Effect of a somatostatin infusion on circulating levels of adipokines in obese women.

OBJECTIVE: Changes in circulating levels of many adipocyte-derived peptides, including adipokines such as adiponectin, leptin and tumor necrosis factor alpha (TNF-α), have been reported in obesity (OB). Somatostatin (SRIF) inhibits circulating levels of adiponectin and leptin in lean (LN) subjects, but the effect of a SRIF infusion on these adipokines, including TNF-α, in OB is to date unknown. METHODS: Ten young women (5 OB and 5 LN) were studied. All subjects underwent an infusion of SRIF (9 µg/kg/h i.v., over 60 min), with blood samples drawn prior to and at different time intervals after SRIF administration. Plasma levels of adiponectin, leptin and TNF-α were measured at each interval. RESULTS: Basal levels of leptin and TNF-α were significantly higher in OB than LN women, whereas levels of adiponectin were significantly lower in OB than LN subjects. SRIF significantly inhibited plasma concentrations of adiponectin (at 60 min) in both OB and LN women, without affecting those of leptin and TNF-α in either group. In LN subjects, the inhibitory effect of SRIF on plasma adiponectin persisted up to 150 min, whereas SRIF infusion withdrawal in OB women resulted in a prompt restoration of basal levels of the adipokine. CONCLUSIONS: Plasma concentrations of leptin and TNF-α, which are higher in OB than LN subjects, are unaffected by a SRIF infusion, which, in contrast, inhibits circulating levels of adiponectin in both groups, with a delayed return to the baseline secretion of the adipokine in LN subjects.

Effect of somatostatin infusion on peptide YY secretion: studies in the acute and recovery phase of anorexia nervosa and in obesity.

OBJECTIVE: Changes in many gastrointestinal peptides, including the anorexigenic peptide YY (PYY), which is produced by L cells, occur in both anorexia nervosa (AN) and obesity (OB). High PYY levels are present in AN, whereas in morbid OB fasting and postprandial PYY secretion is blunted. Somatostatin (somatotropin release-inhibiting factor (SRIF)) reportedly inhibits plasma PYY concentrations in animals and healthy humans, but the effect of a SRIF infusion on spontaneous PYY secretion in AN and OB is unknown. METHODS: A total of 18 young women, seven with acute AN (A-AN), four with AN in the recovery phase (R-AN), and seven with morbid OB, were studied. All subjects underwent an infusion of SRIF (9 µg/kg i.v./h, over 60 min), with blood samples drawn before and at different time intervals after SRIF administration. Plasma PYY levels were measured at each time point. RESULTS: SRIF significantly inhibited plasma PYY concentrations in R-AN and OB, without affecting PYY titers in A-AN. In OB, the inhibitory effect of SRIF also persisted at 90 min. Withdrawal of SRIF infusion in R-AN resulted in a prompt restoration of basal plasma PYY levels, whereas termination of SRIF infusion in OB was followed by a slower increase of PYY titers toward baseline levels. After infusion, PYY Δ area under the curve (ΔAUC) in R-AN was significantly higher than those in A-AN and OB patients. A significant difference in PYY ΔAUC between A-AN and OB was present. CONCLUSIONS: These results suggest the existence of a hypo- and hyper-sensitivity of L cells to the inhibitory effect of SRIF in A-AN and OB respectively.

Testosterone inhibition of growth hormone release stimulated by a growth hormone secretagogue: studies in the rat and dog.

Anabolic steroids are frequently taken by athletes and bodybuilders together with recombinant human GH (rhGH), though there is some scientific evidence that the use of anabolic steroids reverses the rhGH-induced effects. Recently, we have shown that treatment with rhGH (0.2 IU/kg s.c., daily x 12 days) in the dog markedly reduced the canine GH (cGH) responses stimulated by EP51216, a GH secretagogue (GHS), evaluated after 3 and 5 daily rhGH injections, and that the inhibition was still present a few days after rhGH discontinuation. The aim of the present study was to evaluate in the dog the GH response to EP51216 (125 mug/kg i.v.) in a condition of enhanced androgenic function (i.e. acute injection or 15-day treatment with testosterone at the dose of 2 mg/kg i.m. on alternate days), and in the hypophysectomized rat the hypothalamic and hippocampal expression of ghrelin, the receptor of GHSs (GHS-R), GH-releasing hormone (GHRH) and somatostatin (SS) after specific hormonal replacement therapies (testosterone, 1 mg/kg/day s.c.; hydrocortisone, 500 mug/kg/day s.c.; rhGH, 400 mug/kg/day s.c.; 0.9% saline 0.1 ml/kg/day s.c.; x11 days). In the dog experiments, under baseline conditions, a single injection of EP51216 elicited an abrupt rise of plasma cGH. Twenty-four hours from the acute bolus injection of testosterone, C(max) and AUC(0-90) of the GHS-stimulated cGH response were significantly lower than baseline cGH response; 5 days later, there was still a significant decrease of either parameter versus the original values. Short-term treatment with testosterone markedly reduced the GHS-stimulated cGH responses evaluated during (5th bolus) and at the end (8th bolus) of testosterone treatment. Four and 8 days after testosterone withdrawal, the EP51216-stimulated cGH response was still significantly reduced when compared with that under baseline conditions. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were stable until the 5th bolus of testosterone and decreased progressively in the remaining time of the testosterone treatment; 4 and 8 days from treatment withdrawal, IGF-1 levels were still suppressed. In rat studies, hypothalamic mRNA levels of GHS-R were significantly reduced by treatments with testosterone and hydrocortisone, whereas hippocampal expressions of ghrelin, GHRH and SS were reduced by rhGH replacement therapy. In conclusion, these studies show that a single administration of testosterone can abrogate the cGH response ensuing acute stimulation by a GHS; the inhibitory effect of testosterone on the cGH response to GHS is present during and even 8 days after termination of a short-lived treatment with testosterone; these events occur via a

Early tolerance to the hypophagic effect of the cannabinoid receptor antagonist SR141716 does not impede blockade of an orexigenic stimulus.

The cannabinoid CB1 receptor antagonist SR141716 (Rimonabant) is known to reduce food intake by central and peripheral mechanisms. Recently, SR141716 has been reported to block the orexigenic effect of ghrelin, a potent orexigenic peptide produced by the stomach. This study investigated whether in rats, made tolerant to the hypophagic effect of SR141716, the drug was still capable to block the orexigenic activity of another non-natural (hypothalamic) peptide, i.e., the growth hormone releasing peptide (GHRP) hexarelin, a ghrelin mimetic. In the acute experiments, each dose of SR141716 (1, 5 and 10 mg/kg i.p.) reduced food intake with respect to vehicle-treated rats, whereas hexarelin (160 microg/kg s.c.) markedly stimulated feeding. All doses of SR141716 were capable to reduce the orexigenic effect of the GHRP. A 15-day administration of SR141716 (10 mg/kg i.p.) reduced both food intake and body weight. Tolerance to the hypophagic effect of SR141716 developed within 5 days, but in contrast, body weight remained markedly below that of vehicle-treated group throughout the entire treatment period. Interestingly, despite development of tolerance to its hypophagic effect, SR141716 was capable to suppress the orexigenic effect of repeated hexarelin challenge tests performed throughout the chronic experiments. In conclusion, the results of the present study confirm and broaden the existence of a functional relationship between ghrelin and endocannabinoids in the control of food intake, and bespeak the ability of a CB1 receptor antagonist to suppress orexia caused by stimuli alien to direct stimulation of the cannabinoid system.

Orexigenic effects of a growth hormone secretagogue and nitric oxide in aged rats and dogs: correlation with the hypothalamic expression of some neuropeptidergic/receptorial effectors mediating food intake.

Hypothalamic neurochemical alterations in mammals underlie disturbances of food intake. There is scarce information on these topics in elderly persons; therefore, the aims of the present study were: (i) to evaluate the orexigenic effects of a growth hormone secretagogue, administered to young and old rats and dogs, alone or in combination with molsidomine, a donor of nitric oxide and (ii) to evaluate by reverse transcription-polymerase chain reaction in the whole hypothalamus of young and old rats messenger RNA levels of a wide number of anabolic and catabolic peptides, receptors, and enzymes involved in the control of feeding behavior, relating the detected titers, whenever possible, to the feeding responses to growth hormone secretagogue. In all, the results obtained strengthen the proposition that, in the hypothalamus of old rats, anti-anorexigenic compensatory mechanisms are operative, aimed at maintaining a "normal" feeding pattern. Thus, the occurrence of a primary, age-related alteration in the feeding mechanisms is unlikely.

Molsidomine antagonizes L-NAME-induced acquisition deficits in a recognition memory task in the rat.

The present study was designed to investigate the role of nitric oxide (NO) on the acquisition of a recognition memory task in the rat. For this purpose, the effects on memory exerted by pre-training administration of the NO synthase inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester) and the NO donor molsidomine (N-[ethoxycarbonyl]-3-[4-morpholinosydnomine]) were assessed by using the object recognition task, a working memory paradigm based on the differential exploration of a new and familiar object. In a first dose-response study, it was found that L-NAME (10, 30, and 60 mg kg(-1), i.p.) at 30 but not at 10 mg kg(-1) disrupted animals performance, whereas the dose of 60 mg kg(-1) induced side effects. Molsidomine (2 and 4 mg kg(-1), i.p.) at 4 but not at 2 mg kg(-1), antagonized the L-NAME-induced performance deficits. These results indicate that NO is involved in the acquisition of a recognition memory task.