Dominant role of thyrotropin-releasing hormone in the hypothalamic-pituitary-thyroid axis

Hypothalamic thyrotropin-releasing hormone (TRH) stimulates thyroid-stimulating hormone (TSH) secretion from the anterior pituitary. TSH then initiates thyroid hormone (TH) synthesis and release from the thyroid gland. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback is thought to be the primary regulator. This hypothesis, however, has yet to be proven in vivo. To elucidate the relative importance of TRH and TH in regulating the hypothalamic-pituitary-thyroid axis, we have generated mice that lack either TRH, the beta isoforms of TH receptors (TRbeta KO), or both (double KO). TRbeta knock-out (KO) mice have significantly higher TH and TSH levels compared with wild-type mice, in contrast to double KO mice, which have reduced TH and TSH levels. Unexpectedly, hypothyroid double KO mice also failed to mount a significant rise in serum TSH levels, and pituitary TSH immunostaining was markedly reduced compared with all other hypothyroid mouse genotypes. This impaired TSH response, however, was not due to a reduced number of pituitary thyrotrophs because thyrotroph cell number, as assessed by counting TSH immunopositive cells, was restored after chronic TRH treatment. Thus, TRH is absolutely required for both TSH and TH synthesis but is not necessary for thyrotroph cell development.     

Effects of leucine-enkephalin on hypothalamic-pituitary-thyroid axis in rats

Basal thyrotropin (TSH) levels in plasma and the TSH response to thyrotropin-releasing hormone (TRH) were inhibited after Leucine-enkephalin (L-EK) administration iv in rats. TRH and TSH responses to cold were inhibited after L-EK administration. In the L-DOPA, haloperidol or 5-hydoxytryptophan-treated rats, the inhibitory effect of L-EK on TSH release was restored. Findings suggested that L-EK acted both the hypothalamus and pituitary. Its inhibitory effects on TRH and TSH release at least partially mediated by interaction with amines in the central nervous system.     

Neuro-endocrine correlations of hypothalamic-pituitary-thyroid axis in healthy humans

Neuro-endocrine hormone secretion is characterized by circadian rhythmicity. Melatonin, GRH and GH are secreted during the night, CRH and ACTH secretion peak in the morning, determining the circadian rhythm of cortisol secretion, TRH and TSH show circadian variations with higher levels at night. Thyroxine levels do not change with clear circadian rhythmicity. In this paper we have considered a possible influence of cortisol and melatonin on hypothalamic-pituitary-thyroid axis function in humans. Melatonin, cortisol, TRH, TSH and FT4 serum levels were determined in blood samples obtained every four hours for 24 hours from ten healthy males, aged 36-51 years. We correlated hormone serum levels at each sampling time and evaluated the presence of circadian rhythmicity of hormone secretion. In the activity phase (06:00 h-10:00 h-14:00 h) cortisol correlated negatively with FT4, TSH correlated positively with TRH, TRH correlated positively with FT4 and melatonin correlated positively with TSH. In the resting phase (18:00 h-22:00 h-02:00 h) TRH correlated positively with FT4, melatonin correlated negatively with FT4, TSH correlated negatively with FT4, cortisol correlated positively with FT4 and TSH correlated positively with TRH. A clear circadian rhythm was validated for the time-qualified changes of melatonin and TSH secretion (with acrophase during the night), for cortisol serum levels (with acrophase in the morning), but not for TRH and FT4 serum level changes. In conclusion, the hypothalamic-pituitary-thyroid axis function may be modulated by cortisol and melatonin serum levels and by their circadian rhythmicity of variation.     

Effect of 2-deoxy-D-glucose on hypothalamic-pituitary-thyroid axis in rats

The intraperitoneal administration to rats of 500 mg/kg body weight of 2-deoxy-D-glucose, an analog of glucose which produces intracellular glucopenia with rise in extracellular fluid glucose concentration, is followed by a significant though transient reduction of hypothalamic TRH content, observed at 15 and 25 minutes after drug administration. A subsequent increase in serum thyrotropin followed by that of triiodothyronine concentration was also observed. These findings indicate that the neuroglucopenia induced by 2-deoxy-D-glucose may play a role in the regulating the hypothalamic-pituitary-thyroid axis.     

Effects of streptozotocin-induced diabetes mellitus on hypothalamic-pituitary-thyroid axis in rats

The effects of streptozotocin-induced diabetes mellitus on the hypothalamic-pituitary-thyroid axis in rats were studied. Streptozotocin (60 mg/kg) was injected ip. Rats were decapitated at two and four weeks after the streptozotocin treatment. Thyrotropin releasing hormone (TRH), thyrotropin (TSH), thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), 3,3'-diiodothyronine (3,3'-T2) and 3',5'-diiodothyronine (3',5'-T2) were measured by means of the specific radioimmunoassay for each. Immunoreactive TRH (ir-TRH) contents in the hypothalamus significantly decreased at four weeks (p less than 0.02). Basal TSH levels in plasma significantly decreased (p less than 0.005, p less than 0.001), and plasma ir-TRH and TSH responses to cold were significantly inhibited after the streptozotocin treatment (p less than 0.001). The plasma TSH response to TRH was decreased, but not significantly. The plasma T4 and T3 levels fell significantly. RT3 did not change throughout the experiment. 3,3'-T2 levels in plasma fell significantly, whereas 3',5'-T2 increased. Blood glucose levels rose significantly after streptozotocin treatment, but insulin treatment led to partial restoration. The findings suggest that streptozotocin-induced diabetes mellitus affects various sites of the hypothalamic-pituitary-thyroid axis in rats.     

Screening study of the effects of the hypothalamic-pituitary-thyroid axis on hemostasis in rats

The hormonal regulation of hemostasis has had little attention in research, and the existing literature data are relatively contradictory. The possible effects of the hormones of the hypothalamic-pituitary-thyroid axis on hemocoagulation and the fibrinolytic system are studied here. The study was conducted on 80 white male rats of the Wistar breed. The necessary blood quantity was obtained by cardiac puncture realized under ether narcosis. The basic parameters of the hemocoagulation and fibrinolytic activity of the plasma were determined by Diagnostica Stago tests (France), using an automatic coagulometer (Italy). The hormones employed in the study: Thyreotropin releasing hormone (0.06 mg/kg bw), Thyroid stimulating hormone (1 MU/kg bw), Triiodothyronine (0.08 mg/kg bw), and Thyroxin (0.08 mg/kg bw) applied s.c. for three consecutive days, extended the activated partial thromboplastine time (p less than 0.001), proto-thromboplastine time (p less than 0.001), thrombin time (p less than 0.001), reptilase time (p less than 0.001), and shortened the euglobin clot lysis time of (p less than 0.001). These data indicate that each of the hormones used causes significant changes in hemostasis by suppressing the coagulability by the intrinsic and extrinsic system pathways, and transformation of fibrinogen into fibrin. The shortened euglobim clot lysis time may be recognized as a manifestation of increased levels of plasma plasminogen activators. The results obtained show that hypothalamic-pituitary-thyroid hormones are significant regulators of hemostasis, since they cause an expressed hypocoagulation and increase plasma fibrinolytic activity.     

Permanent alterations in the hypothalamic-pituitary-thyroid axis in the rat following phenytoin exposure in utero

Phenytoin exposure in utero results in permanent alterations of the hypothalamic-pituitary-thyroid axis in the rat. The DPH exposed animals have decreased weight gain, thyroxine and triiodothyronine concentrations. In addition, they have blunted thyroid-stimulating hormone responses to thyrotropin-releasing hormone, propylthiouracil challenge or thyroidectomy. The diminished pituitary response in these animals is similar to that reported in neonatal thyrotoxicosis in the rat. This may be due, in part, to structural similarities between phenytoin and the thyroid hormone.     

Mechanism of the alcohol cyclic pattern: role of the hypothalamic-pituitary-thyroid axis

The cause of the cycle of urinary alcohol levels (UALs) in rats fed ethanol continually at a fixed rate is unknown. Rats were fed ethanol intragastrically at a constant dose for 2 mo, and daily body temperatures and UALs were recorded. Body temperature cycled inversely to UAL, suggesting that the rate of metabolism could be mechanistically involved in the rate of ethanol elimination during the cycle. To document this, whole body O(2) consumption rate was monitored daily during the cycle. The rate of O(2) consumption correlated positively with the change in body temperature and negatively with the change in UAL. Since the metabolic rate responds to changes in body temperature, thyroid hormone levels were measured during the UAL cycle. T(4) levels correlated positively with the O(2) consumption rate and negatively with the UALs. In a second experiment using propylthiouracil treatment, UALs did not cycle and a fall in body temperature failed to stimulate an increase in the rate of ethanol elimination. Consequently, rats died of overdose. Likewise, in a third experiment using rats with severed pituitary stalks, UALs failed to cycle and rats died of overdose. From these observations it was concluded that the UAL cycle depends on an intact hypothalamic-pituitary-thyroid axis response to the ethanol-induced drop in body temperature by increasing the rate of ethanol elimination.     

Role of melanocortin signaling in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis

The melanocortin signaling system is orchestrated by two, independent groups of neurons in the hypothalamic arcuate nucleus with opposing functions that synthesize either alpha-melanocyte stimulating hormone (alpha-MSH) or agouti-related protein (AGRP). These neurons exert regulatory control over hypophysiotropic TRH neurons in the hypothalamic paraventricular nucleus (PVN) at least in part through direct, overlapping, monosynaptic projections to the PVN. Alpha-MSH has an activating effect on hypophysiotropic TRH neurons via the phosphorylation of CREB, and when administered exogenously, can completely reverse fasting-induced suppression of TRH mRNA in the PVN. AGRP has a potent inhibitory effect on the hypothalamic-pituitary-thyroid axis in normally fed animals, mediated through actions at melanocortin 4 receptors. Inhibition of the HPT axis by fasting may be explained by inhibition of melanocortin signaling as a result of a reduction in alpha-MSH and increase in AGRP. Neuropeptide Y may also modulate the effects of the melanocortin signaling system during fasting by potentiating the inhibitory actions of AGRP on hypophysiotropic TRH neurons to prevent the phosphorylation of CREB and through direct inhibitory effects on alpha-MSH-producing neurons in the arcuate nucleus.     

Changes in the activity of selected enzymes during starvation of Physarum polycephalum

The levels of glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, lactate dehydrogenase, and cyclic phosphodiesterase activities were examined in growing and starving plasmodia of Physarum polycephalum. The activities of lactate dehydrogenase, 6-phosphogluconate dehydrogenase, and glucose-6-phosphate dehydrogenase decreased whereas that of cyclic phosphodiesterase increased. The change in activity of lactate dehydrogenase was the result of the variation of the activity of a single enzyme quite similar to the lactate dehydrogenases of higher animals.     

Changes in lipid composition during starvation and germ-tube formation inCandida albicans

The changes in the lipid components ofCandida albicans have been determined during growth, starvation, and germ-tube formation.¹⁴C-Labeled cells were used to determine the extent of synthesis and degradation of the different lipid fractions. On a dry weight basis the percentage of total lipid increased from 18% for blastospores to 22% after starvation but decreased to 11% after 4 h of germination. The major components of the lipid fraction were sterols (36–52%) and phospholipids (28–42%). The free and esterified sterol fractions both increased approximately 45% during starvation. The free sterol content continued to increase over the initial stage of germ-tube formation, then decreased with time. The sterol ester fraction decreased throughout germination to the concentration found in growing blastospores. The changes in specific activity (cpm/μg sterol) of these fractions indicated that sterol esters were precursors for free sterols during germination. The total phospholipid fraction increased during starvation but there was a decrease in both the cellular concentration (60%) and the specific activity during germination. There were only minor changes in the relative concentrations of phosphatidylinositol, phosphatidylserine, phosphatidylcholine, and phosphatidylethanolamine which indicated coordinate synthesis and degradation of these components. Free fatty acids and triacylglycerides are only minor components of the total lipid pool.     

Changes in plasma cortisol during acute cold exposure in euthermic European hedgehogs: thermoregulatory role of the hypothalamo-pituitary-adrenal axis

Summary During acute cold exposure regulatory heat production of European hedgehogs was significantly increased with a simultaneous rise in the plasma cortisol level. Soon after cold exposure, at the time when standard metabolic rate was measured, the plasma cortisol level was reduced again. This finding indicates a highly reactive hypothalamo-pituitary-adrenal axis in euthermic hedgehogs exposed to a cold environment.Two effects of the adrenocorticostatic agent metopirone ditartrate were observed: (1) A metopirone-induced increase in nonshivering thermogenesis (NST) starting 18 min after application, reaching a maximum after 43 min and disappearing after 90 min (Fig. 1, Table 1). Simultaneously a profound long lasting hyperglycemia was observed (Fig. 2). (2) In contrast to untreated hedgehogs, animals which were given metopirone did not show an increase in the plasma cortisol level, when exposed to cold within 2 to 3 h (Fig. 6).When animals were pretreated with dexamethasone the metopirone-induced NST was suppressed, indicating that the effect of metopirone is mediated by the hypothalamo-pituitary-adrenal system (Fig. 4).The effect of metopirone at doses used in this study was reversible.It is suggested that a combined action of corticosteroids and catecholamines is involved in the control of regulatory heat production.Abbreviations SMR standard metabolic rate - NST nonshivering thermogenesis Supported by the Deutsche Forschungsgemeinschaft Wu 63/5     

Changes in body composition of germ-free and conventional chickens during starvation

• 1.1. Changes in body composition during starvation were compared between germ-free (GF) and conventionalized (CVL) chicks in experiment 1. At 8 days of age, the GF birds were divided into two groups, i.e. GF and CVL groups. The CVL birds were inoculated with faeces from conventionally reared birds. Until 14 days of age, both birds were fed a diet ad lib, and thereafter starved for 6 days.
• 2.2. Nitrogen loss during starvation was significantly lower in CVL birds, though the reverse was true for water loss. Fasting heat production was comparable between two environments.
• 3.3. Influence of the gut microflora on body weight and nitrogen losses during starvation was investigated in birds prefed diets high or low in dietary protein in experiment 2.
• 4.4. No significant effect of the gut microflora was observed in body weight and nitrogen losses. Body weight was severely reduced in birds prefed the high protein diet and nitrogen loss was lower in birds prefed the low protein diet.

     

Changes in cell composition and viability of Bdellovibrio bacteriovorus during starvation

1. Washed cell suspensions of Bdellovibrio bacteriovorus harvested shortly after lysis of their substrate organisms and shaken in buffer have a constant and high endogenous respiration rate for a bout 6 h which then declines sharply to a rate approximately 10% of the original. Viability of cell suspensions shows little change over the first 4–6 h and then decreases by some 50% in 10 h.
2. Over the first 5–6 h of starvation there is a loss of about 50% of total cell carbon. This loss is distributed about equally between CO₂ and small molecules released into the suspending buffer. The protein and nucleic acid contents of the cells decrease concomitantly from time zero during starvation while DNA content remains constant. Ribosomal profiles show a rapid degradation of ribosomes.
3. In the presence of glutamate or glutamate plus a balanced amino acid mixture, loss of cell material and loss of viability is partially or completely prevented. There is extensive protein turnover when glutamate and an amino acid mixture are available to the bdellovibrio.
4. The pattern of changes observed in B. bacteriovorus during starvation is compared to reported changes in other species of bacteria, and the significances of its high endogenous respiration and sensitivity to starvation are discussed.

     

Changes in respiration activity and energetics of Candida utilis during starvation

Changes in catabolic activity of exogenous and endogenous metabolism were studied with respect to changes in the intracellular level of adenine nucleotides and pyruvate during long-term yeast starvation at low temperature.