.8 +/- 2.1% (P < 0.05) after training. The cross-sectional area of quadriceps, hamstrings, gluteus maximus, and gluteus medius muscles, measured by computer tomographic scans, increased from 267 +/- 27 to 324 +/- 27 cm2 (P < 0.05) after the training. In conclusion, daily ESLC sessions during a 2-mo period resulted in increased LBM, decreased BF content, and increased muscular endurance in tetraplegic subjects without any noticeable adverse effects.