Parse analysis II. A revised model that accounts for phi.
Explore the source record for details and available documents.
Authorship↗
Biomedical subjects
R I Gregerman
Publications and source records attributed to R I Gregerman.
Aging and hormone-sensitive lipolysis: reconciling the literature.
Explore the source record for details and available documents.
Adenosine↗
Catecholamine-sensitive lipolysis in the rat: different loci for effect of age on the lipolytic cascade in epididymal vs perirenal fat cells.
The biochemical locus of the decrease of lipolytic responsiveness to catecholamines in the aging rat has not heretofore been completely identified. Although increased sensitivity to the inhibitory action of adenosine is the likely explanation for the decrease during maturation, the nature of the age effect during senescence has been unclear. In order to determine whether the proximal or distal portion of the lipolytic pathway is involved, we have studied the lipolytic effect of the distally acting cyclic AMP analogue, 8-(4-chlorophenylthioadenosine)3'5'-monophosphate (cyclic) (Cl-cAMP) on rat fat cells from both the epididymal and perirenal fat pads of mature (6 mo) and senescent (24 mo) Fischer 344 rats. Using an adenosine (N6-1-2-phenylisopropyl-adenosine; PIA) regulated system, the lipolytic response to epinephrine (glycerol release) was measured simultaneously with that to Cl-cAMP. The effects of age on lipolysis are greatly influenced by the anatomic site of origin of the fat cells. The epididymal cells of the old rats showed no decreased responsiveness to either epinephrine or Cl-cAMP. However, the perirenal cells of the old rats showed a grossly impaired maximal response to both epinephrine (60% decrease relative to young; p < .005) and Cl-cAMP (42% and 58% decrease in 2 sets of experiments; p < .05 and .04, respectively). Although decreased lipolytic response to epinephrine in epididymal cells was not seen in these studies, this has been clearly shown in earlier work, suggesting that diminished response to epinephrine is demonstrable only when the system is not already maximally inhibited by PIA.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Deaminase↗
Solitary thyroid nodules.
Explore the source record for details and available documents.
Biopsy, Needle↗
Adipocytes of old rats produce a decreased amount of differentiation factor for preadipocytes derived from adipose tissue islets.
Adipose tissue of young rats (3.5 mo) contains cell formations ("islets") that, in culture, give rise to a variety of preadipocytes, or islet-derived cells (IDCs), that undergo rapid morphologic differentiation into adipocytes. Such adipose conversion depends on a differentiation-promoting factor produced by the mature adipocytes also present in the cultures. Here we report that cultured IDCs from epididymal fat of senescent rats (20 +/- 3 mo) show decreased adipose conversion compared to IDCs from 3.5 mo rats at 3 days of culture (14.2% vs 29.9%; p < .001). Both the number of co-cultured adipocytes and increased fragility with age were excluded as having a substantial role in explaining the decreased conversion. In order to determine whether the decrease differentiation of the IDCs of the old rats was intrinsic or due to reduced production of the differentiation factor by the old adipocytes, cross-over cultures of IDCs from young and old rats were grown in the presence of young or old adipocytes. When IDCs of old rats were cultured in the presence of young adipocytes, a significant twofold increase in differentiation was seen compared to old IDCs grown with old adipocytes (22.7% vs 10.3%; p < .001). This response was comparable to that of young IDCs grown with young adipocytes. Thus, old IDCs retain their ability to undergo extensive morphologic differentiation when appropriately stimulated. Reduced production of the differentiation-promoting factor by old adipocytes rather than the ability of IDCs to differentiate appears to be responsible for the decreased adipose conversion of IDCs seen in cultures of adipose tissue from senescent rats.
Adipose Tissue↗
Islets of preadipocytes highly committed to differentiation in cultures of adherent rat adipocytes. Light- and electron-microscopic observations.
Cultures of adherent mature adipocytes, obtained from collagenase-digests of adipose tissue of the rat, invariably contain rapidly proliferating, fibroblast-like cells despite the washing and centrifugation procedures employed during isolation of the fat cells. Such spindle-like cells originate from low-density structures, which we term "islets", that are present, together with the mature adipocytes, in the floating layer of the digest of adipose tissue. Islets are found in preparations from adult (3-4 months old) as well as aging (17-24 months old) rats. By light- and electron microscopy, the islets appear as clusters of closely associated cells containing a variable amount of lipid-like material. Cells of endothelial or pericytic origin are also present in the islets. Within a few hours of culture, the islets give rise to those spindle-like cells that have been seen to proliferate in the cultures. By 36-48 hours, such cells begin to accumulate lipid droplets and, by 150 hours, assume the morphology of small mature adipocytes (diameter 20-35 microns) with a large central lipid droplet. The pattern of differentiation of these cells recalls that of preadipocytes derived from the stromal-vascular fraction of adipose tissue digests. Nonetheless, the extent and rapidity of their adipose conversion, as well as the culture conditions necessary for differentiation, are different and suggest that these cells are a substantially uniform subpopulation of adipocyte-precursor cells highly committed to differentiation.
Adipose Tissue↗
Adipose tissue islets: tissue culture of a potential source of fat cells in the adult rat.
Collagenase digests of adipose tissue of the 3 to 4-month-old rat contain groups of 20-100 tightly arranged cells (islets) that copurify with the free-floating fat cells. When cultured along with mature adipocytes the islets give rise to cells, initially fibroblast-like, which rapidly proliferate, acquire lipid droplets, and differentiate into small adipocytes within 4-6 days without the addition to the medium of the agents usually required to produce differentiation in stromal-vascular preadipocytes. Differentiation of these cells is independent of confluence and begins as early as day 2 of culture. The proportion of islet-derived cells that differentiate is directly correlated with the number of mature adipocytes simultaneously present in the culture (r = .709; P less than 0.001). Culture medium exposed to mature adipocytes demonstrated differentiation-promoting activity, suggesting a paracrine effect of these cells. Islets may in vivo constitute a source for newly formed adipocytes in the adult rat. The differentiation of these potential adipocytes may be regulated, at least in part, by the mature fat cells via a paracrine effect.
Adipose Tissue↗
Thyroid hormone elevations during acute psychiatric illness: relationship to severity and distinction from hyperthyroidism.
Acute psychiatric illness may be accompanied by transient hyperthyroxinemia. The mechanism of this phenomenon was examined by determining the role of thyrotropin (TSH) in the genesis of this state. Serial measurements of TSH, thyroxine (T4), free T4 index (FT4I), triiodothyronine (T3), and free T3 index (FT3I) were performed in 45 acutely hospitalized patients with major psychiatric disorders. Twenty-two (49%) patients exhibited significant elevations (greater than or equal to 2 SD above mean value of controls) of one or more thyroid hormone (or index) levels. Among depressed patients with elevated FT4I, TSH was higher (p less than .05) on the day of the peak FT4I than on the day of the FT4I nadir. There were significant positive correlations between psychiatric symptom severity and levels of FT4I among both depressed (p less than .01) and schizophrenic (p less than .025) patients. These data show that elevations of T4, FT4I, T3, and FT3I are common among psychiatric inpatients, especially early in their hospitalization, and that levels of thyroid hormones are correlated with severity of psychiatric symptomatology. TSH is higher early in the acute phase of illness and is not suppressed in the face of elevated thyroid hormone levels, a finding that distinguishes this phenomenon from ordinary hyperthyroidism. Elevations of peripheral thyroid hormone levels, particularly among depressed patients, may result from a centrally-mediated hypersecretion of TSH.
Adult↗
Altered glucagon- and catecholamine hormone-sensitive adenylyl cyclase responsiveness in rat liver membranes induced by manipulation of dietary fatty acid intake.
Glucagon-stimulated adenylyl cyclase activity has been shown to change in liver membranes manipulated to alter either their fatty acid composition or fluidity. We examined whether membrane alterations induced by dietary manipulation affected receptor function. Glucagon- and beta-adrenergic-stimulated receptor-adenylyl cyclase systems were examined in liver membranes of rats fed diets containing 10% corn oil, 10% coconut oil (essential FFA deficient), or 8.5% coconut oil with 1.5% corn oil (essential FFA repleat). Basal and maximal nonreceptor-mediated adenylyl cyclase activity (stimulated by NaF, guanylylimidodiphosphate, and forskolin) was the same in membranes of each of the dietary groups, suggesting that Gs-protein and the catalytic unit activity per se were unaltered by the manipulations. Glucagon-stimulated adenylyl cyclase activity increased with increasing unsaturation of dietary fatty acids; activity in coconut oil-fed rats was 527 +/- 30 (mean +/- SEM) pmol/mg.10 min, that in coconut/corn oil-fed rats was 752 +/- 74 pmol/mg.10 min, and that in corn oil-fed rats was 981 +/- 94 pmol cAMP/mg.10 min. [125I]Monoiodoglucagon binding did not increase in parallel to the adenylyl cyclase alterations; coconut oil-fed animals (614 fmol/mg) differed from the other groups (450 and 430 fmol/mg). Isoproterenol (beta-adrenergic)-stimulated adenylyl cyclase activity was also highest in the corn oil-fed animals, but was similar in the other dietary groups, with no difference in other characteristics of [125I]iodopindolol binding between the groups. The results demonstrate that alterations in the glucagon-stimulated adenylyl cyclase response are different from those in the beta-adrenergic adenylyl cyclase response. Further, they suggest that although direct activations of the catalytic unit or its interaction with the guanine nucleotide-sensitive protein are apparently not affected, hormone receptor-mediated adenylyl cyclase activity may be altered by these dietary manipulations.
Adenylyl Cyclases↗
Preadipocyte stimulating factor in rat serum: evidence for a discrete 63 kDa protein that promotes cell differentiation of rat preadipocytes in primary cultures.
In primary cultures of rat preadipocytes (PA) isolated from epididymal or perirenal depots, rat serum is more effective than other animal sera (fetal calf, newborn calf, human, horse, rabbit, cat, sheep, goat, dog, pig) in promoting adipogenic conversion, biochemical differentiation, and mitogenesis. Only mouse serum is comparable to rat serum. This activity is attributable to a specific growth factor (preadipocyte stimulating factor, PSF). An assay for PSF in rat serum was devised using PA from perirenal fat of 3-month-old Fischer 344 rats grown first to confluence in FCS for 8 days and then for the next 3 days in test serum, followed by measurement of triglyceride (TG) and glycerol-3-phosphate dehydrogenase (GPDH). Rat serum induces dose-dependent rapid cell division, which coincides with accumulation of TG and increase of GPDH; for routine quantitation, TG is assayed. The biochemical characteristics of PSF in serum are as follows: stable at 4 degrees C for up to 1 year; inactivated at 100 degrees C (80% loss, 30 min) but stable at 56 degrees C for 1 hr; stable at pH 2-12; non-dialyzable; completely resistant to pepsin, trypsin, and chymotrypsin but destroyed by pronase and subtilisn; stable to DTT and periodate; and m.w. between 68 kDa (Sephacryl-300) and 58 kDa (Sephacryl-300 in 5 M urea). PSF activity is greater in serum from Wistar than from Fischer 344 rats, while activity of serum from Zucker obese (fa/fa) rats is at least as great as that from Wistar rats and, like serum of rats made obese by feeding a high-fat, high-carbohydrate diet, is not suppressed. PSF activity is not due to insulin, insulin-like growth factor-1 (IGF-1), growth hormone, glucocorticoids, or combinations of these hormones. PSF activity was not seen with a number of growth factors including colony-stimulating factor (CSF-1), GM-CSF, interleukins 1, 2, and 3, neuroleukin, tumor necrosis factor, and others. PSF is distinct from the low molecular weight (4-8 kDa) differentiation factor present in rat serum, FCS, and human serum that promotes the adipogenic conversion and cellular differentiation of 3T3-L1, 3T3-F442A, and Ob17 cells. PSF appears to be a new differentiation factor for rat preadipocytes, has properties suggestive of a highly glycosylated protein, and may be highly species specific.
Adipose Tissue↗
Food restriction prevents an age-associated increase in rat liver beta-adrenergic receptors.
In male Wistar rats fed ad libitum (24% protein, 4.5 Kcal/gm), the [125I]iodopindolol binding capacity of the beta-adrenergic receptors in liver of 24-month-old animals is 3-4 times greater than that of 6-month-old counterparts. In rats fed the same diet, on alternate days from weaning, the receptor capacity did not increase significantly between 6 and 24 months (10.20 +/- 0.55 vs 9.20 +/- 0.72 fmol/mg) or between 24 and 30 months. This was not due to acute dietary deprivation, as rats food-restricted for only 2 weeks, at 23.5 months of age, also showed elevated receptor capacities compared to 6-month-old ad libitum fed animals. Moreover, intermittent feeding produced no significant effects among 6-month-old animals, whether restricted since weaning or for two weeks prior to sacrifice. Many biochemical parameters that decrease with aging in rats fed ad libitum are prevented by dietary restriction. Our results demonstrate that a reproducible biochemical process that increases with aging is also prevented with dietary restriction. The age-related, liver beta-receptor increase may be a potentially reliable marker for studying biochemical perturbations that modify life span.
Adrenergic beta-Antagonists↗
Prostaglandin-sensitive adenylyl cyclase of cultured preadipocytes and mature adipocytes of the rat: probable role of Gi in determination of stimulatory or inhibitory action.
Preadipocytes of rats were obtained from the stromal-vascular fraction of collagenase-digested perirenal fat pads and grown in serum-containing medium. By day 8 of culture the cells reached confluence and by 12 days were lipid-laden. The adenylyl cyclase of the plasma membranes was compared to that of mature fat cells. Unlike the membranes from adipocytes, the preadipocytes showed adenylyl cyclase activity that was stimulated by GTP. Stimulation of preadipocyte membranes by Gpp(NH)p, NaF, and forskolin was comparable to that of membranes from adipocytes, but the response to epinephrine and isoproterenol was minimal (approximately 1.5-fold for preadipocytes vs. 4-5-fold for adipocytes). In contrast, GTP-dependent stimulation of adenylyl cyclase of preadipocytes by PGE1 was nearly 8-fold. Stimulation occurred even in the presence of both GTP and 140 mM NaCl, a condition that leads to inhibition by PGE1 of adenylyl cyclase in membranes of adipocytes. Other characteristics of the adenylyl cyclase of preadipocyte membranes that differ from those of adipocytes include lack of inhibition by GTP of forskolin-activated activity, and, following treatment with pertussis toxin, enhanced stimulation by PGE1. ADP-ribosylation of Gi and Gs with pertussis and cholera toxins, respectively, indicated that the membranes of preadipocytes contained only 5-11% of the Gi of adipocytes and a much lower ratio of Gi:Gs. These findings suggest that cultured preadipocytes have an incompletely developed Gi pathway that may account for the stimulatory effect of prostaglandins on the adenylyl cyclase of these cells as opposed to the inhibitory action of PG in mature fat cells.
Adenosine Diphosphate Ribose↗
Hormone-sensitive adenylyl cyclase in preadipocytes cultured from adipose tissue: comparison with 3T3-L1 cells and adipocytes.
The adenylyl cyclase system of preadipocytes derived from the stromal vascular fraction of perirenal rat fat pads was characterized. Unlike mature adipocytes, preadipocyte adenylyl cyclase was only weakly stimulated by catecholamines and adrenocorticotrophic hormone, but was stimulated by guanine nucleotides. Parathyroid hormone and 2-chloroadenosine also stimulated preadipocyte adenylyl cyclase. The adenylyl cyclase system of preadipocytes resembled that of undifferentiated 3T3-L1 cells. However, agents which induced the differentiation of the 3T3-L1 cell adenylyl cyclase system did not have a similar effect on preadipocytes. A medium (CDM6) which induced some differentiation of preadipocyte adenylyl cyclase was developed. The observations that the adenylyl cyclase system of preadipocytes and undifferentiated 3T3-L1 cells are similar, that preadipocyte adenylyl cyclase can be induced to develop along lines similar to early differentiation of 3T3-L1 cells, and that the adenylyl cyclase system of fully-differentiated 3T3-L1 cells has characteristics intermediate between preadipocytes and adipocytes, suggest that the differentiation of preadipocyte and 3T3-L1 adenyly cyclase in vitro mimics adipose adenylyl cyclase development in vivo. The increased catecholamine and ACTH stimulation, and reduced GTP and adenosine sensitivities of adipocytes compared to preadipocytes suggest that a number of genes affecting adenylyl cyclase-associated regulatory and receptor proteins are coordinately repressed and derepressed during development.
Adenylyl Cyclases↗
Beta-adrenergic receptors, glucagon receptors, and their relationship to adenylate cyclase in rat liver during aging.
The beta-adrenergic and glucagon receptor-binding capacities in rat livers from 6-27 months of age were measured to investigate the mechanism of a previously observed rise in beta-adrenergic stimulated adenylate cyclase with increasing age. There was no concomitant increase in glucagon-stimulated adenylate cyclase. In the present study neither glucagon-binding capacity nor glucagon-stimulated adenylate cyclase changed with age. In contrast, the beta-adrenergic receptor capacity, measured in the same membranes by [125I]iodopindolol binding, increased nearly 3-fold from 6.6 +/- 0.6 fmol/mg at 6 months to 19.1 +/- 3.3 fmol/mg at 18-19 months. The increase was directly proportional to the maximum isoproterenol-stimulated adenylate cyclase activity in livers of rats up to 19 months of age. By 24-27 months the binding capacity had increased to 24.9 +/- 3.3 fmol/mg, but there was no further increase in adenylate cyclase activity. Thus, there appeared to be a beta-receptor-adenylate cyclase uncoupling in livers from the senescent animals (25-27 months). The defect could not be demonstrated by studies examining isoproterenol competition of [125I]iodopindolol from agonist-induced high affinity sites on the membranes, a procedure that examines receptor-Ns protein coupling. Activation of adenylate cyclase by the nonhormonal stimulators F- and forskolin did not change with age, indicating that the catalytic unit was not a limiting factor. Since the relationship between the glucagon receptor and adenylate cyclase also remained unaltered, the uncoupling apparently lies in an alteration of the interaction between the beta-adrenergic receptor and the guanine nucleotide-sensitive Ns protein.
Adenylyl Cyclases↗
Mechanisms of age-related alterations of hormone secretion and action. An overview of 30 years of progress.
Explore the source record for details and available documents.
Adenylyl Cyclases↗
Membrane association of soluble protein activators of rat liver adenylate cyclase. Evidence for distinctness from the guanine nucleotide-binding stimulating protein (Ns).
Sonication of a crude rat liver membrane preparation and centrifugation at 100,000 X g yielded a supernatant which activated basal and hormone-sensitive adenylate cyclases [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]. The membrane origin of the stimulatory activity was confirmed by the use of lactate dehydrogenase as a marker for contamination by cytosol. The solubility of the activating factors was verified by their passage through 0.05 micron diameter pores of Millipore filters. The membrane-derived activators were nondialyzable and destroyed by heat and trypsin in the same manner as adenylate cyclase activators detectable in cytosol. Stimulation by factors from membranes and cytosol was not additive. The amount of the activators which could be freed from membranes by sonication was 12-15% of that contained in cytosol previously separated from the membranes. Soluble activators from the two sources had limited ability to restore adenylate cyclase activity to membranes from the cyclone of S49 mouse lymphoma cells which are deficient in the enzyme's guanine nucleotide-binding stimulatory protein, Ns. Cytosol did not contain a substrate for ADP-ribosylation by cholera toxin that corresponded electrophoretically to Ns. Furthermore, purified Ns did not affect adenylate cyclase activity in preparations stimulated by the soluble activators. These findings suggest that the activating factors found in cytosol may be released from membranes during tissue homogenization. Because these protein activators can be obtained from membranes without use of detergents and can neither substitute for nor be substituted for by Ns in functional assays, they are distinct from Ns.
Adenylyl Cyclases↗
(-)[125I]iodopindolol binding to beta-adrenergic receptors in tissues of the rat with particular reference to the characterization in liver.
The high affinity beta-adrenergic antagonist (-)[125I]iodopindolol was used to characterize and quantitate beta-adrenergic binding in liver and other tissues of the rat. Saturable, stereospecific binding with typical characteristics of beta-adrenergic receptors was demonstrated in all tissues examined (liver, lung, heart, kidney, fat and brain). Unlike the case with other radioactive ligands that have been used to measure beta-adrenergic receptors, assays were possible in crude homogenates as well as in purified membranes. Specific binding was defined as [125I]iodopindolol displaced by 0.1 mM isoproterenol. The percentage of [125I]iodopindolol specifically bound was greater than with other labelled antagonist ligands and it ranged from 95-60% of total binding over [125I]iodopindolol concentrations of 15-1000 pM. beta-Adrenergic binding could be quantitated in liver of animals of all ages whereas previously quantitation in liver was possible only using rats less than 2 months of age. Binding capacities ranged from a low of approximately 6 fmol/mg in liver particles precipitated at 4500 g to approximately 550 fmol/mg in 4500 g lung particles. The Kd of binding obtained by kinetic analysis was similar in all tissues. [125I]Iodopindolol is a nearly ideal ligand for the quantitation of beta-adrenergic receptors in various tissues of the rat. Because of its high affinity, stability and availability at high specific activity, this ligand should be especially useful in physiological studies requiring the accurate quantitation of receptor capacities.
Adrenergic beta-Agonists↗
Suppression of thyrotropin in the low-thyroxine state of severe nonthyroidal illness.
In a prospective study, we assessed the role of thyrotropin in the development of the low-thyroxine state that is associated with severe illness. We measured the serum thyrotropin and thyroid hormone concentrations longitudinally in 35 patients with hematopoietic cancer or aplastic anemia who were treated by bone-marrow transplantation. In 19 patients thyroxine declined sharply after bone-marrow transplantation and was associated with a reduction of the serum thyrotropin in the 17 patients tested, often to levels below the normal range. The serum triiodothyronine level, free thyroxine index, and free thyroxine level also declined in these patients. In the patients who recovered, clinical improvement was accompanied by the return of thyrotropin and thyroid hormone concentrations to their pretreatment ranges. These and related findings suggest that the low-thyroxine state of severe illness is the result of several events, one of which is failure of the normal negative-feedback control of the pituitary-thyroid axis due to illness-associated, decreased secretion of thyrotropin. The notion that such patients are "euthyroid" must be questioned, but the possible value of thyroid hormone-replacement therapy in these circumstances remains to be determined.
Adolescent↗