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G Tulipano, A V Vergoni, D Soldi, E E Muller and D Cocchi

Leptin produced by adipocytes controls body weight by restraining food intake and enhancing energy expenditure at the hypothalamic level. The diet-induced increase in fat mass is associated with the presence of elevated circulating leptin levels, suggesting the development of resistance to its anorectic effect. Rats, like humans, show different susceptibility to diet-induced obesity. The aim of the present study was to compare the degree of leptin resistance in obesity-prone (OP) vs obesity-resistant (OR) rats on a moderate high-fat (HF) diet and to establish if the effects of leptin on hypothalamo–pituitary endocrine functions were preserved. Starting from 6 weeks after birth, male Sprague–Dawley rats were fed on either a commercial HF diet (fat content: 20% of total calorie intake) or a standard pellet chow (CONT diet, fat content: 3%). After 12 weeks of diet, rats fed on HF diet were significantly heavier than rats fed on CONT diet. Animals fed on HF diet were ranked according to body weight; the two tails of the distribution were called OP and OR rats respectively. A polyethylene cannula was implanted into the right ventricle of rats 1 week before central leptin administration. After 12 weeks of HF feeding, both OR and OP rats were resistant to central leptin administration (10 μg, i.c.v.) (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 62 [50; 78]; OR, 93 [66; 118]; OP, 90 [70; 120] as medians and 95% confidence intervals (CIs) of six rats for each group). Conversely, after 32 weeks of diet both OR and OP rats were partially responsive to 10 μg leptin i.c.v. as compared with CONT rats (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 60 [50; 67]; OR, 65 [50; 80]; OP, 80 [60; 98] as medians and 95% CIs of six rats for each group); the decrease of food intake following 200 μg leptin i.p. administration was similar in all the three groups (calorie intake as a percent of vehicle-treated rats: 86 [80; 92] as median and 95% CI). The long-term intake of HF diet caused hyperleptinemia, hyperinsulinemia and higher plasma glucose levels in OP rats as compared with CONT rats. Plasma thyroxine (T4) was lower in all the rats fed the HF diet as compared with CONT. i.c.v. administration of leptin after 32 weeks of diet restored normal insulin levels in OP rats. Moreover, leptin increased plasma T4 concentration and strongly enhanced GH mRNA expression in the pituitary of OP as well as OR rats (180±10% vs vehicle-treated rats). In conclusion, long-term intake of HF diet induced a partial central resistance to the anorectic effect of leptin in both lean and fat animals; the neuroendocrine effects of leptin on T4 and GH were preserved.

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D Cocchi, V De Gennaro Colonna, M Bagnasco, D Bonacci and EE Muller

Leptin is a hormonal product of adipose tissue whose expression reflects the body state of nutritional reserves. Previous experiments have demonstrated that leptin is one of the metabolic signals capable of regulating GH secretion. The aim of the present study was to evaluate whether CNS-mediated mechanisms underlie the GH-releasing activity of leptin. Freely moving mature male rats were injected i.c.v with leptin or isovolumetric amounts of diluent once daily for 3 days and were killed 2 h after the last administration. Central injection of leptin increased pituitary GH mRNA levels by 53. 2% and hypothalamic GHRH mRNA by 61.8%, and reduced somatostatin mRNA levels by 41.5%. To evaluate the direct effect of leptin on the pituitary, it was added alone or in combination with GHRH to primary cultures of anterior pituitary cells. Addition of leptin (10(-11)-10(-7) M) did not alter basal GH release nor the GH-releasing activity of GHRH. These results demonstrate that leptin is a metabolic signal that regulates GH secretion in the rat by acting on hypothalamic GH-regulatory hormones.

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Injections of insulin (0·2 or 0·01 i.u./20 μl) into the lateral ventricle of the rat brain, while not changing blood glucose levels or altering the pituitary content of growth hormone (GH), blocked the release of GH from the pituitary and the decrease of growth-hormone releasing activity (GHRF) of stalk median eminence (SME) extracts in the presence of the hypoglycaemic effect on insulin (2 i.u./kg) given intraperitoneally. Intraventricular administration of insulin also impaired the GH release elicited by cold exposure (4 °C, 1 h) but not the release induced by electric shock. The possibility that insulin injected into the brain acts on glucose-sensitive GH-regulating structures is suggested.

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M. Parenti, D. Cocchi, G. Ceresoli, C. Marcozzi and E. E. Müller


The mechanisms underlying the age-related decrease and increase in somatotroph responsiveness to growth hormone-releasing factor (GHRF) and somatostatin respectively were studied in rat pituitary membranes in vitro.

Basal adenylate cyclase (AC) activity was similar in pituitary membranes from rats of 8 days (either sex) and male rats of 3 months, but it was almost threefold higher in membranes from male rats of 21–23 months. GHRF induced a lower percentage stimulation of AC activity in membranes from infant and old than adult rats. Somatostatin inhibited stimulation of AC induced by forskolin more effectively in membranes from adult than infant and old rats. In parallel experiments, since the tissue we used is formed by a mixed population of pituitary cells, we evaluated, for comparison, the effect on AC of neurohormones, i.e. vasoactive intestinal polypeptide (VIP) and dopamine which act primarily on lactotrophs. VIP induced a lower fold-stimulation of AC activity in membranes from infant and old than adult rats. Dopamine inhibited forskolin-induced stimulation of AC in the following rank order of magnitude: old, adult and infant rats, and was also more effective in inhibiting basal AC activity in old than in adult rats. The stimulatory and inhibitory G proteins (Gs and Gi) coupled to AC were measured indirectly by evaluating stimulatory and inhibitory effects of different concentrations of GTP on AC. GTP, at stimulatory concentrations, increased AC activity in membranes from infant and adult rats similarly whereas its effect was significantly greater in membranes from old rats. Conversely, GTP, at inhibitory concentrations, decreased AC activity similarly in membranes from adult and infant rats, whereas in old rats inhibition was apparent at more than a tenfold lower concentration of GTP.

These data suggest (1) that the greater somatotroph sensitivity to GHRF in terms of GH secretion of the early postnatal period is not due to supersensitive GHRF receptors but rather may be accounted for, at least partially, by the low function of somatostatinergic receptors; (2) that the inability of GHRF to stimulate GH release in aged rats probably results from an uncoupling between the GHRF receptor and the G protein; and (3) that in aged rats the decreased ability of somatostatin to inhibit AC activity, in spite of the high Gi activity, results from a reduced number of somatotroph cells and, hence, receptors.

Journal of Endocrinology (1991) 131, 251–257

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V De Gennaro-Colonna, G Rossoni, D Cocchi, AE Rigamonti, F Berti and EE Muller

Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with hexarelin (80 microgram/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 microgram, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in ! lean but not in obese rats (pretreated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexare! lin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.

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F. Petraglia, V. Locatelli, F. Facchinetti, M. Bergamaschi, A. R. Genazzani and D. Cocchi


Endogenous opioid peptides have a tonic inhibitory control on LH secretion, participating in the functional changes of the hypothalamic-pituitary-ovarian axis. To evaluate the activity of the endogenous opioid systems during the oestrous cycle, we measured plasma LH levels after naloxone administration (5 mg/kg, s.c.) at 09.00 and 16.00 h on all days of the cycle (two further measurements were taken at 14.00 and 18.00 h on the day of pro-oestrus) and after one dose or one week's treatment with oestradiol benzoate (OB; 0·2 μg/rat). Concentrations of LH were measured in the same experimental models after injection of LH-releasing hormone (LHRH; 1 μg/kg, i.p.) or saline. Naloxone induced a significant rise in LH levels on the day of oestrus, dioestrus day-1 and dioestrus day-2; this response was blunted on the morning of pro-oestrus and absent in the afternoon and after acute and chronic OB treatment. Conversely LHRH was most effective in increasing LH levels on the day of pro-oestrus and in OB-treated rats.

These results indicate that opioid mechanisms, independently of the time of day and the pituitary responsiveness, exhibit a reduced activity when preovulatory changes occur, probably as a result of increased oestrogen levels.

J. Endocr. (1986) 108, 89–94

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F. Petraglia, V. Locatelli, A. Pen̄alva, D. Cocchi, A. R. Genazzani and E. E. Müller


The effect of acute administration of the opioid receptor antagonist naloxone hydrochloride (5 mg/kg, s.c.) on plasma LH levels was evaluated in female and male rats 24, 36 and 48 h and 1,3 and 5 weeks after gonadectomy and in 5-week gonadectomized rats after acute or chronic (2 weeks) administration of oestradiol benzoate (OB, 10 μg/rat per day, s.c.), testosterone propionate (TP, 150 μg/rat, s.c.) or dihydrotestosterone propionate (DHT, 150 μg/rat, s.c.) respectively. Concurrent evaluation of plasma LH after administration of LH releasing hormone (LHRH, 1 μg/kg, i.p.) was performed in the same experimental groups.

In rats of both sexes, a significant rise in plasma LH after naloxone was observed in sham-operated and recently gonadectomized rats (24–48 h); in female rats 36 and 48 h after gonadectomy the rise was higher than in controls. One, 3 and 5 weeks after gonadectomy, naloxone failed to stimulate LH release in both female and male rats. In gonadectomized rats undergoing steroid replacement therapy, OB administered 72 h before testing, TP (16 and 72 h) and DHT (16 h) were the most effective in reinstituting the LH response to naloxone. Chronic administration of gonadal steroids did not restore normal LH responsiveness to naloxone. In most experimental groups, LH responses after naloxone were clearly unrelated to pituitary LH responsiveness to LHRH, which indicates that the opioid antagonist was acting via the central nervous system. In conclusion, these results demonstrate that: (1) gonadal steroids are critically important for the inhibitory effect of endogenous opioids on LH secretion to be manifested; (2) inhibition by the opiatergic system on LH secretion is more dependent on a modulatory action of gonadal steroids than on their simple presence or absence.

J. Endocr. (1984) 101, 33–39

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L Cattaneo, V De Gennaro Colonna, M Zoli, E E Müller and D Cocchi


Obesity is coupled to several disturbances of the endocrine axes. It has previously been shown that genetically obese Zucker male rats have an impaired secretion of growth hormone (GH), probably originating from a primary reduction of hypothalamic GH-releasing hormone (GHRH) function and resulting in a decrease of GH gene expression and release. We sought to evaluate the somatotropic function in another model of experimental obesity. Normal male Sprague-Dawley rats were fed an energy-rich highly palatable diet for 7 months until they reached body weights overlapping those reported for obese Zucker rats. They were then evaluated for different indices of the hypothalamo–pituitary–somatomedin-C (IGF-I) axis. At the end of the overfeeding period, rats were divided into overtly obese (obese group) and overweight (overweight group) rats according to the degree of overweight and the Obesity Lee Index, while rats fed ad libitum with the standard pellet chow served as controls. Acute administration of a supramaximal dose of GHRH (2 μg/rat i.v.) elicited a significantly (at least P<0·05) lower plasma GH rise in the overweight and obese groups compared with the controls although no difference was seen in the pituitary GH content and gene expression and plasma concentrations of free IGF-I in the two experimental groups vs the controls. In addition, evaluation of hypothalamic GHRH and somatostatin mRNAs (slot-blot hybridization) did not show any significant differences between the three groups. Of the different metabolic indices investigated, plasma glucose and insulin concentrations were significantly (P<0·01) higher in the obese than in the overweight and control groups. A sharp decrease in plasma testosterone levels, together with a reduction in testis weight, was seen in both groups of rats fed the palatable diet compared with the controls. These findings underline the 'peripheral' feature of the hyposomatotropinism of rats chronically fed an energy-rich diet, and may account for the reversibility of the GH impairment in many obese subjects once a normal body weight has been restored. Moreover, the peripherally-driven hyposomatotropinism of these rats is in sharp contrast with the hypothalamic-driven GH secretory impairment of the obese Zucker rats.

Journal of Endocrinology (1996) 148, 347–353

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V. Locatelli, J. A. Apud, G. A. Gudelsky, D. Cocchi, C. Masotto, F. Casanueva, G. Racagni and E. E. Müller


The effect of intracerebroventricularly (i.v.t.)-injected rat prolactin (2 μg/rat) on the function of tuberoinfundibular γ-aminobutyric acid (GABA)ergic neurones was assessed in adult male rats by measuring the activity of glutamic acid decarboxylase (GAD) in the mediobasal hypothalamus (MBH) and the concentrations of GABA in hypophysial portal plasma and in the anterior pituitary gland. Fourteen hours after i.v.t. injection of rat prolactin the activity of GAD in the MBH was significantly (P <0·05) increased and it remained elevated for at least 16 h after injection.

The mean concentrations of GABA in hypophysial portal plasma and in the anterior pituitary were twice those found in vehicle-treated controls 16 h after administration of rat prolactin; no significant effects were observed at earlier time-periods. A significant (P <0·01) and long-lasting decrease in endogenous plasma prolactin concentrations was detected 2 h after the i.v.t. injection of rat prolactin and the concentrations remained suppressed for up to 16 h. The present results are consistent with the concept that the activity of tuberoinfundibular GABAergic neurones is regulated, at least in part, by circulating prolactin. The ability of prolactin to accelerate the synthesis and release of GABA in the MBH might constitute a short loop feedback system by which the hormone regulates its own secretion.

J. Endocr. (1985) 106, 323–328