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D. J. Flint
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The current EEC ban on the use of steroid growth promoters in animal production programmes has resulted in increased efforts to find alternative strategies to improve animal performance and, in view of the current advice to reduce dietary fat intake, great emphasis is being placed on producing heavier but leaner carcasses.

The approach closest to introduction is probably the use of recombinant bovine growth hormone (rbGH) which not only enhances carcase protein:fat ratios in sheep (Muir, Wien, Duquette et al. 1983), pigs (Machlin, 1972; Chung, Etherton & Wiggins, 1985) and calves (Brumby, 1959) but also produces large increases (10–30%) in the milk yield of lactating dairy cows (Bauman, Eppard, de Geeter & Lanza, 1985). The major limitations to its use appear to be the necessary frequency of administration and its cost-effectiveness. As a consequence, ways of enhancing the bioactivity of rbGH are being pursued vigorously. A novel and curious phenomenon

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D. J. Flint
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Bromocriptine treatment of lactating rats, or removal of the litter, led to a decrease in the number of insulin receptors in the mammary gland and an increase in the concentration of insulin in the serum. Bromocriptine also induced a decrease in the concentration of both prolactin and progesterone in the serum, whilst concurrent treatment with the former but not the latter prevented all the effects of bromocriptine for 48 h. Removal of the litter produced a similar decrease in the concentration in the serum of prolactin but not of progesterone. Treatment with prolactin prevented all of the effects of removal of the litter for 24 but not 48 h. This suggests that these effects of prolactin may require a mammary gland actually synthesizing milk since the gland rapidly fills with milk after removing the litter whereas milk removal continues to take place in bromocriptine-treated rats allowed to continue nursing their litters.

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M. J. Gardner
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D. J. Flint
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ABSTRACT

Treatment of neonatal rats on days 2–5 with antibodies against rat GH (rGH) markedly reduced body weight gain and serum concentrations of insulin-like growth factor-I for 6–8 weeks in both females and males, after which weight gain normalized without evidence of catch-up growth. There were no significant effects on serum prolactin, tri-iodothyronine or corticosterone. Testis and ovarian weights were reduced, although only in proportion to body size. In females, but not males, the treated rats, though lighter, had increased fat deposition in the parametrial depot. Pituitary weight was considerably reduced over 100 days later, as was the pituitary content of GH, but not prolactin. The response to GH-releasing factor of both male and female rats was also greatly reduced at this time. Taken together with the fact that these rGH antibodies can bind directly to somatotrophs, we propose that the long-term effects of the antibodies are induced by specific somatotroph destruction.

Journal of Endocrinology (1990) 124, 381–386

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J. Beattie
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D. J. Flint
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The past few years have seen a dramatic increase in knowledge in relation to the molecular structures of both growth hormone(s) (GH) and their polypeptide receptors (GHR). In addition to older data providing the sequences of numerous mammalian and nonmammalian GHs, cDNAs for mouse (Smith et al. 1989), rat (Mathews et al. 1989), rabbit, human (Leung et al. 1987), ovine (Adams et al. 1990), bovine (Hauser et al. 1990) and porcine (Cioffi et al. 1990) GHRs have recently been cloned and sequenced. Further to this, a high resolution X-ray crystal structure for porcine GH has been published (AbdelMeguid et al. 1987), and very recently the cocrystallization of human (h) GH with the extracellular domain of the GHR has been achieved (De Vos et al. 1992). These studies have revealed GHs to be 4α helix bundle proteins with one molecule of GH binding in an asymmetric fashion to two molecules of

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D. J. Flint
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M. J. Gardner
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ABSTRACT

Neonatal female rats were treated for 3 weeks (short term) or 8 weeks (long term) with antiserum to rat GH (anti-rGH) with or without replacement therapy with recombinant bovine GH (bGH). Body weight gain and tail length were significantly suppressed within the first 3 weeks and were even more markedly suppressed when treatment was continued for 8 weeks. When treatment was stopped in short-termtreated animals the rate of body weight gain recovered, although without evidence of catch-up growth. These effects were all normalized by concurrent treatment with bGH. Long-term anti-rGH treatment caused a profound reduction (80%) in the number of differentiated adipocytes in two internal fat depots, whilst the subcutaneous depot was only moderately affected (20%). In contrast, after recovery from short-term treatment with anti-rGH, the internal depots were only marginally decreased in both weight and adipocyte numbers, whereas the subcutaneous depot was actually doubled in size compared with controls, due entirely to an increase in the number of differentiated adipocytes. These data clearly demonstrate for the first time that GH is required for the differentiation of adipocytes in vivo. In addition, the results demonstrate distinct effects at different anatomical sites and suggest that GH may be one factor responsible for the differences described in numerous metabolic parameters and hormonal sensitivities of adipose tissue derived from different locations within the body.

Journal of Endocrinology (1993) 137, 203–211

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D. J. Flint
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M. J. Gardner
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ABSTRACT

Treatment of rats for 24 h on day 2, 10 or 20 of age with a specific antiserum to rGH (anti-(rGH)), GH, bromocriptine (CB-154) or prolactin failed to influence body weight gain or serum concentrations of insulin-like growth factor-I (IGF-I). On day 28 of age, however, anti-(rGH) completely inhibited body weight gain and markedly reduced circulating IGF-I concentrations, effects which were completely prevented by exogenous ovine GH (oGH). When administered to control rats on day 28 oGH caused supranormal weight gain and serum IGF-I concentrations. These results suggested that GH does not play a significant role in growth or regulation of serum IGF-I until after day 20 of age.

By contrast, when anti-(rGH) was given for 4 consecutive days beginning on day 2 of life, body weight gain was reduced within 48 h and remained so until at least 28 days of age. Tail length was also significantly reduced. The effect was due to inhibition of GH effects since serum GH concentrations were low and exogenous GH prevented the effect. Inhibition of growth during the first 14 days of life occurred in the absence of any effect on serum IGF-I although by 21 days of age serum IGF-I was considerably lower than in control rats.

The prolonged reduction in growth after treatment has stopped appeared to be due to a cytotoxic effect on the pituitary gland since pituitary weight and GH but not prolactin content were significantly decreased. The data are consistent with the hypothesis that in the neonate GH may be processed in serum so that a proportion of it is not recognized by an antiserum to pituitary GH.

It would appear that inhibition of GH secretion reduces growth rate by at least 30–40% up to 14 days of age, 50% by 21 days of age and completely by 28 days. Effects of GH on growth could not be fully explained by regulation of serum IGF-I concentrations.

Journal of Endocrinology (1989) 122, 79–86

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R. J. Madon
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D. M. Panton
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D. J. Flint
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ABSTRACT

A specific antiserum to rat GH (anti-rGH) raised in sheep was used in young male and lactating rats. In both models a group of rats was found which appeared to generate a low response (low responders) to the injected sheep immunoglobulin, and was characterized by the ability of the antiserum to cause inhibition of growth for more than 21 days in the male rats, and to abolish milk yield when prolactin concentrations were lowered in the females. In the groups which generated a high response to the anti-rGH (high responders), growth was retarded for only 2–3 days in male rats, with a moderate milk yield maintained in lactating animals.

The low-response animals were found to have a significantly longer half-life for circulating anti-rGH, when compared with the high-response animals. After 21 days, in the age-matched male rats, levels of anti-rGH were undetectable in the high-responders, whereas the low-response animals, which were nearly 160 g lighter, still had approximately 4·5 ml anti-rGH/1 in their circulation. This anti-rGH was still capable of neutralizing GH, as concentrations of insulin-like growth factor-I (IGF-I) were 13·6±3·5 (mean ± s.e.m.) and 76·9±2·0 nmol/l in the low-response and high-response groups respectively. The reason for these differences would appear to be that the immune response mounted by these low-response animals to the exogenous sheep immunoglobulin (i.e. rat anti-sheep) 7 days after treatment was less than 10% of that seen in the high-response group.

In male animals the concentration of IGF-I was positively correlated with growth rate.

It is concluded that the effectivenes of the anti-rGH was related to its clearance rate which in turn depended on the ability of the animal to mount an effective anti-sheep response.

Journal of Endocrinology (1991) 128, 229–237

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R. J. Madon
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D. M. Ensor
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D. J. Flint
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ABSTRACT

An in-vitro perifusion system was devised in order to examine the secretory profiles of isolated islets of Langerhans, derived from different physiological states, when subjected to various stimuli relevant to lactation. Islets from pregnant rats secreted more insulin than did those from virgin animals; however, islets from lactating and virgin animals secreted similar amounts of insulin with all stimuli, including glucose, amino acids, cations and neurotransmitters. When virgin rats were pretreated for 5 days in vivo with GH or prolactin, insulin responses in vitro were unchanged. Cannulation of the hepatic portal vein and inferior vena cava in vivo revealed that both insulin and glucose concentrations were lower in the portal vein of the lactating rat compared with the virgin animal. It was therefore concluded that insulin concentrations are depressed during lactation as a consequence of the pancreas receiving a diminished glycaemic stimulus rather than because of any change in β-cell sensitivity.

Journal of Endocrinology (1990) 125, 81–88

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J H Shand
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D W West
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D J Flint
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Lactating rats were treated for 48 h with bromocriptine (to inhibit prolactin release) or bromocriptine together with an antiserum to rat GH. Animals given the combined treatment were also supplemented concurrently with bovine GH (bGH) or human insulin-like growth factor-I (hIGF-I). The effects of these treatments on the activities of 3-methyl-3-glutaryl-CoA reductase (HMG-CoA reductase), acyl-CoA:cholesterol acyltransferase (ACAT) and neutral cholesteryl ester hydrolase (CEH) and on the microsomal concentrations of non-esterified and esterified cholesterol were measured.

Lack of prolactin decreased HMG-CoA reductase but did not affect ACAT, neutral CEH or the concentrations of microsomal cholesterol or cholesteryl esters. In the absence of both hormones, an even greater reduction in HMG-CoA reductase together with increases in ACAT, neutral CEH and both of the microsomal sterols were observed. Concurrent supplementation with either bGH or hIGF-I wholly or partially prevented the effects on HMG-CoA reductase but only bGH was active against the increase in ACAT. Neither bGH nor hIGF-I could prevent the effects of the anti-hormone treatment on neutral CEH, and the changes in ACAT and CEH activities were broadly reflected in the microsomal sterol concentrations.

The results indicate that the cessation of lactation brings about rapid changes in the activities of the enzymes involved in cholesterol metabolism within the mammary gland with a definite switch from synthesis to storage. Supplementation with bGH alone was sufficient to maintain cholesterol synthesis at control levels and could also significantly inhibit storage of the sterol as its ester. In the absence of GH, hIGF-I partially supported cholesterol synthesis but had no effect on its conversion to the ester. On a whole-tissue basis, enzyme activities could be correlated with the physiological effects of the anti-hormone treatments.

Journal of Endocrinology (1997) 152, 447–454

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D. J. Flint
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E. Tonner
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J. Beattie
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D. Panton
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ABSTRACT

The role of GH was examined using an antiserum to rat GH (anti-rGH). When administered to lactating rats on day 2 of lactation it was without effect, whereas bromocriptine markedly suppressed milk production, with no additional effect of combined treatment. On day 6 of lactation, treatment with anti-rGH was also without effect, whilst bromocriptine again suppressed milk production. Combined treatment, however, suppressed milk synthesis completely, suggesting that GH was capable of maintaining about 50% of normal milk yield in the absence of prolactin at day 6 of lactation. By day 14 of lactation, anti-rGH treatment alone was capable of decreasing milk yield by about 20%, and again milk secretion only stopped completely when GH and prolactin were suppressed. These data suggest that the role of GH in supporting lactation increases as lactation progresses.

The effects of GH in stimulating growth and in increasing milk yield in ruminants have been proposed to be mediated via insulin-like growth factor-I (IGF-I). In rats treated with anti-rGH, both IGF-I and IGF-II were decreased in serum. The concentration of the major IGF-binding protein (IGFBP-3) was not, however, affected by inhibition of GH or prolactin individually, but was decreased in animals treated with bromocriptine and anti-rGH. In animals given both bromocriptine and anti-rGH, concurrent treatment with recombinant bovine GH maintained milk yield at 50% of control values and normalized serum IGF-I, IGF-II and IGFBP-3 concentrations. By contrast, concurrent treatment with IGF-I or IGF-II, despite normalizing their respective concentrations in serum, failed to affect milk yield.

These results suggest that neither IGF-I nor IGF-II is capable of mediating the effects of GH alone. It is, however, possible that they play a part in a coordinated series of responses to GH involving IGF-I, IGF-II and IGFBP-3.

Journal of Endocrinology (1992) 134, 377–383

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