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J. M. Fletcher and N. McKenzie

ABSTRACT

Lean (Fa/-) and genetically obese (fa/fa) Zucker rats were adrenalectomized at 18 days of age (3 days before weaning) before the onset of hyperinsulinaemia. At 40–41 days of age, basal and glucose-stimulated insulin concentrations did not differ significantly between lean and obese rats. Plasma insulin and glucose concentrations were higher in both phenotypes 24 h after administration of corticosterone (2·0 mg at 12-h intervals). Corticosterone-treated obese rats had higher basal and glucose-stimulated insulin levels than similarly treated lean animals, although plasma glucose concentrations did not differ between phenotypes. The basal plasma insulin concentration of obese rats treated with corticosterone for 24 h was reduced 15, 30 and 45 min after injection of atropine (0·3 mg) without any significant change in the plasma glucose level. Injection of atropine (0·3 mg) 20 min before a glucose load prevented the greater increment in plasma insulin concentration of corticosterone-treated obese rats compared with similarly treated lean animals. Atropine administration (0·3 mg) to intact obese rats at 40 days of age reduced, but did not abolish, their hyperinsulinaemia compared with intact lean animals. It is concluded that (1) pre-weaning adrenalectomy prevents the development of hyperinsulinaemia in genetically obese rats, (2) corticosterone replacement for only 24 h restores the hyperinsulinaemia of obese rats, (3) the differential effects of corticosterone on insulin secretion by lean and obese rats are mediated by the parasympathetic nervous system and (4) the parasympathetic nervous system contributes to, but is not the only cause of, hyperinsulinaemia in intact obese rats.

J. Endocr. (1988) 118, 87–92

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J. N. SHELTON and I. C. FLETCHER

Several 9α-halogenated progestagens are of high biological activity in the ewe. Cronolone (9α-fluoro-11β-hydroxy-17α-acetoxyprogesterone), SC-21110 (9α-chloro-11β-hydroxy-17α-acetoxyprogesterone and SC-5848 (9α-chloro-11β-hydroxyprogesterone) are indistinguishable from progesterone in priming the spayed ewe to respond to oestrogen and moreover are 20 times as potent as progesterone in this bioassay (Shelton, Robinson & Holst, 1967; Holst & Moore, 1968; R. Sinclair, personal communication). Cronolone has a similar potency in the inhibition of oestrus (Shelton & Robinson, 1967), and in a flock of ewes allows precise synchronization of oestrus and ovulation after termination of treatment (Robinson, Moore, Holst & Smith, 1967). These findings indicate that 9α-halogenated progestagens are similar to progesterone in duration of activity and are of high potency. To study further the biological activity of these compounds, they were tested for ability to maintain pregnancy in rats.

Virgin female rats weighing 200–250 g. were housed in a constant temperature environment with free access to food and

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T P Fletcher and I J Clarke

Abstract

This study examined the effect of thyroidectomy (TX) on the GH axis in sheep. The secretion of GH was monitored 10 and 77 days after TX or sham-TX when the effects on plasma GH and prolactin levels of the injection of 0·5 μg GH-releasing factor (GRF)/kg and 1 μg thyrotrophin-releasing hormone (TRH)/kg were also assessed.

There were no significant differences in GH pulse amplitude, pulse frequency, inter-pulse interval and GH secreted/h between sham-TX and TX animals at 10 or 77 days after TX.

There was no difference in the GH response to GRF injection in sham-TX sheep at any time but in TX sheep the GH response was significantly (P<0·05) attenuated 10 days after TX. After 77 days the GH response was similar to the response before TX. There was no measurable GH response to injection of TRH in sham-operated or TX sheep at any time. The prolactin response to TRH was not affected by TX or sham-TX.

These results suggest that TX in sheep does not affect GH secretion but paradoxically the response to GRF is attenuated in hypothyroid sheep in the short term. TRH causes release of prolactin but not GH in sheep.

Journal of Endocrinology (1994) 140, 495–502

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J. Oben, L. Morgan, J. Fletcher, and V. Marks

ABSTRACT

The effect of gastric inhibitory polypeptide (GIP), glucagon-like peptide-1(7–36) amide, (GLP-1(7–36) amide), glucagon-like peptide-2 (GLP-2), glucagon and insulin on fatty acid synthesis in explants of rat adipose tissue from various sites was investigated. GIP, GLP-1(7–36) amide and insulin stimulated fatty acid synthesis, as determined by measuring the incorporation of [14C]acetate into saponifiable fat, in a dose-dependent manner, over the concentration range 5–15 ng/ml (0·87–2·61 nmol/l) for insulin and 0·5–7·5 ng/ml for GIP (0·10–1·50 nmol/l) and GLP-1(7–36) amide (0·15–2·27 nmol/l). Insulin and GIP caused a significantly greater stimulation of [14C]acetate incorporation into fatty acids in omental adipose tissue than in either epididymal or subcutaneous adipose tissue. Both GIP and GLP-1(7–36) amide had the ability to stimulate fatty acid synthesis within the physiological range of the circulating hormones. At lower concentrations of the hormones, GLP-1(7–36) amide was a more potent stimulator of fatty acid synthesis than GIP in omental adipose tissue culture; the basal rate of fatty acid synthesis was 0·41±0·03 pmol acetate incorporated/mg wet weight tissue per 2 h; at 0·10 nmol hormone/l 1·15±0·10 and 3·40±0·12 pmol acetate incorporated/mg wet weight tissue per 2 h for GIP and GLP-1(7–36) amide respectively (P < 0·01). GLP-2 and glucagon were without effect on fatty acid synthesis in omental adipose tissue. The study indicates that GIP and GLP-1(7–36) amide, in addition to stimulating insulin secretion, may play a direct physiological role in vivo, in common with insulin, in promoting fatty acid synthesis in adipose tissue.

Journal of Endocrinology (1991) 130, 267–272

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I. C. FLETCHER, A. J. ALLISON, and D. R. LINDSAY

Seasonal variation in the incidence and duration of behavioural oestrus in spayed ewes treated with progesterone and oestrogen has been attributed to changes in the sensitivity of ewes to oestrogen (Reardon & Robinson, 1961; Fletcher & Lindsay, 1971). This interpretation is open to question, however, in view of suggestions from Lamond & Bindon (1962) and Lamond (1964) that intact ewes showed seasonal changes in sensitivity to progesterone. The investigation reported here was designed to determine whether changes in sensitivity to progesterone contributed to seasonal variation in the expression of oestrous behaviour in spayed ewes.

The experiment was of factorial design with three different doses of progesterone for priming, two breeds of ewe and two seasons of observation. Sixty spayed Merino and 60 spayed Border Leicester × Merino cross-bred ewes were each allotted at random to three groups of 20. They were injected daily with 5, 10 or 20 mg progesterone

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J. M. Fletcher, G. E. Lobley, and A. Connell

ABSTRACT

The effects of endogenous gonadal hormones on the regulation of body composition and energy retention have been investigated under conditions of controlled food intake. Male and female rats were fed the same amount from weaning to 82 days of age. The carcases of males contained more protein, less lipid and yielded more ash than females, but they had the same amount of total energy in their carcases as females. In a second experiment, male rats were sham-operated or castrated at 19 days and then fed equal amounts from weaning. At 40 days, intact and castrated rats did not differ in total carcase energy content nor in carcase composition. At 82 days the carcases of intact rats had more protein but had retained the same amount of energy as castrated rats. By 131 days, the difference in protein content was larger and intact rats had less carcase lipid, less carcase energy and gave less ash than castrated rats. At the same age and with a similar food intake, the differences in carcase composition between intact males and females were considerably larger than between intact and castrated males. In a third experiment, male rats were sham-operated or castrated at 1 day post partum and fed the same amount as in the second experiment from weaning to 82 days. Both sham-castrated and castrated rats grew less well than rats operated on at 19 days. The differences in carcase composition between intact and castrated rats were in the same direction but of greater magnitude than in rats operated at the later age. In a fourth experiment the effects on body compositon and energy retention of sham-operation, castration or immunization to LH-releasing hormone (LHRH) at weaning were compared in male rats fed the same amount from weaning to 131 days. Intact rats retained less carcase energy, less lipid and produced less ash than castrated and LHRH-immunized animals. Castrated and LHRH-immunized rats did not differ in carcase composition or amount of energy retained. It is concluded that (1) endogenous sex steroids affect growth and carcase composition independently of food intake, (2) the characteristic carcase composition of the female rat is largely due to the presence of ovarian steroids rather than lack of testicular steroids, (3) in the absence of increased food intake the effects of testicular steroids upon growth and energy expenditure are small but similar to those found in animals with free access to food, (4) the long-terms effects of perinatal exposure to testicular steroids upon growth and carcase composition are not only a consequence of changed food intake and (5) surgical castration and functional castration, induced by LHRH auto-immunization, produce the same effects on carcase composition.

J. Endocr. (1986) 110, 97–102

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G. M. Almahroos, K. Docherty, J. A. Fletcher, T. Webb, and D. A. Heath

ABSTRACT

Familial benign hypercalcaemia (FBH) closely resembles primary hyperparathyroidism (PHPT) both clinically and biochemically. Using a cDNA probe for the parathyroid hormone (PTH) gene we have studied restriction fragment length polymorphisms in normal British subjects and have shown them to be similar to those found in previous studies in a German population. The pattern of inheritance of these restriction fragment length polymorphisms in a family with FBH shows that the PTH gene is not involved in the pathogenesis of the condition. Limited studies in PHPT indicate that it is unlikely that a major structural defect or rearrangement is responsible for the sporadic form of the disease.

J. Endocr. (1987) 115, 183–186

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G. E. Lobley, A. Connell, V. Buchan, P. A. Skene, and J. M. Fletcher

ABSTRACT

The effects of episodic infusion of testosterone into the vascular system on energy expenditure, nitrogen retention and whole body protein synthesis (determined from [1-14C]leucine kinetics) were studied in castrated male lambs under conditions of controlled food intake. Comparisons were made between a 10-day control period and a 10-day treatment period for each lamb. Infusion of testosterone produced a significant increase in heat production, but the magnitude (198 kJ/day, +2·5% was less than the differences in energy expenditure expected between entire and castrated male ruminants. The retention of nitrogen improved by 1·24 g/day ( + 22%) in response to the administration of androgen, and this was accompanied by a decrease in amino acid oxidation. Total protein synthesis also declined, and the anabolic nature of testosterone supply must, therefore, be effected through a reduction in the breakdown of protein, the mechanism being similar to that proposed for certain anabolic steroids and the β-agonist, clenbuterol. Contrary to other reports, the presence of testosterone had no effect on the plasma concentration of GH.

J. Endocr. (1987) 115, 439–445

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K. G. Braslis, A. Shulkes, D. R. Fletcher, and K. J. Hardy

ABSTRACT

Calcitonin gene-related peptide (CGRP) is a product of the calcitonin gene with a widespread distribution in neural tissue of the brain, gut and perivascular nerves. Infusion of CGRP produces multiple biological effects, but the physiological significance of these findings will be influenced by the sites and rates of CGRP metabolism.

The metabolic clearance rate and half-life of disappearance of human CGRP were estimated in conscious sheep after infusing CGRP at 1 or 5 pmol/kg per min to steady-state conditions. The particular organs involved in the clearance of CGRP were assessed by measuring the inflow and outflow concentrations across the liver, gut, kidney, lung and brain.

The metabolic clearance rate at steady state was 22·6 ± 2·1 (s.e.m.) and 15·0±1·7 ml/kg per min for the 1 and 5 pmol/kg per min doses respectively. The half-life of disappearance was bi-exponential: 3·6±0·3 min for the first phase and 13·6±1·0 min for the second phase. High-pressure liquid chromatography of plasma at equilibrium revealed only a single peak coeluting with CGRP(1–37): no immunoreactive metabolites were detected. These pharmacokinetic values are intermediate between that of a neurotransmitter and a hormone and are therefore consistent for a peptide with both circulatory and neurotransmitter modes of action. The kidney, with an arterial–renal vein gradient of 14%, and the liver, with a portal– hepatic vein gradient of 25%, were the major organs involved in the clearance of CGRP. The specific organ clearance, however, accounted for only one-third of the whole body metabolic clearance rate of CGRP, suggesting that other more generalized degradative systems are involved, such as endothelial-bound enzymes of blood vessels. This information on clearance and organ-specific metabolism should form a basis for evaluating the physiological roles and modes of action of CGRP.

J. Endocr. (1988) 118,25–31

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T P Fletcher, G B Thomas, F R Dunshea, L G Moore, and I J Clarke

Abstract

The putative negative feedback effects of IGF-I and IGF-II on GH secretion were tested by intracerebroventricular (icv) and intrapituitary administration to sheep. Over two consecutive days, serial jugular blood samples were taken at 10 min intervals for 6 h from ewes (n=3/group) fitted with indwelling stainless steel cannulae into the lateral or third cerebral ventricles. The sheep were injected (icv) with either vehicle or purified ovine IGF-I (2, 4 or 8 μg). IGF-I injection had no effect on plasma GH secretion. Serial blood samples were taken from a second group of nine ewes in which ovine or recombinant human (rh) IGF-I was infused (2·5 μg/h for 2 h) into the third ventricle; once again, IGF-I failed to affect the episodic pattern of GH secretion. Three ewes fitted with indwelling stainless steel cannulae placed in the anterior pituitary gland were consecutively infused with either ovine or rhIGF-I (2·5 μg/h for 2 h) or vehicle. Plasma GH concentrations were suppressed in 3/3 sheep from 1–1·5 h after the commencement of infusion and GH levels remained low for the remainder of the sampling period. In another group of five ewes synergistic effects of IGF-I and IGF-II on GH secretion were tested by icv infusion of rhIGF-I, rhIGF-II, or rhIGF-I+rhIGF-II (5 μg/h for 2 h) or vehicle (sterile 10 mm HCl/saline). Each sheep received each treatment in a randomised design. Infusion (icv) of IGF-I and IGF-II alone or in combination failed to alter GH secretion.

These observations suggest that IGF-I derived from peripheral tissues may modulate GH release at the pituitary level but that IGF-I acts neither alone nor in conjunction with IGF-II as a negative feedback regulator of GH secretion via the hypothalamus in the ewe.

Journal of Endocrinology (1995) 144, 323–331