Lorena Cattaneo

Hypothalamic Neuropeptide Y and Galanin in Overweight Rats Fed a Cafeteria Diet

We evaluated neuropeptide Y (NPY) and galanin (GAL) immunoreactivity (IR) and mRNA in the paraventricular and arcuate nucleus, respectively, in rats that became overweight (Ov) or not (NOv) when fed a cafeteria diet. After 2 months of diet, NOv rats showed a significant increase in NPY IR, whereas Ov rats showed a significant increase in GAL mRNA levels. None of these changes was present in rats overfed for 6.5 months. These differential changes in hypothalamic GAL and NPY transmissions may contribute to the different susceptibility of the two rat subpopulations to the weight-promoting effects of the hypercaloric diet.

Somatostatin Withdrawal as Generator of Pulsatile GH Release in the Dog: A Possible Tool to Evaluate the Endogenous GHRH Tone?

Reportedly, somatostatin (SS) withdrawal is an effective generator of pulsatile GH release in mammals and it has been proposed that the amplitude of the GH bursts is related to the functional activity of GHRH-producing neurons. Our study was designed to test this hypothesis in the unanesthetized dog, under different conditions of endogenous GHRH function. First, we evaluated the ability of withdrawal of SS infusion to induce a GH secretory burst under basal conditions when GHRH function is thought to be enhanced, i.e. in young (2- to 3-year-old) dogs under sustained (30 days) caloric restriction (CR) or a 2-day fast. Secondly, we performed experiments in aged (11- to 17-year-old) dogs, in which hypothalamic GHRH secretion is thought to be reduced. Old dogs were evaluated under basal conditions, after a 2-day fast and after a 10-day administration of GHRH alone or followed by fasting. Both before and 14 h after the end of each experimental period, young and old dogs underwent a 3-hour (from 10.00 to 13.00 h) intravenous SS infusion (4 micrograms.kg-1.h-1). The secretory profile of GH was generated by 15-min sampling from 09.00 to 15.00 h. Under baseline conditions, SS withdrawal induced a significant burst of GH in young but not in old dogs. After CR, termination of SS infusion was followed in young dogs by a robust GH burst, significantly higher than that observed when dogs were fed ad libitum. In this instance, reduction of plasma IGF-I concentrations was unlikely to be responsible for the higher GH burst; the same pattern was present in the young dogs after a 2-day fast, when circulating IGF-I was unaltered. In old dogs, SS withdrawal did not modify baseline GH levels even after fasting, but induced a significant GH increase after GHRH priming. When GHRH priming was followed by fasting, SS withdrawal resulted in a GH burst higher than that occurring after fasting or GHRH alone. Altogether, these data support the view that the rebound rise in GH induced by withdrawal of SS is related to the endogenous GHRH tone. It is suggested that extrapolation of these findings to humans might permit probing, albeit inferentially, the endogenous GHRH tone under different physiologic or pathologic conditions.

Worsening of ischemic damage in hearts from rats with selective growth hormone deficiency.

The effects of growth hormone (GH) deficiency on cardiac function were studied in young male rats administered an anti-GH-releasing hormone (GHRH) serum from postnatal day 20 to 40. Dependence of heart abnormalities on GH deficiency was ascertained by giving a group of anti-GHRH serum-treated rats GH replacement therapy. Heart preparations from anti-GHRH serum-treated rats, undergoing low-flow ischemia, showed a progressive increase in left ventricular end-diastolic pressure with poor recovery of mechanical activity and increased coronary perfusion pressure upon reperfusion. Hearts from anti-GHRH serum + GH-treated rats, undergoing global reduction to the flow, showed only a minimal increase of left ventricular end-diastolic pressure and, upon reperfusion, cardiac mechanical activity recovered almost completely. Similar findings were also observed in heart preparations from control (normal rabbit serum-treated) rats. Infusion of acetylcholine (10(-6) M) into heart preparations in the preischemic period increased coronary perfusion pressure values more markedly in hearts from normal rabbit serum- and anti-GHRH serum + GH-treated rats than in those from anti-GHRH serum-treated rats. These results indicate that selective GH deficiency in young male rats renders the heart more sensitive to ischemic damage and leads to an impairment of cardiac muscarinic receptor function.

Hypothalamo-pituitary-IGF-1 axis in female rats made obese by overfeeding.

A gender-related impairment of the somatotrophic axis is present in obese Zucker rats, female rats being better preserved than males. We showed that another animal model of obesity, i.e., male rats made obese by feeding a hypercaloric diet had a reduced function of somatotrophic axis which was likely related to impairment of gonadal function. Aim of this work was that of studying the function of somatotrophic axis in female overfed rats and comparing it to that of male rats of the previous study. Sprague-Dawley female rats were fed an energy-rich palatable diet for seven months. At the end of overfeeding, according to the degree of overweight, rats were divided into overtly obese (Obese), overweight (Overweight) and Non-Obese, i.e. rats whose weights were similar to those of controls. Rats fed ad libitum with the standard pellet chow served as controls (Controls). Acute administration of a supramaximal dose of GHRH (2 microg/rat, iv) elicited a plasma GH rise similar to that of Controls in all the groups, except in Obese which had a lower GH response. Growth hormone responses after GHRH administration were inversely related to plasma levels of free fatty acids (FFA). Pituitary GH content and gene expression as well as hypothalamic GHRH and SS mRNA content, were similar in all experimental groups and in Controls and the same was true for plasma concentrations of free IGF-I. These results indicate that, similarly to obese female Zucker rats, also overfed female rats had a better preservation of the somatotrophic axis than their male counterparts. In diet-induced obese rats, also the etiology of the impairment of somatotrophic axis seems to be gender-related i.e. due to a reduction of gonadal function in males and to an elevation of FFA in females.

Growth Hormone Secretion Is Differently Affected in Genetically Obese Male and Female Rats

Growth hormone (GH) secretion is markedly blunted in obesity. Reportedly, genetically obese Zucker rats show a reduced GH secretion due to an impaired function of hypothalamic neurons producing the GH-releasing hormone (GHRH). The aim of this work was: (1) to compare the in vitro GH responsiveness to GHRH in genetically obese female versus male Zucker rats and, (2) to evaluate the function of hypothalamic GHRH and somatostatin and of pituitary receptors for these neurohormones as assessed by the effectiveness of GHRH and somatostatin on adenylate cyclase (AC) activity. Baseline GH secretion of pituitaries obtained from male and female obese rats was not different and similar to that present in lean counterparts. Stimulation with 10(-7) M GHRH elicited a significantly lower GH secretion from the pituitaries of obese male rats but induced a similar GH secretion from the pituitaries of lean and obese female rats. In these pituitaries, GH concentration was similar in obese versus lean male and female rats [corrected]. A sex-related difference was also evidenced when plasma concentrations of somatomedin C (IGF-I) were evaluated. Obese male rats had lower IGF-I concentrations than lean counterparts, while this was not the case for obese versus lean female rats. Evaluation of AC activity following GHRH disclosed a lower activation in obese than in lean male rats, whereas in the females the enzyme activation was higher in obese than in lean animals. Conversely, the inhibitory effect of somatostatin on forskolin-stimulated AC was similar in pituitary membranes of obese and lean rats of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo Microdialysis of the Hypothalamus: a Suitable Method to Study the Function of Hypophysiotropic Neurons in the Rat

Brain microdialysis is a method commonly exploited by neuropharmacologists to study the mechanism of action and preclinical features of centrally acting drugs. It allows measurement of chemical messengers released into the extracellular space, providing a first approximation of neuronal function in selected areas.

Effect of acute and short-term administration of cholinomimetic drugs on corticosterone secretion in the rat

Centrally acting cholinomimetic drugs have been proposed for the therapy of cognitive disorders in aged subjects. Among the possible adverse side effects of this class of compounds, of great relevance is the stimulatory action on the adrenocortical axis, in view of the toxicity of glucocorticoids for hippocampal neurons and the immune system. The aim of the present study was to evaluate in conscious male rats the effect of acute and short-term administration of three novel cholinomimetic drugs on the release of corticosterone. The potent agonist of muscarinic receptors RU 35963 strikingly increased corticosterone levels after acute but not after short-term (6 days) administration. Similar results were obtained after administration of the reversible inhibitor of cholinesterase, eptastigmine. In contrast to RU 35963 and eptastigmine, acute administration of a choline precursor, L-alpha-glycerylphosphorylcholine, only slightly affected plasma corticosterone concentrations after both acute and short-term administration. It is concluded that activation of adrenocortical function by cholinomimetic drugs is a short-lasting event which does not represent an important side effect of these compounds when given on a long-term basis.