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P. K. De and R. K. Banerjee

ABSTRACT

A highly active soluble peroxidase has been identified in the preputial glands of the rat. The enzyme was detectable in the sebaceous secretion of the glands and showed catalytic properties characteristic of true peroxidase. It had a native molecular weight of around 73 000 as determined by gel-permeation studies. Immunologically the enzyme cross-reacted with an antiserum against bovine lactoperoxidase. Administration of progesterone resulted in a significant increase in the total activity of the enzyme, while testosterone and oestradiol had no such effect. The enzyme had a similar molecular weight and similar catalytic and immunological properties to rat uterine fluid peroxidase but differed markedly in respect to sensitivity to oestradiol.

J. Endocr. (1987) 112, 239–245

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C. F. FARVER, D. DE WIED and P. T. K. TOIVOLA

Wisconsin Regional Primate Research Center, University of Wisconsin, Madison, Wisconsin 53706, U.S.A.

(Received 22 May 1978)

In a wide variety of species corticotrophin (ACTH) is known to stimulate the synthesis and secretion of adrenocortical steroids. Studies with rhesus monkeys have shown that these responses can be affected by a number of factors including the method of handling and the type of physical restraint (Mason, 1959). In addition, androgens may depress plasma levels of glucocorticoids in primates (Brown & Migeon, 1956; Huis in't Veld, Louwerens & van den Spek, 1960). It was therefore decided to study the response of plasma cortisol to ACTH without these neural or hormonal influences. This report describes the effects of ACTH on castrated rhesus monkeys adapted to chronic restraint.

Four chair-restrained, orchidectomized rhesus monkeys (Macaca mulatta) bearing chronic indwelling venous catheters were used as experimental subjects and were housed, maintained and subjected to blood sampling as

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A Sanigorski, D Cameron-Smith, P Lewandowski, K Walder, A de Silva, G Morton and GR Collier

We examined the effects of leptin treatment on the expression of key genes in adipocyte metabolism in Psammomys obesus (P. obesus), a polygenic rodent model of obesity. Lean and obese P. obesus were given three daily intraperitoneal injections of either saline or leptin (total of 45 mg/kg per day) for 7 days. In lean animals, leptin treatment led to reductions in food intake, body weight and fat mass. Pair-fed animals matched for the reduction in food intake of the lean leptin-treated animals demonstrated similar reductions in body weight and fat mass. In obese P. obesus, leptin treatment failed to have any effect on body weight or body fat mass, indicating leptin resistance. Lipoprotein lipase, hormone-sensitive lipase and peroxisome proliferator activated receptor gamma 2 mRNA levels were significantly reduced in lean leptin-treated animals, whereas pair-fed animals were similar to lean controls. Uncoupling protein 2 and glycerol phosphate acyltransferase were also reduced in the lean leptin-treated animals, but not significantly so. Obese animals did not show any gene expression changes after leptin treatment. In conclusion, high circulating concentrations of leptin in lean P. obesus resulted in decreased gene expression of a number of key lipid enzymes, independent of changes in food intake, body weight and fat mass. These effects of leptin were not found in obese P. obesus.

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Y Okuma, K Saito, A E O’Connor, D J Phillips, D M de Kretser and M P Hedger

In several biological systems, the inhibin βA homodimer activin A is stimulated by, and in turn, inhibits the action of interleukin (IL)-1 (both IL-1α and IL-1β) and IL-6. The possibility that a similar regulatory relationship operates within the testis was investigated. Sertoli cells from immature (20-day-old) rats were cultured with human IL-1α or IL-1β, human IL-6 and/or ovine FSH or dibutyryl cAMP. Activin A and the inhibin dimers, inhibin A and inhibin B, were measured by specific ELISA. Immunoreactive inhibin (ir-inhibin) was measured by RIA. Activin/inhibin subunit mRNA expression was measured by quantitative real-time PCR. Both IL-1 isoforms, but not IL-6, stimulated activin A secretion through increased synthesis of βA-subunit mRNA. IL-1 also stimulated activin A secretion by testicular peritubular cells. In contrast to the effect on activin A, IL-1 suppressed inhibin βB-subunit and, to a lesser extent, α-subunit mRNA expression, thereby reducing basal and FSH-stimulated inhibin B secretion by the Sertoli cells. Conversely, FSH inhibited basal activin A secretion and antagonised the stimulatory effects of IL-1. Dibutyryl cAMP partially inhibited the action of IL-1 on activin A secretion, but had no significant effect on basal activin A secretion. Secretion of inhibin A was low in all treatment groups. These data demonstrate that IL-1 and FSH/cAMP exert a reciprocal regulation of activin A and inhibin B synthesis and release by the Sertoli cell, and suggest a role for activin A as a potential feedback regulator of IL-1 and IL-6 activity in the testis during normal spermatogenesis and in inflammation.

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M. C. Ruiz de Elvira, A. K. Sinha, M. Pickard, M. Ballabio, M. Hubank and R. P. Ekins

ABSTRACT

Calmodulin-regulated phosphatase activity was measured in the brain of 2-month-old rats born from hypothyroid and normal dams, using a fluorometric enzyme assay developed for this purpose. Calmodulin content was measured in the same brain regions by radioimmunoassay. Significant differences between groups in weight and protein content, basal phosphatase and calmodulin-regulated phosphatase activity were found. The brain region most affected was the cerebellum, where basal and calmodulin-regulated phosphatase activities, and protein content were increased. The data point towards a lasting effect of maternal hypothyroxinaemia on the brain function of the progeny.

Journal of Endocrinology (1989) 121, 331–335

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Y Okuma, A E O’Connor, T Hayashi, K L Loveland, D M de Kretser and M P Hedger

Production and regulation of activin A and inhibin B during the cycle of the seminiferous epithelium were investigated in adult rats. Immunohistochemistry localised the activin βA-subunit to the Sertoli cell cytoplasm, with much weaker expression in spermatocytes and spermatids. Both activin A and inhibin B, measured by ELISA were secreted by, seminiferous tubule fragments over 72 h in culture. Activin A was secreted in a cyclic manner with peak secretion from tubules isolated at stage VIII. Tubules collected during stage VI produced the least activin A. Inhibin B secretion was highest from stage IX-I tubules and lowest from stage VII tubules. Addition of interleukin-1β (IL-1β) had relatively little effect on activin A or inhibin B secretion in culture. In contrast, the peak secretion of activin A by stage VIII tubules was blocked by co-incubation with an excess of human recombinant IL-1 receptor antagonist, whereas inhibin B secretion increased slightly. Dibutyryl cAMP stimulated activin A secretion by late stage VII and VIII tubules and stimulated inhibin B across all stages. These data indicate that activin A and inhibin B are cyclically regulated within the seminiferous epithelium, with endogenous IL-1 (presumably IL-1α produced by the Sertoli cells), responsible for a peak of activin A production subsequent to sperm release at stage VIII. These data provide direct evidence that production of activin A and inhibin B by the Sertoli cell is locally modulated by IL-1α , in addition to FSH/cAMP, under the influence of the developing spermatogenic cells.

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G A C van Haasteren, E Linkels, W Klootwijk, H van Toor, J M M Rondeel, A P N Themmen, F H de Jong, K Valentijn, H Vaudry, K Bauer, T J Visser and W J de Greef

Abstract

The purpose of this study was to investigate the mechanisms involved in the reduced thyroid function in starved, young female rats. Food deprivation for 3 days reduced the hypothalamic content of prothyrotrophin-releasing hormone (proTRH) mRNA, the amount of proTRH-derived peptides (TRH and proTRH160–169) in the paraventricular nucleus, the release of proTRH-derived peptides into hypophysial portal blood and the pituitary levels of TSHβ mRNA. Plasma TSH was either not affected or slightly reduced by starvation, but food deprivation induced marked increases in plasma corticosterone and decreases in plasma thyroid hormones. Refeeding after starvation normalized these parameters. Since the molar ratio of TRH and proTRH160–169 in hypophysial portal blood was not affected by food deprivation, it seems unlikely that proTRH processing is altered by starvation. The median eminence content of pGlu-His-Pro-Gly (TRH-Gly, a presumed immediate precursor of TRH), proTRH160–169 or TRH were not affected by food deprivation. Since median eminence TRH-Gly levels were very low compared with other proTRH-derived peptides it is unlikely that α-amidation is a rate-limiting step in hypothalamic TRH synthesis.

Possible negative effects of the increased corticosterone levels during starvation on proTRH and TSH synthesis were studied in adrenalectomized rats which were treated with corticosterone in their drinking water (0·2 mg/ml). In this way, the starvation-induced increase in plasma corticosterone could be prevented. Although plasma levels of thyroid hormones remained reduced, food deprivation no longer had negative effects on hypothalamic proTRH mRNA, pituitary TSHβ mRNA and plasma TSH in starved adrenalectomized rats. Thus, high levels of corticosteroids seem to exert negative effects on the synthesis and release of proTRH and TSH. This conclusion is corroborated by the observation that TRH release into hypophysial portal blood became reduced after administration of the synthetic glucocorticosteroid dexamethasone.

On the basis of these results, it is suggested that the reduced thyroid function during starvation is due to a reduced synthesis and release of TRH and TSH. Furthermore, the reduced TRH and TSH synthesis during food deprivation are probably caused by the starvation-induced enhanced adrenal secretion of corticosterone.

Journal of Endocrinology (1995) 145, 143–153

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K Fosgerau, P Galle, T Hansen, A Albrechtsen, C de Lemos Rieper, B Klarlund Pedersen, L Kongskov Larsen, A Randrup Thomsen, O Pedersen, M Bagge Hansen and A Steensberg

Abstract

Interleukin-6 (IL6) is critically involved in inflammation and metabolism. About 1% of people produce IL6 autoantibodies (aAb-IL6) that impair IL6 signaling in vivo. We tested the hypothesis that the prevalence of such aAb-IL6 is increased in type 2 diabetic patients and that aAb-IL6 plays a direct role in causing hyperglycemia. In humans, the prevalence of circulating high-affinity neutralizing aAb-IL6 was 2.5% in the type 2 diabetic patients and 1% in the controls (odds ratio 2.5, 95% confidence interval 1.2–4.9, P=0.01). To test for the role of aAb-IL6 in causing hyperglycemia, such aAb-IL6 were induced in mice by a validated vaccination procedure. Mice with plasma levels of aAb-IL6 similar to the 2.5% type 2 diabetic patients developed obesity and impaired glucose tolerance (area under the curve (AUC) glucose, 2056±62 vs 1793±62, P=0.05) as compared with sham-vaccinated mice, when challenged with a high-fat diet. Mice with very high plasma levels of aAb-IL6 developed elevated fasting plasma glucose (mM, 4.8±0.4 vs 3.3±0.1, P<0.001) and impaired glucose tolerance (AUC glucose, 1340±38 vs 916±25, P<0.001) as compared with sham-control mice on normal chow. In conclusion, the prevalence of plasma aAb-IL6 at levels known to impair IL6 signaling in vivo is increased 2.5-fold in people with type 2 diabetes. In mice, matching levels of aAb-IL6 cause obesity and hyperglycemia. These data suggest that a small subset of type 2 diabetes may in part evolve from an autoimmune attack against IL6.

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R.G. Forage, R.W. Brown, K.J. Oliver, B.T. Atrache, P.L. Devine, G.C. Hudson, N.H. Goss, K.C. Bertram, P. Tolstoshev, D.M. Robertson, D.M. de Kretser, B. Doughton, H.G. Burger and J.K. Findlay

ABSTRACT

Seven Merino–Border Leicester cross–bred ewes were immunized with a purified fusion protein, produced by recombinant DNA methods, of the a subunit of bovine inhibin. Four animals were immunized with the fusion protein alone and three with a conjugate made by coupling the fusion protein to keyhole limpet haemocyanin (KLH) using glutaraldehyde. Each animal received four injections of the fusion protein over 93 days. The animals were synchronized using progestagen sponges and subjected to laparoscopy for the determination of ovulation rates in two consecutive cycles (days 115 and 135). The immunized animals had overall mean ovulation rates for each cycle of 3.4 and 3.4 which was significantly (P < 0.001) above the rates of 1.1 and 1.4 determined for the controls, which had either received no treatment (n=5) or had been immunized with 300 μg KLH (n=4). Analysis of antisera taken on day 115 showed significant fusion protein antibodies and iodinated inhibin–binding capacity in the test but not control groups. Furthermore, antisera to the fusion protein in four out of seven ewes neutralized the inhibin bioactivity of ovine follicular fluid in an in–vitro bioassay. These data demonstrate that neutralization of inhibin can be effected by immunization with bovine inhibin a subunit and that such immunization results in increased ovulation rates as predicted from the biological role of inhibin as a suppressor of FSH.