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At least 703 records · Page 39Linked to original sources

PubMed2003

Deregulation of iron homeostasis and cold-preservation injury to rat liver stored in University of Wisconsin solution.

Very little is known about iron metabolism and the mediators of iron metabolism in liver subjected to cold storage before transplantation. Therefore, in this study, we investigated the effect of cold storage on iron homeostasis in the rat liver. When livers were stored at 4 degrees C in University of Wisconsin solution for up to 6 and 24 hours, significant increases occurred in the labile iron pool, ferritin protein, and heme oxygenase activity. Significant decreases in heme content and iron regulatory protein 1 and 2 binding activities occurred by 24 hours. Liver injury indicated by significant increases in University of Wisconsin solution transaminase activity and liver lipid hydroperoxide levels occurred by 6 and 24 hours. Taken together, these results suggest that during pretransplantation cold storage of the liver, an aberrant iron homeostasis develops that contributes to preservation injury, and predisposes the liver to reperfusion injury by iron-dependent reactive oxygen species/Fenton reaction.

Adenosine↗

PubMed2002

Control of extracellular matrix homeostasis of normal cartilage by a TGFbeta autocrine pathway. Validation of flow cytometry as a tool to study chondrocyte metabolism in vitro.

OBJECTIVE: To validate flow cytometry as an experimental technique for the study of the homeostasis of the extracellular matrix (ECM) of human articular cartilage. METHODS: Given the established insights in the relation between the transforming growth factor (TGF)-beta type II Receptor (TGF-betaRII)/TGF-beta auto/paracrine pathway, the intracellular levels of matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs), and the accumulation of ECM molecules in the ECM of articular cartilage, this metabolic pathway was used as a reference model to fulfill the objective. Chondrocytes were liberated from visually intact femoral condyle cartilage and cultured in gelled agarose to maintain their differentiated phenotype. After 2 weeks of culture, the chondrocytes were isolated from the agarose and flow cytometry was used to analyse the expression of TGF-betaRII on the plasmamembrane, the expression of TGFbeta1, MMP-1, MMP-3, TIMP-1 and TIMP-3 inside the cells, as well as the amounts of aggrecan, type II collagen and hyaluronan in the cell-associated matrix (CAM). The expression of the different substances was analysed with flow cytometry and reported as mean fluorescence intensity (MFI), which is due to the binding of FITC-labeled antibodies to their specific antigens. In addition, the effects of exogenous TGFbeta1 on the expression of these proteins was investigated on chondrocytes cultured in serum-free media. Enzyme Linked Immunosorbent Assay (ELISA) was performed to evaluate the MMP-1, MMP-3, TIMP-1 and MMP-1/TIMP-1 complex in the culture medium collected after the last 3 days of the culture period. The correlations between the data were analysed with the Spearman's test. RESULTS: Exogenous TGF-beta1 increased the accumulation of aggrecan and hyaluronan in the CAM of chondrocytes and down-regulated the intracellular levels of MMP-1 and -3. TIMP-1 and -3 were increased after exposure to TGF-beta1. Baseline expression of TGF-betaRII on the plasmamembrane of normal human articular chondrocytes significantly correlated with the intracellular levels of TGFbeta1, TIMP-1 and TIMP-3. TGFbeta1 was correlated with TIMP-1, TIMP-3 and MMP-1. Aggrecan in the CAM was inversely correlated with the ratio of MMP-1 to TIMPs. In addition, there were correlations between TIMP-1 and TIMP-3, aggrecan and hyaluronan. ELISA also revealed the correlation between MMP-1 and TIMP-1 secreted by the chondrocytes into the nutrient medium. MMP-1/TIMP-1 complex was hardly found in the medium. CONCLUSIONS: Some aspects of ECM metabolism of normal cartilage were evaluated by flow cytometry. Chondrocytes from normal human cartilage, when cultured in gelled agarose, showed correlations between the expression of TGF-betaRII/TGF-beta1 and the intracellular levels of TIMPs, indicating that TGF-beta autocrine pathway may contribute to homeostasis of the ECM in the normal cartilage. The relations between MMPs, TIMPs and the ECM molecules support that a physiological balance between MMPs and TIMPs results in a well-controlled matrix turnover in normal cartilage.

Aggrecans↗

PubMed2002

Creatine supplementation alters insulin secretion and glucose homeostasis in vivo.

Dietary creatine supplementation has been used to improve skeletal muscle performance. However, dietary creatine manipulation also affects glucose homeostasis. The aim of this study was to investigate the effect of dietary creatine supplementation on insulin secretion, glucose tolerance, and quadriceps glycogen metabolism in chow-fed rats. Forty-eight rats in total were divided into 2 groups of 24 and were then subdivided into 6 groups of 8. Rats were fed a diet supplemented with 0% (CON) or 2% (CREAT) creatine for 2, 4, or 8 weeks. At these 3 time points an oral glucose tolerance test was performed. Two days later, rats were euthanized and the pancreas and quadriceps muscles were collected. The peak insulin response to a glucose challenge was significantly elevated after both 4 (CON 327 +/- 72 v CREAT 735 +/- 140 pmol/L, P =.01) and 8 (CON 248 +/- 48 v CREAT 588 +/- 136 pmol/L, P =.02) weeks. Fasting insulin levels were also increased by creatine supplementation for 8 weeks (CON 78 +/- 14 v CREAT 139 +/- 14 pmol/L, P =.01). Glucose tolerance was not affected until 8 weeks at which point the peak plasma glucose was elevated in the creatine supplemented group (CON 10.1 +/- 0.6 v CREAT 13.5 +/- 1.5 mmol/L, P =.05). A significant increase in pancreatic total creatine content was seen in supplemented animals at 2 (CON 1.2 +/- 0.1 v CREAT 2.7 +/- 0.1 micromol/g wet wt, P =.005), 4 (CON 1.5 +/- 0.2 v CREAT 2.7 +/- 0.3 micromol/g wet wt, P =.02) and 8 (CON 1.5 +/- 0.1 v CREAT 2.6 +/- 0.1 micromol/g wet wt, P =.005) weeks, whereas no change in quadriceps total creatine or glycogen content was observed at any individual time point. This study shows that prolonged creatine supplementation induces abnormalities in pancreatic insulin secretion and changes in glucose homeostasis.

Animals↗

PubMed2000

Mitochondrial Ca(2+)homeostasis in the regulation of apoptotic and necrotic cell deaths.

Using distinct models of apoptosis and necrosis, we have investigated the effect of mitochondrial Ca(2+)(Ca(m)) homeostasis in the regulation of cell death in neuroblastoma cells as well as cardiac myocytes. The steady state level of Ca(m)was determined as the FCCP-releasable Ca(2+). Culturing cells with low concentration of extracellular Ca(2+)(Ca(o)) or with EGTA triggered an early reduction in both the Ca(m)store and the membrane potential (DeltaPsi(m)). This was followed by the detection of cytochrome c release, caspase activation, and apoptosis. Inhibitors of the mitochondrial permeability transition pore such as cyclosporin A and Bcl-2 blocked the release of Ca(m)and inhibited apoptosis. In contrast, mitochondrial Ca(2+)overload resulted in necrotic cell death. Culturing cells in the presence of excess Ca(o)led to increased Ca(m)load together with a decrease of DeltaPsi(m)that reached maximum at 1 h, with necrosis occurring at 2 h. While the decline of Ca(m)and DeltaPsi(m)was a coupled reaction for apoptosis, this relationship was uncoupled during necrosis. Clonazepam, a relatively specific inhibitor of the mitochondrial Na/Ca exchanger, was able to protect the cells from necrosis by reducing Ca(m)overload. Importantly, combination of clonazepam and cyclosporin showed a cooperative effect in further reducing the Ca(m)overload and abolished cell death. The data imply the participation of Ca(m)homeostasis in the regulation of apoptosis and necrosis.

Animals↗

PubMed1983

Effect of fasting on posthyperglycemic glucose homeostasis in obesity--experimental model for reactive hypoglycemia.

The relationship between altered glucose-insulin interaction in the hyperglycemic period of oral glucose tolerance test (oGTT) and impaired posthyperglycemic glucose homeostasis was studied in 9 obese females. They underwent 6-hour oGTT following 72-96 hour total fast, and the results of blood glucose, insulin, growth hormone, cortisol, glucagon and free fatty acids were compared to those of the control test. Blood glucose values in the hyperglycemic period of oGTT were higher during the post-fasting than in the control study. Posthyperglycemic glucose levels following fast dropped below the control values and four patients showed subjective symptoms of reactive hypoglycemia. Mean maximum blood glucose irrespective of time was significantly higher, mean glucose nadir lower after fast than in the control experiment (138.4 +/- 7.1 mg/dl vs. 112.4 +/- 5.2 and 47.3 +/- 1.4 vs. 61.3 +/- 3.0, respectively). Insulin response following fast was significantly reduced in 0-2 h period with delayed maximum value obtained at 123.3 +/- 14.5 min vs. 60.0 +/- 10.0 min in the basal experiment. Post-fasting counter-regulatory cortisol response was higher when compared to control, but there was no difference in growth hormone and glucagon secretion. Basal and post-glucose values of free fatty acids were significantly higher after fast than in the control study. The data suggest that fasting-induced impairment of glucose-insulin interaction in the hyperglycemic period of oGTT decreases the ability of obese subjects to maintain posthyperglycemic glucose homeostasis and provokes reactive hypoglycemia in some of them. Examination of glucose metabolism in fasted subjects is a convenient experimental model for the investigation of reactive hypoglycemia.

Blood Glucose↗

PubMed1988

Insulin receptors and glucose homeostasis in type 2 diabetics influenced by acetyl-salicylic acid treatment.

The effect of acetyl-salicylic acid administration on insulin receptors on the erythrocytes and the changes of glucose homeostasis examined by hyperglycaemic clamps were evaluated in 8 Type 2 diabetics. Significantly increased number of insulin receptors and decreased insulin affinity constants were found in diabetics after the acetyl-salicylic acid treatment (p less than 0.02). Significantly decreased tissue sensitivity to insulin and metabolic clearance rate of insulin (p less than 0.02) were observed in Type 2 diabetics after the acetyl-salicylic acid treatment. We conclude that acetyl-salicylic acid may impair glucose homeostasis due to interference with insulin action in peripheral tissues.

Aged↗

PubMed2000

Regulation of ionic homeostasis by mammalian embryos.

Control and regulation of cellular homeostasis are essential for normal embryo development and maintenance of viability. By understanding the role of ionic homeostasis in normal cell development and homeostatic control by the developing embryo, it is possible to develop culture systems that minimize cellular stress and therefore maintain embryo viability. This article discusses the regulation of intracellular levels of protons (pHi), calcium, magnesium, and phosphate in mammalian embryos.

Animals↗

PubMedDate not supplied

[Glucose homeostasis in mucoviscidosis].

In patients with cystic fibrosis (CF) of the pancreas an endocrine imbalance especially of insulin secretion due to progressive structural abnormalities of the pancreas must be expected. 30-75 percent of CF-patient exhibit impaired oral glucose tolerance tests (oGTT). Deterioration of the glucose homeostasis leads to a secondary diabetes mellitus that mimics a type II diabetes in the early stage, in the later course of disease it resembles a type I diabetes with absolute insulinopenia. In this study glucose homeostasis was investigated after an oral glucose load with 1.75 g glucose/kg bodyweight. Glucose, C-peptide and insulin were measured during 180 minutes. 32 nondiabetic CF-patients were studied. 16 patients revealed an impaired oral glucose tolerance according to the criteria of the National Diabetes Data Group. 6 patients showed a normal glucose tolerance and 10 patients with normal fasting and 120 minute glucose concentrations were hyperglycemic at midtest determinations. Impaired oGTTs were observed in malnourished CF-patients in a higher rate than in normal weight patients. A delayed and exceeded C-peptide and insulin response to the oral glucose load was determined with deteriorating glucose tolerance. Glucose values did not drop to fasting values at the 180 minute determination in cases of impaired oral glucose tolerance.

Adolescent↗

PubMedDate not supplied

Hormonally regulated components of the adrenocortical cell environment and the control of adrenal cortex homeostasis.

The extracellular matrix (ECM) strongly contributes to the regulation of cell proliferation and cell differentiation, and thereby of embryonic development and adult tissue homeostasis. We review here the ongoing characterization of the structure and functions of the extracellular matrix components secreted by adrenocortical cells and discuss their possible implication in the hormonal regulation of adrenal cortex homeostasis. Fibronectin (FN) and laminin (LN) are both major adhesive proteins for adrenocortical cells. FN is synthesized by bovine fasciculata cells in primary culture, and its synthesis is stimulated by TGF(beta)1, TGF(beta)2, and FGF-2 but is not modified by IGF-1 or by the hormones ACTH and angiotensin II. LN is also synthesized by bovine fasciculata cells and its synthesis is specifically stimulated by ACTH. Both proteins are haptotactic and chemotactic for adrenocortical cells, suggesting a physiological role in adrenocyte migration. Their distribution in the adrenal gland is quite distinct. LN is uniformly present in the steroidogenic cells from the three zones, whereas FN is abundant in the fibrovascular structures of the capsule and the cortex. ACTH treatment of adrenocortical cells strongly induces the expression and secretion of thrombospondin-2 (TSP2), a large trimeric matricellular protein. The multimodular structure of TSP2 is the support of a variety of biological functions. TSP2 promotes attachment but prevents spreading of adrenocortical cells. On the other hand, TSP2 induces the activation of latent TGFbeta through an indirect mechanism and is anti-angiogenic in vitro. The overall distribution of TSP2 in the glomerulosa and fasciculata zones of the adrenal cortex, and its absence from the reticularis zone, argue in favor of a role in the protection of adrenocortical cells against apoptosis. In the adrenal cortex, five main biological functions are potentially regulated by components of the extracellular matrix : stem cell commitment into the adrenocyte differentiation pathway, terminal differentiation toward the three distinct adrenocyte phenotypes, centripetal migration, apoptosis and the formation of the capillary network. Future studies will aim at deciphering which extracellular component(s) is involved in each of these regulations.

Adrenal Cortex↗

PubMed1985

Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electrolyte homeostasis.

The renin-angiotensin-aldosterone axis exerts major control over sodium and potassium balance and arterial blood pressure. These three functions are continuously regulated by changes in angiotensin II and aldosterone levels in response to wide variations in dietary intake of sodium and potassium. In addition, changes in intrarenal physical factors cause changes in the supply of distal tubular sodium that, in turn, work to determine sodium and potassium excretion and to modulate the release of renal renin. However, certain aspects of sodium homeostasis cannot be fully explained either by the activity of the renin system or by intrarenal physical factors, and this has led investigators to search for other natriuretic hormonal mechanisms. Recently, it has become clear that atrial tissue contains a group of peptides, at least one of which is probably secreted as a regulatory hormone. In animals, these atrial peptides produce immediate, marked natriuresis associated with a rise in glomerular filtration rate (but no alteration of total renal flow) and a simultaneous decrease in arterial blood pressure. Atrial peptides also inhibit renal renin secretion and adrenal cortical secretion of aldosterone, and they oppose the vasoconstrictive action of angiotensin II. One of these atrial peptides may therefore be the long-sought natriuretic hormone, though in a different form and shape than was envisioned. The fact that atrial peptide works to oppose the renin system at four points suggests that this new hormone could have a major complementary role in long-term regulation of blood pressure and electrolyte homeostasis. In this construction the renin system primarily defends sodium balance and blood pressure, with the atrial hormone having an increasing counter-influence in situations involving high blood pressure or sodium surfeit. We can soon expect to learn more about this atrial hormone, including which peptide is the active circulating hormone, what induces or inhibits its release, and what part it plays in cardiovascular diseases.

Aldosterone↗

PubMed2004

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca2+ entry pathway.

At central synapses, P/Q-type Ca(2+) channels normally provide a critical Ca(2+) entry pathway for neurotransmission. Nevertheless, we found that nerve terminals lacking alpha(1A) (Ca(V)2.1), the pore-forming subunit of P/Q-type channels, displayed a remarkable preservation of synaptic function. Two consistent physiological changes reflective of synaptic homeostasis were observed in cultured hippocampal neurons derived from alpha(1A) (-/-) mice. First, the presynaptic response to an ionophore-mediated Ca(2+) elevation was 50% greater, indicating an enhanced Ca(2+) sensitivity of the release machinery. Second, basal miniature excitatory postsynaptic current frequency in alpha(1A) (-/-) neurons was increased 2-fold compared with WT neurons and occluded the normal response of presynaptic terminals to cAMP elevation, suggesting that the compensatory mechanism in alpha(1A) (-/-) synapses and the modulation of presynaptic function by PKA might share a final common pathway. We used cDNA microarray analysis to identify molecular changes underlying homeostatic regulation in the alpha(1A) (-/-) hippocampus. The 40,000 entries in our custom-made array included likely targets of presynaptic homeostasis, along with many other transcripts, allowing a wide-ranging examination of gene expression. The developmental pattern of changes in transcript levels relative to WT was striking; mRNAs at 5 and 11 days postnatal showed little deviation, but clear differences emerged by 22 days. Many of the transcripts that differed significantly in abundance corresponded to known genes that could be incorporated within a logical pattern consistent with the modulation of presynaptic function. Changes in endocytotic proteins, signal transduction kinases, and candidates for Ca(2+)-sensing molecules were consistent with implications of the direct physiological experiments.

Animals↗

PubMed2004

The voltage-gated Na+ channel NaVBP has a role in motility, chemotaxis, and pH homeostasis of an alkaliphilic Bacillus.

The prokaryotic voltage-gated Na(+) channel, NaChBac, is one of a growing channel superfamily of unknown function. Here we show that Na(V)BP, the NaChBac homologue encoded by ncbA in alkaliphilic Bacillus pseudofirmus OF4, is a voltage-gated Na(+) channel potentiated by alkaline pH. Na(V)BP has roles in motility, chemotaxis, and pH homeostasis at high pH. Reduced motility of bacteria lacking functional Na(V)BP was reversed by restoration of the native channel but not by a mutant Na(V)BP engineered to be Ca(2+)-selective. Motile ncbA mutant cells and wild-type cells treated with a channel inhibitor exhibited behavior opposite to the wild type in response to chemoeffectors. Mutants lacking functional Na(V)BP were also defective in pH homeostasis in response to a sudden alkaline shift in external pH under conditions in which cytoplasmic [Na(+)] is limiting for this crucial process. The defect was exacerbated by mutation of motPS, the motility channel genes. We hypothesize that activation of Na(V)BP at high pH supports diverse physiological processes by a combination of direct and indirect effects on the Na(+) cycle and the chemotaxis system.

Animals↗

PubMed2004

Identification of tandem duplicate regulatory small RNAs in Pseudomonas aeruginosa involved in iron homeostasis.

In many bacteria, iron homeostasis is controlled primarily by the ferric uptake regulator (Fur), a transcriptional repressor. However, some genes, including those involved in iron storage, are positively regulated by Fur. A Fur-repressed regulatory small RNA (sRNA), RyhB, has been identified in Escherichia coli, and it has been demonstrated that negative regulation of genes by this sRNA is responsible for the positive regulation of some genes by Fur. No RyhB sequence homologs were found in Pseudomonas aeruginosa, despite the identification of genes positively regulated by its Fur homolog. A bioinformatics approach identified two tandem sRNAs in P. aeruginosa that were candidates for functional homologs of RyhB. These sRNAs (PrrF1 and PrrF2) are >95% identical to each other, and a functional Fur box precedes each. Their expression is induced under iron limitation. Deletion of both sRNAs is required to affect the iron-dependent regulation of an array of genes, including those involved in resistance to oxidative stress, iron storage, and intermediary metabolism. As in E. coli, induction of the PrrF sRNAs leads to the rapid loss of mRNAs for sodB (superoxide dismutase), sdh (succinate dehydrogenase), and a gene encoding a bacterioferritin. Thus, the PrrF sRNAs are the functional homologs of RyhB sRNA. At least one gene, bfrB, is positively regulated by Fur and Fe(2+), even in the absence of the PrrF sRNAs. This work suggests that the role of sRNAs in bacterial iron homeostasis may be broad, and approaches similar to those described here may identify these sRNAs in other organisms.

Bacterial Proteins↗

PubMed2005

{gamma}{delta} T cell homeostasis is established in competition with {alpha}{beta} T cells and NK cells.

gammadelta T cells are a diverse population of lymphocytes that play an important role in immune regulation. The size of the gammadelta T cell pool is tightly regulated, comprising only 1-10% of total lymphoid T cells in mice and humans. We examined the homeostatic regulation of gammadelta T cells using a model of lymphopenia-induced homeostatic expansion. We found that IL-15 and, to a lesser extent, IL-7 play an important role in lymphoid gammadelta T cell homeostasis. Moreover, gammadelta T cell homeostatic expansion was limited not only by gammadelta T cells themselves but also by natural killer cells and alphabeta T cells. Our results suggest that CD8(+) alphabeta T cells are the most potent inhibitors of gammadelta T cell homeostasis and exert their effect by competing for IL-15.

Animals↗

PubMed2006

Adipocyte enhancer-binding protein 1 is a potential novel atherogenic factor involved in macrophage cholesterol homeostasis and inflammation.

Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) and liver X receptor alpha (LXRalpha) play pivotal roles in macrophage cholesterol homeostasis and inflammation, key biological processes in atherogenesis. Herein we identify adipocyte enhancer-binding protein 1 (AEBP1) as a transcriptional repressor that impedes macrophage cholesterol efflux, promoting foam cell formation, via PPARgamma1 and LXRalpha down-regulation. Contrary to AEBP1 deficiency, AEBP1 overexpression in macrophages is accompanied by decreased expression of PPARgamma1, LXRalpha, and their target genes ATP-binding cassette A1, ATP-binding cassette G1, apolipoprotein E, and CD36, with concomitant elevation in IL-6, TNF-alpha, monocyte chemoattractant protein 1, and inducible NO synthase levels. AEBP1, but not the C-terminally truncated DNA-binding domain mutant (AEBP1DeltaSty), represses PPARgamma1 and LXRalpha in vitro. Expectedly, AEBP1-overexpressing transgenic (AEBP1TG) macrophages accumulate considerable amounts of lipids compared with AEBP1 nontransgenic macrophages, making them precursors for foam cells. Indeed, AEBP1-overexpressing transgenic macrophages exhibit diminished cholesterol efflux compared with AEBP1 nontransgenic macrophages, whereas AEBP1-knockout (AEBP1-/-) macrophages exhibit enhanced cholesterol efflux compared with wild-type (AEBP1+/+) macrophages. Our in vitro and ex vivo experimental data strongly suggest that AEBP1 plays critical regulatory roles in macrophage cholesterol homeostasis, foam cell formation, and proinflammation. Thereby, we speculate that AEBP1 may be critically implicated in the development of atherosclerosis, and it may serve as a molecular target toward developing antiinflammatory, antiatherogenic therapeutic approaches.

Animals↗

PubMed2005

WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis.

WNK1 and WNK4 [WNK, with no lysine (K)] are serine-threonine kinases that function as molecular switches, eliciting coordinated effects on diverse ion transport pathways to maintain homeostasis during physiological perturbation. Gain-of-function mutations in either of these genes cause an inherited syndrome featuring hypertension and hyperkalemia due to increased renal NaCl reabsorption and decreased K(+) secretion. Here, we reveal unique biochemical and functional properties of WNK3, a related member of the WNK kinase family. Unlike WNK1 and WNK4, WNK3 is expressed throughout the nephron, predominantly at intercellular junctions. Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively. In contrast to WNK4's inhibitory activity, kinase-active WNK3 is a potent activator of both NKCC2 and NCC-mediated transport. Conversely, in its kinase-inactive state, WNK3 is a potent inhibitor of NKCC2 and NCC activity. WNK3 regulates the activity of these transporters by altering their expression at the plasma membrane. Wild-type WNK3 increases and kinase-inactive WNK3 decreases NKCC2 phosphorylation at Thr-184 and Thr-189, sites required for the vasopressin-mediated plasmalemmal translocation and activation of NKCC2 in vivo. The effects of WNK3 on these transporters and their coexpression in renal epithelia implicate WNK3 in NaCl, water, and blood pressure homeostasis, perhaps via signaling downstream of vasopressin.

Animals↗

PubMed2006

Vital functions of corticotropin-releasing factor (CRF) pathways in maintenance and regulation of energy homeostasis.

Regulation of energy homeostasis is a vital function of the CNS requiring adaptive responses to maintain and support life after stress perturbations. The mechanisms whereby these processes occur are, however, only partially understood. A major determinate of these responses is corticotropin-releasing factor (CRF). Receptors for CRF, CRFR1 and CRFR2, have been hypothesized to play distinct roles in the alterations necessary for homeostatic maintenance. The function of CRFR2, in particular, has remained elusive despite its presence in both the CNS and periphery. In this work, we have used complimentary gene deletion and pharmacological approaches to elucidate the crucial role CRFR2 plays in the regulation of regional tissue thermogenesis and adaptive physiology. Analyses of interscapular brown adipose tissue (IBAT) thermogenesis by thermal signature analysis and the concordant biochemical changes in key sympathetic components in mice deficient for CRFR2 revealed significantly elevated basal IBAT thermogenesis and prolonged adrenergic responsivity of IBAT in older mice. Measurement of metabolic rates by indirect calorimetry after chronic high-fat diet challenge and treatment with the CRFR1 antagonist NBI-27914 revealed a decreased respiratory exchange ratio of these mice that was normalized with NBI-27914. Further, as a definitive measure for physiological pathology, mice examined in a behavioral model of differential temperature selection showed a predilection for warmer external temperatures, supporting a loss of body heat in these mice. These studies provide physiological, biochemical, and behavioral evidence for the critical participation of CRF pathways in the maintenance and adaptive responses necessary for regulation of energy homeostasis.

Adipose Tissue, Brown↗

PubMed2002

Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments.

Following transfer into lymphopenic hosts, naive CD8 T cells proliferate and acquire memory phenotype. Although the acquired phenotype is stable in recombination activating gene-1-deficient (RAG-/-) recipients, in sublethally irradiated mice naive CD8 T cells of donor origin gradually accumulate. The naive cells have been attributed to phenotypic reversion of homeostatic memory cells, implying instability of memory phenotype and restoration of the naive T cell compartment by homeostasis-driven proliferation. We show here that (i) the accumulation of naive CD8 T cells of donor origin only occurs in recipients that have been irradiated and have an intact thymus; (ii) the apparent reversion of memory to naive cells actually results from de novo T cell development of hematopoietic stem cells, present in the donor spleen or lymph node cell populations, in the thymus of irradiated recipients; and (iii) the number of homeostatic memory cells generated in both RAG-/- and irradiated hosts reaches a plateau value and their phenotype is stably maintained even after retransfer into nonirradiated normal mice for 30 days. These findings demonstrate that homeostatic memory T cells do not revert to naive cells. After severe T cell depletion homeostasis-driven proliferation restores only the memory T cell compartment, whereas thymopoiesis is required for the reconstitution of the naive T cell compartment.

Adoptive Transfer↗