The cagE gene sequence as a diagnostic marker to identify JP2 and non-JP2 highly leukotoxic Aggregatibacter actinomycetemcomitans serotype b strains.

BACKGROUND AND OBJECTIVE: Aggregatibacter actinomycetemcomitans is involved in oral and systemic infections, and is associated with, eg aggressive forms of periodontitis and with endocarditis. The cagE gene encodes a ≈39 kDa putative exotoxin expressed by A. actinomycetemcomitans. The level of conservation of cagE, and its possible significance in periodontal disease, has not yet been thoroughly investigated. In the present study, the role of the cagE gene as a diagnostic marker has been investigated. MATERIAL AND METHODS: We have used conventional polymerase chain reaction (PCR), quantitative PCR and whole genome sequencing data to determine the prevalence of cagE in A. actinomycetemcomitans based on analysis of: (i) 249 isolates, collected and cultivated in a Ghanaian longitudinal cohort study; (ii) a serotype b collection of 19 strains; and (iii) the 36 A. actinomycetemcomitans genomes available in the NCBI database. RESULTS: Whereas cagE was absent in the other serotypes, our data support that this gene sequence is linked to a virulent and highly leukotoxic group of serotype b strains, including both JP2 and non-JP2 genotypes of A. actinomycetemcomitans. CONCLUSION: We propose that cagE has the potential to be used as a PCR-based gene marker for the identification of a virulent and highly leukotoxic group of serotype b strains, including both JP2 and non-JP2 genotypes. This finding might be of importance in the risk assessment of the development of periodontal attachment loss in young individuals and hence suggested to be a relevant discovery in future development of new diagnostic tools and/or treatment strategies.

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1ß involves reductions in long-chain acyl-CoA levels and oxidative stress.

AIMS/HYPOTHESIS: To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1ß [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance. METHODS: Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1ß in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1ß on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp. RESULTS: Pgc-1ß gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1ß. In rats fed a HFD, increasing the levels of Pgc-1ß partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. CONCLUSIONS: Our data show that an increase in Pgc-1ß expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.

Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus.

In several species, including humans, the dentate granule cell layer (GCL) of the hippocampus exhibits neurogenesis throughout adult life. The ability to regulate adult neurogenesis pharmacologically may be of therapeutic value as a mechanism for replacing lost neurons. Insulin-like growth factor-I (IGF-I) is a growth-promoting peptide hormone that has been shown to have neurotrophic properties. The relationship between IGF-I and adult hippocampal neurogenesis is to date unknown. The aim of this study was to investigate the effect of the peripheral administration of IGF-I on cellular proliferation in the dentate subgranular proliferative zone, which contains neuronal progenitor cells, and on the subsequent migration and differentiation of progenitor cells within the GCL. Using bromodeoxyuridine (BrdU) labeling, we found a significant increase of BrdU-immunoreactive progenitors in the GCL after 6 d of peripheral IGF-I administration. To determine the cell fate in progenitor progeny, we characterized the colocalization of BrdU-immunolabeled cells with cell-specific markers. In animals treated with IGF-I for 20 d, BrdU-positive cells increased significantly. Furthermore, the fraction of newly generated neurons in the GCL increased, as evaluated by the neuronal markers Calbindin D(28K), microtubule-associated protein-2, and NeuN. There was no difference in the fraction of newly generated astrocytes. Thus, our results show that peripheral infusion of IGF-I increases progenitor cell proliferation and selectively induces neurogenesis in the progeny of adult neural progenitor cells. This corresponds to a 78 +/- 17% (p < 0.001) increase in the number of new neurons in IGF-I-treated animals compared with controls.

Sex differences in fatty acid composition of rat liver phosphatidylcholine are regulated by the plasma pattern of growth hormone.

The effects of continuous and intermittent (at 12 h intervals) administration of growth hormone (GH), and the effects of gonadal steroids on the regulation of the fatty acid composition of liver phosphatidylcholine were studied in gonadectomized and hypophysectomized adult female Sprague-Dawley rats. Gonadal steroids have been shown to influence the fatty acid composition of liver phosphatidylcholine in the rat. It is shown in the present study that neither testosterone nor estradiol had any effects on liver phosphatidylcholine in hypophysectomized rats. There was a 'masculinizing' effect of hypophysectomy of female rats on the fatty acid composition of liver phosphatidylcholine (i.e., an increase in the proportion of palmitic, oleic and linoleic acids and a decrease in the proportion of stearic and arachidonic acids). Continuous infusion of human GH and bovine GH partly reversed the 'masculinizing' effect of hypophysectomy. In contrast, there were no effects of intermittent administration of human GH. Also, there was no effect of prolactin infusion. It is concluded that the sexually dimorphic secretory pattern of GH may be involved in the regulation of the sexual differentiation of the fatty acid composition of liver phosphatidylcholine in the rat.

Hormonal regulation of liver fatty acid-binding protein in vivo and in vitro: effects of growth hormone and insulin.

Liver fatty acid-binding protein (LFABP) is an abundant protein in hepatocytes that binds most of the long chain fatty acids present in the cytosol. It is suggested to be of importance for fatty acid uptake and utilization in the hepatocyte. In the present study, the effects of bovine GH (bGH) and other hormones on the expression of LFABP and its messenger RNA (mRNA) were studied in hypophysectomized rats and in vitro using primary cultures of rat hepatocytes. One injection of bGH increased LFABP mRNA levels about 5-fold after 6 h, but there was no effect of this treatment on LFABP levels. However, 7 days of bGH treatment increased both LFABP mRNA and LFABP protein levels 2- to 5-fold. Female rats had higher levels of LFABP than male rats. Hypophysectomy of female rats, but not that of male rats, decreased LFABP levels markedly. Treatment of hypophysectomized rats with bGH for 7 days as two daily injections or as a continuous infusion increased LFABP levels to a similar degree. This finding indicates that the sex difference in the expression of LFABP is not regulated by the sexually dimorphic secretory pattern of GH. Neither insulin nor insulin-like growth factor I treatment of hypophysectomized rats for 6-7 days had any effect on LFABP mRNA or LFABP levels. In vitro, bGH dose-dependently increased the expression of LFABP mRNA, but only in the presence of insulin. Insulin alone had a marked dose-dependent effect on LFABP mRNA levels and was of importance for maintaining the expression of LFABP mRNA during the culture. Incubation with bGH increased LFABP mRNA levels within 3 h. GH had no effect on LFABP mRNA levels in the presence of actinomycin D, indicating a transcriptional effect of GH. Incubation with glucagon in vitro decreased LFABP mRNA levels markedly, indicating that glucagon, in contrast to GH, has an effect opposite that of insulin on LFABP mRNA expression. It is concluded that GH is an important regulator of LFABP in vivo and in vitro. In contrast to the effect of GH on insulin-like growth factor I mRNA, the presence of insulin was a prerequisite for the effect of GH on LFABP mRNA expression in vitro. The results emphasize the role of GH in the regulation of hepatic fatty acid metabolism.

Insulin-like growth factor-I and growth hormone have different effects on serum lipoproteins and secretion of lipoproteins from cultured rat hepatocytes.

GH has previously been shown to regulate serum lipoprotein levels and hepatic secretion of apolipoprotein-B (apo-B) and apo-E in the rat. The aim of this investigation was to study a possible role of insulin-like growth factor-I (IGF-I) in this regulation. Adult female rats were hypophysectomized and treated with recombinant human IGF-I (1.25 mg/kg.day) as a sc continuous infusion for 7 days. The effects of IGF-I were compared with those of bovine GH, given either as a continuous sc infusion or as two daily sc injections. All hypophysectomized rats were given replacement therapy with L-T4 and cortisol. Serum IGF-I concentrations increased to similar levels as a result of treatment with bovine GH and IGF-I. There was no effect of IGF-I on serum concentrations of glucose or insulin, whereas GH, independent of its mode of administration, increased serum insulin concentrations. Food intake was not affected by treatment with IGF-I. IGF-I had no effect on serum concentrations of cholesterol or apo-E, whereas GH given twice daily decreased serum cholesterol concentrations, and a continuous infusion of GH increased serum apo-E concentrations. Serum triglyceride and apo-B concentrations increased markedly as a result of IGF-I treatment, whereas GH had no effect on serum triglycerides, but decreased serum apo-B concentrations. Hepatocytes were isolated from hypophysectomized rats treated with L-T4 and cortisol alone or in combination with IGF-I and kept in short term cultures. In this system, IGF-I had no effect on the incorporation of [3H]glycerol in triglycerides or the mass of triglycerides in the cells and medium. There was no effect of IGF-I treatment on the secretion of apo-E or apo-B. Moreover, there was no effect of IGF-I treatment on the relationship between newly synthesized and secreted apo-B 48 and apo-B 100, as determined by [35S]methionine labeling of the proteins. In conclusion, the previously observed effects of GH on serum lipoproteins and hepatic apolipoprotein secretion does not seem to be mediated via IGF-I, but IGF-I has its own unique effects on serum triglyceride and apo-B levels. The increases in serum apo-B and serum triglyceride concentrations after IGF-I treatment were not dependent on increased hepatic secretion of apo-B or triglycerides.

Differential effects of continuous versus intermittent administration of growth hormone to hypophysectomized female rats on serum lipoproteins and their apoproteins.

The effects of the plasma pattern of GH on serum and lipoprotein levels of total cholesterol, triglycerides, apolipoprotein A-I (apo A-I), apolipoprotein B 48/100 (apo B), and apolipoprotein E (apo E) were studied in hypophysectomized female Sprague-Dawley rats, which had been given replacement therapy with L-T4 and hydrocortisone. Bovine GH (1 mg/kg.day) was administered sc either continuously by means of osmotic minipumps or by two daily injections. Serum lipoproteins were separated by sequential ultracentrifugation into very low density lipoproteins [density (d) less than 1.006 g/ml], low density lipoproteins (LDL; d 1.006-1.063 g/ml) and high density lipoproteins (HDL; d 1.063-1.21 g/ml). The content of total cholesterol and triglycerides were then determined. Apo A-I, apo B, and apo E were isolated from rat serum and antibodies raised in rabbits. In serum and in lipoprotein fractions, the content of apo A-I, apo-B, and apo E were determined by electroimmunoassay. After hypophysectomy, there occurred a decrease in serum cholesterol and serum levels of apo A-I and apo E, in spite of replacement therapy with T4 and cortisone. Similar changes were also observed in HDL. In contrast, apo B, cholesterol, and triglycerides were increased in LDL. Estradiol treatment had no effect on these changes. Continuous infusion of GH resulted in an increase in cholesterol and apo E in serum and HDL to the levels of intact females. In contrast, GH given twice daily had no effect. Therefore, the sexually dimorphic secretion of GH may be important for the regulation of sex differences in apo E and HDL cholesterol levels. There were no consistent effects of GH treatment on the levels of apo A-I in serum or HDL, but GH treatment resulted in a decrease in apo B and triglycerides in both serum and LDL, regardless of the mode of administration. This suggests that GH regulates the serum and LDL levels of apo B and triglycerides independently of the secretory pattern.

Continuous but not intermittent administration of growth hormone to hypophysectomized rats increases apolipoprotein-E secretion from cultured hepatocytes.

Hypophysectomy of female rats has been shown to decrease the serum levels of apolipoprotein E (apoE). Continuous but not intermittent administration of GH to hypophysectomized (HX) rats increases these levels to those of normal rats, indicating that the sexually dimorphic secretion of GH is important in the regulation of apoE metabolism. In this study, these effects of GH were further investigated by studying the biosynthesis and secretion of apoE from isolated hepatocytes. Hepatocytes were isolated from HX rats as well as from HX rats that had received hormonal treatment with T4 and cortisol (C) or T4 and C together with GH given either as two daily sc injections (GH x 2) or as a continuous infusion (GHc). Hypophysectomy decreased by 47% the amount of apoE present in the culture medium after a 4-h incubation. Treatment of HX rats with T4 and C alone or in combination with GH x 2 did not influence the amount apoE present in the medium, whereas treatment with T4, C, and GHc increased the amount of apoE to that of normal controls. The different levels of apoE in the medium was not due to differences in the disappearance of apoE, indicating that it was caused by changes in the rate of apoE secretion. Consistent with this, hypophysectomy decreased the rate of intracellular accumulation of apoE measured by incubation of the cells with [35S]methionine for 0, 8, and 20 min. Treatment with T4, C, and GHc increased the rate of accumulation, but T4, C, and GH x 2 had no effect. The differences in the initial rate of intracellular accumulation of apoE were not due to variations in apoE messenger RNA pools or to differences in the degradation of apoE at a step early in the secretory pathway. These results indicate that the differences in the initial rate of accumulation of apoE results from differences in the translational rate. The major amount of apoE that was secreted to the medium appeared in the high-density lipoprotein fraction, whereas small amounts were present in the very-low-density lipoprotein fraction (VLDL). Hypophysectomy decreased the amount of newly secreted apoE in the VLDL fraction. Only therapy with T4, C, and GHc could restore the normal distribution of apoE in the VLDL fraction. In conclusion, the results indicate that the secretory pattern of GH is involved in the regulation of the apoE secretion by influencing the rate of translation.

Effects of growth hormone on apolipoprotein-B (apoB) messenger ribonucleic acid editing, and apoB 48 and apoB 100 synthesis and secretion in the rat liver.

Apolipoprotein-B 48 (apoB 48) and apoB 100 expression and the editing of apoB mRNA have previously been shown to be hormonally regulated in rat liver. We have investigated the effects of hypophysectomy and replacement therapy with T4, cortisol (C), and GH in vivo on the proportion of edited apoB mRNA in rat liver and cultured rat hepatocytes as well as the synthesis and secretion of apoB 48 and apoB 100 in cultured rat hepatocytes. Hypophysectomy decreased the proportion of edited apoB mRNA in intact liver from 62% in normal rats to 29% in hypophysectomized rats. Treatment of hypophysectomized rats with T4 and C did not influence the proportion of edited apoB mRNA, whereas treatment with GH, either alone or together with T4 and C, increased the proportion of edited apoB mRNA to the levels observed in normal rats. In cultured hepatocytes isolated from normal rats, the proportion of apoB 48 (percentage of total labeled apoB) was 78% and decreased to 40% in cells isolated from hypophysectomized rats. Treatment of hypophysectomized rats with T4 and C had no effect on the proportion of apoB 48 present in isolated cells, whereas it increased to 60% after treatment with GH together with T4 and C. The proportion of apoB 48 in the medium was affected by hypophysectomy and the various hormonal treatments in a similar way to that observed in the cells. Results from in vivo labeling experiments suggested that GH alone had the capacity to increase the percentage of apoB 48 in hypophysectomized rats. On the contrary, T4 and C was needed, in addition to GH, to increase the proportion of apoB 48 in isolated hepatocytes from hypophysectomized rats. Our results suggest that this discrepancy is due to a difference between the effect of GH alone on apoB mRNA editing in the intact liver and that in isolated hepatocytes. The total secretion of apoB into the cell culture medium was not affected by hypophysectomy and hormonal treatments of the rats. In conclusion, these results indicate that GH is involved in the regulation of editing of apoB mRNA and the proportion of apoB 48 synthesized and secreted in rat liver. Thus, our observations emphasize the importance of GH as a regulator of lipoprotein metabolism.

Growth hormone increases connexin-43 expression in the cerebral cortex and hypothalamus.

Several studies indicate that systemic GH influences various brain functions. Connexin-43 forms gap junctions that mediate intercellular communication and establish the astroglial syncytium. We investigated the effects of peripheral administration of bovine GH (bGH) and recombinant human insulin-like growth factor I (rhIGF-I) on the expression of connexin-43 in the rat brain. Hypophysectomized female Sprague Dawley rats were substituted with cortisol (400 microg/kg x day) and L-T4 (10 microg/kg x day) and treated with either bGH (1 mg/kg x day) or rhIGF-I (0.85 mg/kg x day) for 19 days. The abundance of connexin-43 messenger RNA (mRNA) and protein in the brainstem, cerebral cortex, hippocampus, and hypothalamus was quantified by means of ribonuclease protection assays and Western blots. Treatment with bGH increased the amounts of connexin-43 mRNA and protein in the cerebral cortex and hypothalamus. No changes were found in the brainstem or hippocampus. Infusion of rhIGF-I did not affect connexin-43 mRNA or protein levels in any of the brain regions studied. These results show that administration of bGH increases the abundance of cx43 in specific brain regions, suggesting that GH may influence gap junction formation and thereby intercellular communication in the brain.

Growth hormone (GH) therapy in GH-deficient adults influences the response to a dietary load of cholesterol and saturated fat in terms of cholesterol synthesis, but not serum low density lipoprotein cholesterol levels.

An increased dietary load of cholesterol (ch) and saturated fat increases serum low density lipoprotein ch (LDL-ch) levels. GH therapy in GH-deficient adults decreases serum LDL-ch levels. In the rat, GH is important for resistance to dietary cholesterol in terms of serum cholesterol levels. The aim of this study was to investigate the influence of GH on the effects of an increase in the intake of cholesterol and saturated fat on serum lipoproteins and markers for cholesterol synthesis in man. Six GH-deficient adults were given an isocaloric diet enriched in cholesterol and saturated fat for 17 days with and without GH therapy (1-1.5 U/day). Serum cholesterol, LDL-ch, apolipoprotein B (apoB), and apoA1 levels increased during the diet period with GH therapy and tended to increase during the diet period without GH. However, GH therapy did not influence the dietary effect on serum cholesterol, LDL-ch, apoA1, or apoB levels. Serum levels of triglycerides, very low density lipoprotein ch, high density lipoprotein ch, and apoE were not affected by diet or GH therapy. GH therapy increased serum lipoprotein(a) levels, but did not affect the response to diet. The serum total delta7-lathosterol/cholesterol ratio increased less during the diet period with GH therapy than during the diet period without GH. Serum 7alpha-hydroxy-4-cholesten-3-one levels tended to increase during both diet periods, but were not influenced by GH treatment. Serum plant sterol levels did not change. These results indicate that GH counteracts an increase in cholesterol synthesis induced by a high fat diet without affecting bile acid synthesis or sterol absorption. GH therapy did not have any major influence on the dietary effects on serum lipoprotein levels.

Plasma growth hormone pattern and androgens influence the levels of corticosteroid-binding globulin in rat serum.

The serum concentration of corticosteroid-binding globulin (CBG) is higher in female rats than in males. Combined hypophysectomy and gonadectomy of female rats reduced the serum concentration of CBG as measured by steady-state polyacrylamide gel electrophoresis, whereas hypophysectomy of male rats increased serum CBG. These effects were seen despite replacement therapy with thyroxine and glucocorticoids. Moreover, neither androgen nor oestrogen treatment affected the serum concentrations of CBG in hypophysectomized rats. Continuous infusions of human or bovine GH (1.4 U/kg per day), by means of osmotic minipumps for 1 week, increased serum concentrations of CBG in both hypophysectomized male and female rats. In contrast, intermittent GH replacement therapy by s.c. injections at 12-h intervals either had no effect or suppressed serum CBG levels. In male rats, neonatal (days 1-2) gonadectomy increased CBG levels more than did prepubertal (day 25) gonadectomy, and testosterone replacement therapy reversed these effects. It is concluded that GH increases the serum CBG levels of hypophysectomized rats when it is given in a continuous manner, but not when given intermittently. The sex difference in serum CBG levels of normal rats may, therefore, be attributed to the more continuous secretory pattern of GH previously observed in female rats.

Growth hormone but not gonadal steroids influence lipoprotein lipase and hepatic lipase activity in hypophysectomized rats.

Lipoprotein lipase and hepatic lipase are involved in the degradation and cellular uptake of lipids in peripheral tissues and the liver. These enzymes seem to be influenced by gonadal steroids in the rat as well as in man. Since gonadal steroids have been shown to influence the secretory pattern of GH and since the effect of gonadal steroids on several metabolic functions may be dependent upon their effects on GH secretion, the present study was undertaken to investigate the developmental regulation of heparin-releasable lipoprotein lipase and hepatic lipase activities in female and male rats, and to study the effects of gonadal steroids and different modes of GH administration to hypophysectomized rats on these enzyme activities. Female and male Sprague-Dawley rats from 20 to 65 days of age were studied. Hypophysectomy was performed at 50 days of age and these rats were given replacement therapy with thyroxine and cortisone. Groups of hypophysectomized rats were treated with either oestradiol valerate (0.1 mg/kg per day) or testosterone enanthate (1 mg/kg per day). Bovine GH (1 mg/kg per day) was given to groups of hypophysectomized rats either by two daily subcutaneous injections or by continuous infusion using osmotic minipumps. Hormone treatment was given for 1 week. Lipoprotein lipase and hepatic lipase activities were measured in heparinized plasma. There was no difference in lipoprotein lipase activity between male and female rats at 20 to 45 days of age. Lipoprotein lipase activity decreased between 45 and 65 days of age in male rats but not in females and, at 65 days of age, lipoprotein lipase activity was higher in females compared with males.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for the role of the secretory pattern of growth hormone in the regulation of serum concentrations of cholesterol and apolipoprotein E in rats.

Adult male Sprague-Dawley rats were hypophysectomized and connected to an automatic i.v. infusion system. The same daily dose of human GH (hGH) was given either as eight daily pulses (3-h intervals) to mimic the male specific secretory pattern of GH or as a continuous infusion of GH, to mimic the female secretory pattern. Hypophysectomized rats received i.v. replacement therapy with L-thyroxine and cortisol. The rats were treated for 5 days. The serum cholesterol concentration was higher when hGH was given continuously than when hGH was given as eight daily pulses. The concentration of high-density lipoprotein (HDL)-cholesterol was not influenced by intermittent GH treatment, but increased when hGH was given as a continuous infusion. The serum concentration of apolipoprotein (Apo) E increased following treatment with a continuous infusion of hGH, whereas eight daily pulses of hGH had no effect. The serum concentration of ApoA-I was unaffected by hGH treatment. The serum concentration of ApoB decreased to the same degree whether hGH was given as a continuous infusion or as eight daily pulses. The serum concentration of triglycerides was not affected by hGH treatment. These results indicate that the higher serum HDL-cholesterol and serum ApoE concentrations of female rats may be due to their more continuous secretion of GH. In contrast, the effects of GH on the serum concentration of ApoB, which is not sexually differentiated, may be independent of the mode of GH secretion.

GH but not IGF-I or insulin increases lipoprotein lipase activity in muscle tissues of hypophysectomised rats.

Changes in GH secretion are associated with changes in serum lipoproteins, utilisation of fuels and body composition. Since lipoprotein lipase (LPL) is a key enzyme in the regulation of lipid and lipoprotein metabolism, changes in LPL activity may contribute to these effects of GH. The present study was undertaken to investigate the role of GH and the GH-dependent growth factor, IGF-I, in the regulation of LPL in heart, skeletal muscle and adipose tissue. Female rats were hypophysectomised at 50 days of age. One week later, hormonal therapy was commenced. All hypophysectomised rats received l-thyroxine and cortisol. Adipose tissue, the heart, soleus and gastrocnemius muscles were excised after 1 week of hormonal therapy. The effect of insulin injections on adipose tissue and heart LPL activity was also studied. In separate experiments, LPL activity in post-heparin plasma was measured. Hypophysectomy had no effect on adipose tissue LPL activity, whereas activity was reduced in heart, soleus and gastrocnemius muscle tissues. GH treatment had no significant effect on LPL activity in adipose tissue or soleus muscle, but increased the LPL activity in heart and gastrocnemius muscle. GH treatment increased post-heparin plasma LPL activity. Recombinant human IGF-I treatment (1.25 mg/kg per day) markedly reduced LPL activity in adipose tissue, but had no effect in muscle tissues. The effect of IGF-I treatment on adipose tissue LPL was not reflected by a decrease in post-heparin plasma LPL activity. Daily injections of insulin for 7 days increased LPL activity in adipose tissue but had no effect on heart LPL activity. In adipose tissue, LPL mRNA levels tended to decrease as a result of IGF-I treatment. In the muscle tissues, no significant effects of hypophysectomy, GH or IGF-I treatment on LPL mRNA levels were observed.%It is concluded that GH increases heart and skeletal muscle tissue LPL activity, which probably contributes to an increased post-heparin plasma LPL activity. The effect of GH on muscle LPL activity is probably not mediated by IGF-I or insulin. Insulin and IGF-I have opposite effects on LPL activity in adipose tissue.

Growth hormone regulation of serum lipoproteins in the rat: different growth hormone regulatory principles for apolipoprotein (apo) B and the sexually dimorphic apo E concentrations.

Growth hormone (GH) regulation of serum lipoproteins and apolipoproteins was studied using hypophysectomized (Hx) male and female Sprague-Dawley rats. Hypophysectomies were performed at 45 or 50 days of age. Hx rats were given replacement therapy with L-thyroxine (10 micrograms/kg/d) and hydrocortisone (400 micrograms/kg/d) unless otherwise specified. Bovine GH (bGH) was given either as two daily subcutaneous (SC) injections at 12-hour intervals or as a continuous SC infusion. Serum cholesterol and apolipoprotein (apo) E concentrations decreased after Hx of female rats. In contrast, Hx of male rats resulted in increased serum cholesterol concentrations and had no effect on serum apo E concentrations. There were no effects of Hx on high-density lipoprotein (HDL) apo E levels in male rats in contrast to female rats. bGH given twice daily to Hx male rats had no effect on HDL apo E levels, but a continuous infusion of bGH resulted in a marked increase in HDL apo E concentration, to levels above those of intact male rats. As previously observed in female rats, serum and HDL apo A-I concentrations decreased and serum and low-density lipoprotein (LDL) concentrations of apo B increased after Hx of male rats. Treatment with L-thyroxine and hydrocortisone reduced the serum concentrations of apo B. bGH given alone resulted in even lower concentrations of apo B. Serum concentrations of cholesterol and apo E were unaffected by replacement therapy with L-thyroxine and hydrocortisone. Treatment with bGH alone had similar effects on serum cholesterol, apo E, and apo B concentrations as treatment with L-thyroxine, hydrocortisone, and bGH in combination.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of gonadal steroids and the pituitary on the levels and composition of plasma phospholipids in the rat.

Gonadal steroids have been shown to influence plasma phospholipids. In the present study, the possible interaction between gonadal steroids and the pituitary in the regulation of plasma phospholipids was studied in rats. The total phospholipid concentration (higher in females) and the fatty acid composition of plasma lecithin was different in male compared to female rats. Gonadectomy resulted in a "feminization" of plasma phospholipids (total concentration and fatty acids in lecithin) in male rats but had no effect in females. Testosterone treatment of gonadectomized males or intact females resulted in a "masculinization" of plasma phospholipids, whereas estrogen treatment of intact males resulted in a "feminization." Hypophysectomy resulted in a marked decrease in plasma phospholipid concentration and the fatty acid composition of lecithin showed a "masculine" pattern in both males and females. Neither testosterone nor estrogen treatment had any effects on plasma phospholipids in hypophysectomized male and female rats, respectively. It is concluded that gonadal steroids and the hypothalamic-pituitary axis interact in the regulation of the synthetic and perhaps also degradative pathways controlling plasma phospholipids.

Two weeks of daily injections and continuous infusion of recombinant human growth hormone (GH) in GH-deficient adults: I. Effects on insulin-like growth factor-I (IGF-I), GH and IGF binding proteins, and glucose homeostasis.

Recombinant human growth hormone (GH) is routinely administered as daily subcutaneous injections to patients with GH deficiency (GHD). However, in the hypophysectomized rat, pulsatile and continuous infusion of GH has been shown to differ in terms of the magnitude of effect on longitudinal bone growth, serum insulin-like growth factor-I (IGF-I) concentrations, and hepatic metabolism. The aim of the present study was to compare the effects of daily injections and continuous infusion of GH in GHD adults on previously well-documented GH-dependent factors. Recombinant human GH (0.25 U/kg/wk) was administered to nine men with GHD for 14 days in two different ways, ie, as a daily subcutaneous injection at 8 PM and as a continuous subcutaneous infusion, with 1 month of washout between treatments. Blood samples and tests were performed in the morning after an overnight fast before the start of GH treatment (day 0) and on day 2 and day 14 of treatment. An oral glucose tolerance test (OGTT) was performed on day 0 and day 14. Daily injections and continuous infusion of GH exerted similar effects in terms of body weight and body composition. The two modes of administration resulted in similar daily urinary GH excretion and similar serum GH concentrations in the morning. GH binding protein (GHBP) concentrations did not change significantly during the various treatment periods. Serum IGF-I and IGF-I binding protein (IGFBP)-3 concentrations increased to a greater degree during continuous infusion of GH versus daily injections. Serum IGFBP-I concentrations decreased to a similar degree during the two modes of administration. Serum concentrations of free triiodothyronine and total triiodothyronine (T3) increased and free thyroxine (T4) decreased to a similar degree, independent of the mode of administration. However, total T4 concentrations were unchanged during both modes of treatment. Serum thyrotropin (TSH) concentrations decreased during continuous infusion, and there was a similar nonsignificant decrease during daily injections of GH. Fasting free fatty acid (FFA) levels increased during treatment with only daily injection of GH, but there was no significant effect from continuous infusion. Results of measurements of fasting concentrations of blood glucose and oral glucose tolerance (OGT) indicated a more impaired glucose tolerance after daily injections of GH versus continuous infusion. In conclusion, continuous infusion and daily injections of GH have similar effects on the variables described, but the magnitude of the effects differs.

Two weeks of daily injections and continuous infusion of recombinant human growth hormone (GH) in GH-deficient adults. II. Effects on serum lipoproteins and lipoprotein and hepatic lipase activity.

Recombinant human growth hormone (GH) administered as daily subcutaneous (SC) injections has been shown to affect serum lipoproteins in GH-deficient subjects. However, the effects of continuous infusion of GH on serum lipoproteins have not been investigated in GH-deficient adults. The aim of the present study was to compare effects of daily injections and continuous infusion of GH on lipoprotein metabolism. Recombinant human GH (0.25 U/kg/wk) was administered to nine GH-deficient adult men during a period of 14 days in two different ways, ie, as a daily SC injection at 8:00 PM and as a continuous SC infusion, with 1 month of washout between the treatments. Blood samples and tests were performed in the morning after an overnight fast before the start of GH treatment (day 0) and on day 2 and day 14 of treatment. Abdominal SC adipose tissue lipoprotein lipase (LPL), postheparin plasma LPL, and hepatic lipase (HL) activity were measured 120 minutes after the intake of 100 g glucose. Adipose tissue LPL activity decreased and postheparin plasma HL activity increased after 14 days of GH treatment irrespective of the mode of GH administration, whereas GH treatment had no effect on postheparin plasma LPL activity. Serum triglyceride and very-low-density lipoprotein (VLDL) triglyceride concentrations increased during GH treatment. However, VLDL triglyceride concentrations increased to a greater degree during treatment with daily GH injections than during continuous infusion of GH. Serum apolipoprotein (apo) B and low-density lipoprotein (LDL) cholesterol concentrations decreased during treatment with daily GH injections, but were not significantly affected by continuous GH infusion. Thus, apo B and LDL cholesterol concentrations were lower after daily GH injections versus continuous GH infusion. Serum lipoprotein(a) [Lp(a)] and apo E concentrations increased during both modes of GH treatment. However, continuous infusion of GH resulted in a more marked increase in Lp(a) and apo E concentrations than daily GH injections. Minor effects were observed on serum apo A-I concentrations but high-density lipoprotein (HDL) cholesterol concentrations were not affected. In conclusion, GH treatment of GH-deficient men influenced adipose tissue LPL and postheparin plasma HL activity, as well as serum lipoprotein concentrations. Moreover, continuous GH infusion and daily GH injections differed with respect to the magnitude of effects on several lipoprotein fractions including VLDL triglycerides, LDL cholesterol, apo B, apo E, and Lp(a) concentrations.

Serum level of placental growth hormone is raised in pregnancy rhinitis.

OBJECTIVE: To describe any relationship between pregnancy rhinitis and weight gain or serum levels of estradiol, progesterone, placental growth hormone, or insulinlike growth factor I. PATIENTS: Twenty-seven nonsmoking healthy pregnant women aged 22 to 38 years (mean age, 28 years) who had no history of respiratory allergy or chronic nasal or sinus problems volunteered to enter the study. They had no nasal complaints at entry. METHODS: Nasal patency was registered daily from early pregnancy until 1 month after delivery. Nasal and oral peak expiratory flow rates were established, and the subjective blockage was scored from 0 to 4, with 0 indicating no blockage. Serum samples were collected and weight was measured on 4 occasions during pregnancy and again at the end of the study. Pregnancy rhinitis was diagnosed if the subjective nasal obstruction score was 1 or higher every morning for at least 6 weeks immediately preceding delivery, then returned to 0 within 2 weeks and remained at 0 until the end of the study. If on any day other signs of respiratory tract infection occurred, that day was excluded. RESULTS: Pregnancy rhinitis was diagnosed in 5 women. These 5 women showed significantly higher levels of placental growth hormone than the women without the diagnosis. No significant difference was found between the 2 groups regarding body weight or any of the other serum levels studied. CONCLUSIONS: Serum level of placental growth hormone is raised in pregnancy rhinitis and may be involved in its pathogeny. Pregnancy rhinitis does not significantly raise weight gain or serum levels of estradiol, progesterone, or insulinlike growth factor I.