Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Structural heterogeneity has been demonstrated for growth hormone (GH) receptors from a number of species, and both high and low affinity art receptors have been characterised by ligand binding studies. In the present study, we have transfected Chinese hamster ovary (CHO-K1) cells with a cDNA clone encoding a full-length transmembrane ovine (o) GH receptor, under the regulatory control of the human metallothionein IIA promoter. A stably transfected cell line was established (GHR9.5) which expresses on the cell surface a single class of receptor which binds 220,000 [125I]oGH molecules at high affinity (Kd = 0.30 nM) which is comparable to the affinity established for endogenous oGH receptors in postnatal sheep liver microsomes (Kd = 0.27 nM, Freemark et al. (1987) Endocrinology 120, 1865-1872). The expressed receptor also binds ovine placental lactogen (oPL, 205,000 binding sites per cell) with high affinity (Kd = 0.76 nM). The presence of two species of oGH receptor was detected in GHR9.5 cells using affinity cross-linking analysis (M(r) 148,000 and M(r) 73,000) and given that the oGH receptor cDNA codes for a non-glycosylated receptor of M(r) 69,914, it is likely that these cross-linked species correspond to homodimeric and monomeric forms of the oGH receptor, each binding to a single molecule of GH. Parallel cross-linking studies with sheep liver microsomes also demonstrated two oGH receptor species (M(r) 133,000 and M(r) 58,000), the difference in relative molecular weights between the transfected and endogenous receptors presumably resulting from tissue-specific post-translational modifications. In the presence of oGH, the GHR9.5 cells respond by increasing total cellular protein synthesis by 27% relative to non-GH-exposed GHR9.5 cells, indicating the functionality of the expressed receptor. We also demonstrate unequivocally that oPL, through a specific interaction with the transfected oGH receptor, is able to mediate a similar cellular response (38% protein synthesis induction). Responsiveness to oGH and oPL in the GHR9.5 cells is dependent on serum starvation prior to oGH exposure and occurs only with prolonged exposure (greater than 2 h) to oGH. This cellular stimulation occurs independently of c-fos transcription which has previously been shown to be one of the earliest events associated with GH action in tissues expressing endogenous GH receptors (Doglio et al. (1989) Proc. Natl. Acad. Sci. USA 86, 1148-1152; Slootweg et al. (1990) J. Mol. Endocrinol. 4, 265-274).
 ...
PMID:Functional expression of an ovine growth hormone receptor in transfected Chinese hamster ovary cells. 151 79

GH specifically binds to receptors on the surface of adipocytes and produces a variety of biological effects in these cells. To gain insight into the nature of the GH receptors, [125I] human GH ([125I]hGH) was cross-linked to surface binding sites on intact rat adipocytes using the bifunctional reagent disuccinimidyl suberate. Plasma membranes were isolated, and after solubilization with sodium dodecyl sulfate (SDS), the proteins were subjected to electrophoresis on 5% or 7.5% polyacrylamide gel. Autoradiography of the 7.5% gels revealed three iodinated bands corresponding to apparent molecular weights of 56, 130, and more than 240 kilodaltons. The more than 240-kilodalton band contained approximately as much 125I as the 130-kilodalton species and about twice as much as the 56-kilodalton species. When run on the more porous 5% gel, the more than 240-kilodalton band resolved into two bands, corresponding to apparent molecular weights of 240 and 310 kilodaltons. Excess unlabeled human or bovine GH, but not ovine PRL, competed with [125I]hGH for binding and prevented the formation of all of the labeled bands. Treatment of the membranes and extracted proteins with dithiothreitol resulted in the generation of additional 130-kilodalton material at the expense of both the 310- and 240-kilodalton species, but failed to alter the amount of 125I that migrated with the 56-kilodalton species. The same pattern of labeling was seen regardless of whether protease inhibitors were present during isolation of membrane proteins or when membrane proteins were isolated under conditions that favored proteolysis, suggesting that the 56-kilodalton species is not a degradative product of the higher molecular weight species. When [125I]hGH was cross-linked to adipocytes in which total binding was decreased by hypophysectomy or starvation of the donor rats or by treatment of the cells with cycloheximide, there was a proportionate diminution in labeling of all species. It thus appears that the GH receptor contains a 130-kilodalton subunit, a portion of which is in disulfide linkage with higher molecular weight complexes and, in addition, contains a 56-kilodalton species. It cannot be determined from these studies if the various labeled protein complexes are components of a single or multiple classes of GH receptors in the adipocyte membrane.
 ...
PMID:Covalent binding of growth hormone to surface receptors on rat adipocytes. 632 41

A signaling pathway was delineated by which GH promotes cell survival. Experiments were performed in human leukemic cells (HL-60) and Chinese hamster ovary (CHO) cells. In HL-60 cells, GH treatment reduced starvation-induced cell death. In contrast, when HL-60 cells were treated with an anti-GH antibody, cell survival was sharply reduced. In CHO cells stably expressing either the wild-type (wtGHR) or a truncated form (delta454GHR) of the GH receptor in which GH induces a sustained activation of the receptor-associated tyrosine kinase JAK2, we found that GH stimulation inhibited programmed cell death induced by withdrawal of survival factors. This effect was enhanced in cells expressing the truncated form. In contrast, GH did not affect cell survival in CHO cells transfected with either the empty vector or a mutated GHR unable to transduce the signal (4P/AGHR). We also showed that the inhibitory action of GH on apoptosis is probably mediated via stimulation of the serine-threonine kinase Akt, as 1) GH treatment induces a prompt phosphorylation of Akt; and 2) GH effects on cell survival are abolished by transfection of an Akt mutant that exhibits dominant negative function. Experiments with pharmacological inhibitors demonstrated that GH-induced Akt phosphorylation is dependent on phosphoinositide 3-kinase activation. In contrast, we found no changes in Bcl-2 levels secondary to GHR activation.
 ...
PMID:Activation of growth hormone receptor delivers an antiapoptotic signal: evidence for a role of Akt in this pathway. 1057 61

Obesity and starvation have opposing affects on normal physiology and are associated with adaptive changes in hormone secretion. The effects of obesity and starvation on thyroid hormone, GH, and cortisol secretion are summarized in Table 1. Although hypothyroidism is associated with some weight gain, surveys of obese individuals show that less than 10% are hypothyroid. Discrepancies have been reported in some studies, but in untreated obesity, total and free T4, total and free T3, TSH levels, and the TSH response to TRH are normal. Some reports suggest an increase in total T3 and decrease in rT3 induced by overfeeding. Treatment of obesity with hypocaloric diets causes changes in thyroid function that resemble sick euthyroid syndrome. Changes consist of a decrease in total T4 and total and free T3 with a corresponding increase in rT3. untreated obesity is also associated with low GH levels; however, levels of IGF-1 are normal. GH-binding protein levels are increased and the GH response to GHRH is decreased. These changes are reversed by drastic weight reduction. Cortisol levels are abnormal in people with abdominal obesity who exhibit an increase in urinary free cortisol but exhibit normal or decreased serum cortisol and normal ACTH levels. These changes are explained by an increase in cortisol clearance. There is also an increased response to CRH. Treatment of obesity with very low calorie diets causes a decrease in serum cortisol explained by a decrease in cortisol-binding proteins. The increase in cortisol secretion seen in patients with abdominal obesity may contribute to the metabolic syndrome (insulin resistance, glucose intolerance, dyslipidemia, and hypertension). States of chronic starvation such as seen in anorexia nervosa are also associated with changes in thyroid hormone, GH, and cortisol secretion. There is a decrease in total and free T4 and T3, and an increase in rT3 similar to findings in sick euthyroid syndrome. The TSH response to TRH is diminished and, in severe cases, thyroid-binding protein levels are decreased. In regards to GH, there is an increase in GH secretion with a decrease in IGF-1 levels. GH responses to GHRH are increased. The [table: see text] changes in cortisol secretion in patients with anorexia nervosa resemble depression. They present with increased urinary free cortisol and serum cortisol levels but without changes in ACTH levels. In contrast to the findings observed in obesity, the ACTH response to CRH is suppressed, suggesting an increased secretion of CRH. The endocrine changes observed in obesity and starvation may complicate the diagnosis of primary endocrine diseases. The increase in cortisol secretion in obesity needs to be distinguished from Cushing's syndrome, the decrease in thyroid hormone levels in anorexia nervosa needs to be distinguished from secondary hypothyroidism, and the increase in cortisol secretion observed in anorexia nervosa requires a differential diagnosis with primary depressive disorder.
 ...
PMID:Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol secretion. 1205 88

One of the long-term effects of growth hormone (GH) in adipocytes is to maintain a state of refractoriness to insulin-like effects, a refractoriness which otherwise declines within a few hours of GH starvation. Here, we examined differences in GH signaling and the possible role for the recently identified family of suppressors of cytokine signaling (SOCS) proteins in the transition between the refractory and the responsive states in rat adipocytes. The ability of GH to stimulate lipogenesis and tyrosine phosphorylation of the GH receptor (GHR), Janus kinase 2 (Jak2), insulin receptor substrate-1 (IRS-1) and -2 (IRS-2) was greatly reduced in refractory as compared to responsive primary rat adipocytes. However, phosphorylation of Signal Transducer and Activator of Transcription 5 (Stat5) was not affected. SOCS-3 and CIS mRNA levels were significantly higher in refractory compared to responsive cells and could be induced by GH, whereas the level of SOCS-2 mRNA was unchanged. With overexpression of GHR, Jak2 and IRS-1 along with each of these SOCS proteins in human A293 cells, we could demonstrate that both SOCS-1 and SOCS-3 completely inhibited the GH-stimulated tyrosine phosphorylation of IRS-1, whereas SOCS-2 and CIS did not. Our data suggest that GH induces refractoriness to the insulin-like effects in a negative-feedback manner by inhibiting GH-induced GHR/Jak2/IRS-1/IRS-2 phosphorylation through upregulation of SOCS-3, which almost completely blocks Jak2 activation.
 ...
PMID:SOCS-3 is involved in the downregulation of the acute insulin-like effects of growth hormone in rat adipocytes by inhibition of Jak2/IRS-1 signaling. 1273 78

The GH/IGF system is a complex regulation network strongly dependent on nutrient availability. While the effect of starvation on the GH/IGF system has been extensively studied, the time course of events leading to the restoration of GH/IGF system activity after starvation is largely unknown. We, therefore, measured the plasma levels of GH, IGF-I and IGF-II and the expression of the GH/IGF system in liver and muscle. Starvation increased the plasma GH level and 1 day of refeeding completely restored it (1.10 +/- 0.27 vs 1.12 +/- 0.28 ng/ml). Thereafter, plasma GH continued to decrease until day 7 and returned to control values from day 15. Starvation decreased plasma IGF-I and IGF-II and refeeding raised plasma IGF-I only from day 4. In contrast, the plasma IGF-II level doubled after 1 day's refeeding (26.5 +/- 1.9 vs 44.0 +/- 3.4 ng/ml; P < 0.01). Starved fish exhibited higher GH receptor (GHR)1 mRNA abundance in liver and muscle than in controls, whereas GHR2 mRNA abundance was increased only in muscle. In liver, 1 day of refeeding, decreased GHR1 (twofold), but increased GHR2 mRNA abundance (twofold). Thereafter, a progressive return to normal values was observed. Liver IGFBP-4 mRNA abundance was lowered in starved fish followed by a progressive restoration during refeeding. Starvation had no effect on liver IGFBP-2 and IGFBP-6 mRNA abundance, whereas refeeding provoked a peak of IGFBP-2 and IGFBP-6 expression at day 7. In muscle, starvation led to a decrease of the IGFBP-2 mRNA level, which was restored only from day 7. IGFBP-4 mRNA abundance in starved fish was lower than in the controls and refeeding led to a transient upregulation (sevenfold) of IGFBP-4 gene at day 1. IGF-I, IGFBP-5, and IGFBP-related protein 1 (rP1) expression profiles were similar, showing a decrease of expression after starvation, a first peak of expression at day 2, a second peak at day 7, and a return to normal value from day 15. Moreover, IGF-I, IGFBP-5, and IGFBP-rP1 mRNA abundance were positively correlated (r = 0.6-0.8; P < 0.0001). In conclusion, plasma IGF-I was restored later than plasma GH level, which suggests that plasma IGF-I levels cannot account for plasma GH changes. The coordinated regulation of IGF-I, IGFBP-5, and IGFBP-rP1 expression would be a signature for the resumption of myogenic activity.
 ...
PMID:Coordinated regulation of the GH/IGF system genes during refeeding in rainbow trout (Oncorhynchus mykiss). 1706 85

Most biological actions of growth hormone (GH) are mediated by the insulin-like growth factor I (IGF-I) that is produced after the interaction of the hormone with a specific cell surface receptor, the GH receptor (GHR). Even though the GH excess on fish metabolism is poorly known, several species have been genetically engineered for this hormone in order to improve growth for aquaculture. In some GH-transgenic fish growth has been dramatically increased, while in others high levels of transgene expression have shown inhibition of the growth response. In this study, we used for the first time different genotypes (hemizygous and homozygous) of a GH-transgenic zebrafish (Danio rerio) lineage as a model for studying the GH resistance induced by different GH transgene expression levels. The results obtained here demonstrated that homozygous fish did not grow as expected and have a lower condition factor, which implies a catabolic state. These findings are explained by a decreased IGF-I and GHR gene expression as a consequence of GH resistance. Together, our results demonstrated that homozygous GH-transgenic fish showed similar characteristics to the starvation-induced fish and could be an interesting model for studying the regulation of the GH/GHR/IGF-I axis in fish.
 ...
PMID:The effect of GH overexpression on GHR and IGF-I gene regulation in different genotypes of GH-transgenic zebrafish. 2048 96

Cichlasoma dimerus is a social cichlid fish capable of growing at high rates under laboratory conditions, but knowledge on somatic growth regulation is still unclear. Growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is the key regulator of somatic growth in vertebrates. Two types of growth hormone receptors have been described in teleost fish, named GH receptor type 1 (GHR1) and type 2 (GHR2). In addition, isoforms of these receptors lacking part of the intracellular region have been described. The aim of this study was to evaluate the somatic growth, liver histology and changes in the GH/IGF-I axis after 4 weeks of food deprivation in C. dimerus. Four-week fasted fish showed reductions in specific growth rates in body weight (p < 0.001) and standard length (p < 0.001). Additionally, the hepatosomatic index (p < 0.001) and hepatocyte area (p < 0.001) decreased in fasted fish, while no changes in glucose levels were detected in plasma. The starvation protocol failed to induce changes in GH mRNA levels in the pituitary and IGF-I mRNA levels in liver. In contrast, IGF-I mRNA levels in muscle decreased in fasted fish (p = 0.002). On the other hand, GHR2 (detected with primer sets designed over the extracellular and intracellular region) was upregulated by starvation both in liver and muscle (p < 0.05), while GHR1 remained unchanged. These results show that a fasting period reduced somatic growth both in length and body weight concomitantly with alterations on liver and muscle GHR2 and muscle IGF-I mRNA expression.
 ...
PMID:GH, IGF-I and GH receptors mRNA expression in response to growth impairment following a food deprivation period in individually housed cichlid fish Cichlasoma dimerus. 2535 58

Weight loss triggers important metabolic responses to conserve energy, especially via the fall in leptin levels. Consequently, weight loss becomes increasingly difficult with weight regain commonly occurring in most dieters. Here we show that central growth hormone (GH) signaling also promotes neuroendocrine adaptations during food deprivation. GH activates agouti-related protein (AgRP) neurons and GH receptor (GHR) ablation in AgRP cells mitigates highly characteristic hypothalamic and metabolic adaptations induced by weight loss. Thus, the capacity of mice carrying an AgRP-specific GHR ablation to save energy during food deprivation is impaired, leading to increased fat loss. Additionally, administration of a clinically available GHR antagonist (pegvisomant) attenuates the fall of whole-body energy expenditure of food-deprived mice, similarly as seen by leptin treatment. Our findings indicate GH as a starvation signal that alerts the brain about energy deficiency, triggering key adaptive responses to conserve limited fuel stores.
 ...
PMID:Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons. 3080 39