Growth hormone (GH) is known to interact with adipose tissue and to induce lipolysis. Adipocytes produce leptin which regulates appetite and energy expenditure. In order to elucidate the role of GH in leptin production, we studied the effect of GH on leptin gene expression and body fat in fatty Zucker rats, a model of obesity with resistance to both leptin and insulin. Recombinant human GH administered subcutaneously at 0.5 mg/kg per day (low dose) as well as at 1.65 mg/kg per day (high dose) reduced leptin mRNA levels in epididymal fat tissue but not in subcutaneous fat tissue after 7 days. GH administration only at the high dose reduced percentage body fat. Insulin-like growth factor-I infusion (200 microg/kg per day) did not change percentage body fat or leptin mRNA levels in epididymal fat. These observations suggest that GH directly interacts with adipose tissue and reduces leptin gene expression in visceral fat tissue.

Abstract

The significance of stress-induced hypogonadism remains unclear. Since plasma testosterone and LH have renotropic activity that is other than reproductive, we hypothesize that stress-induced hypogonadism is an adaptive response to protect the kidney. To examine this hypothesis, we prepared hypogonadal male rats with different levels of LH and testosterone through orchiectomy (castration), through chronic treatment with a slowly secreted form of gonadotropin-releasing hormone agonist (GnRH_A; GnRH_A pretreatment), or through both treatments concomitantly (castration with GnRH_A pretreatment). Castrated rats had undetectable plasma testosterone and high plasma LH. GnRH_A-pretreated rats had low plasma testosterone and normal plasma LH. Castrated rats with GnRH_A pretreatment had undetectable plasma testosterone and normal plasma LH. We compared their sensitivity to HgCl₂ nephrotoxicity and found that, when a low dose of HgCl₂ (1·5 mg/kg body weight (BW)) was injected s.c. to induce acute renal failure, endogenous creatinine clearance (Ccr) decreased from 390 ± 30 to 94 ± 17 ml/h per kg BW in intact (unpretreated) rats. Such a decrease in Ccr was completely prevented in castrated rats (388 ± 30 ml/h per kg BW) and partially prevented in GnRH_A-pretreated rats (216 ± 40 ml/h per kg BW). When a high dose of HgCl₂ (2·25 mg/kg BW) was injected, half of the eight intact rats died but castrated rats and GnRH_A-pretreated rats survived (P<0·05). The elevated resistance in castrated rats was reduced when plasma LH was reduced with GnRH_A pretreatment, but was restored by additional pretreatment with ovine LH (40 μg/day), as evidenced by changes in Ccr. Elevated resistance in castrated rats was also reduced by the administration of testosterone propionate. In conclusion, hypogonadism activated the preventive and defensive mechanisms that protect the kidney through both decreased plasma testosterone and high or even normal plasma LH.

Journal of Endocrinology (1996) 148, 553–559

To explore the clinical significance of p53 in the pathogenesis of adrenal neoplasms, we investigated the incidence of p53 gene mutations in functioning human adrenal tumours using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique to screen p53 exons 4 to 9. We examined 29 adrenocortical adenomas (primary aldosteronism, n=17; Cushing's syndrome, n=12, all benign), and 33 phaeochromocytomas (benign solitary, n=18; benign multiple, n=5; malignant, n=10) in Japanese and Chinese patients. PCR-SSCP did not show any abnormal band-shifts in any of the adrenocortical adenoma and benign solitary phaeochromocytoma tissues. In contrast, six phaeochromocytoma tissues (two cases benign multiple, four cases malignant) showed PCR-SSCP band-shifts. Subsequent DNA sequencing analysis of the shifted bands revealed six cases with nine mutations or intronic sequence alterations: three cases contained sequence alterations within intronic regions, three cases with silent mutation (sequence alteration in codon without amino acid alteration), and three cases contained missense mutations (one case each in exons 5, 6 and 9). Immunohistochemical staining demonstrated that two of three cases with missense mutations and one case with an intronic sequence alteration over-expressed p53 protein in tumour cell nuclei. We observed no association between p53 gene mutation and p21/WAF1/Cip-1 expression. The relatively high incidence of p53 gene mutations or intronic sequence alteration in multiple and malignant phaeochromocytomas, but not in benign solitary cases, suggests that p53 mutation could play some role in the pathogenesis of multiple and/or malignant phaeochromocytomas.

Abstract

Although endothelins were originally discovered as peptides with vasoconstrictor activity, recent studies have indicated a number of endothelin (ET)-induced hormonal functions in various tissues. We have studied the interaction of endothelins with porcine thyroid cells in culture. Specific binding of ¹²⁵I-labelled ET-1 was demonstrated in porcine thyroid cells. The binding was displaced equally by unlabelled ET-1 and ET-2, but receptor affinity for ET-3 was lower than that for ET-1 and -2. Scatchard analysis of the data revealed a single class of high-affinity ET-1 receptors with a K _d of 0·45 nmol/l and a binding capacity of 2100 sites/cell. SDS-PAGE and autoradiography of ¹²⁵I-labelled ET-1 cross-linked with thyroid cell membranes demonstrated ET-1 binding sites with an apparent molecular weight of 50 kDa. These results indicated that ET-1 receptors in thyroid cells are type A ET receptors. In association with the presence of ET-1 receptors, porcine thyroid cells responded to ET-1 and ET-2 with an increase in c-fos mRNA expression. Although ET-1 did not affect DNA synthesis stimulated by either EGF or IGF-I, it dose-dependently inhibited TSH-induced iodide uptake and also inhibited iodide uptake stimulated by forskolin and 8-bromo-cAMP. ET-1 had no effect on TSH-stimulated cAMP production. Thus, ET-1 inhibited TSH-induced iodine metabolism by acting at the steps distal to cAMP production. In agreement with a recent report, immunoreactive ET-1 was detected in medium conditioned by porcine thyroid cells. Antibody to ET-1 was found to increase TSH-induced iodide uptake. These results are compatible with the notion that ET-1 negatively regulates TSH-induced iodide uptake in an autocrine manner.

Journal of Endocrinology (1994) 142, 463–470