Somatostatin mRNA Research Articles

Effect of electroacupuncture at Ganshu and Liangqiu on expression of hippocampal and gastric somatostatin and hippocampal BDNF mRNA in rats with depression associated gastric ulcer

目的：研究电针肝俞穴、梁丘穴对抑郁型胃溃疡大鼠模型生长抑素（somatostatin,SS）及海马脑源性神经营养因子（brain derived neurotrophic factor,BDNF）的影响,探讨电针肝俞穴、梁丘穴对抑郁型胃溃疡的治疗机制.方法：所有大鼠旷场试验后选择合格大鼠60只,按照随机数字表法分为4组：空白组（n=15）、模型组（n=15）、西药组（n=15）、电针组（n=15）.除正常组外,剩下的3组建立慢性不可预见性刺激抑郁症合并醋酸烧灼胃溃疡大鼠模型.电针组采用电针肝俞穴、梁丘穴,西药组采用奥美拉唑灌胃4.2 mg/（kg？d）.肝俞穴位直刺6 mm,梁丘穴直刺4-5 mm,电针治疗仪给予疏密波型,疏波4 Hz,密波20 Hz,强度以局部皮肤肌肉轻微颤动为度,留针20 min,1次/d,连续6 d,中间休息1 d,2 wk为1个疗程,共13 d.观察大鼠一般情况变化、旷场试验结果、溃疡指数结果,运用免疫组织化学法检测下丘脑、胃窦黏膜组织中SS的表达,RT-PCR法检测海马组织中BDNF的表达.结果：造模后和治疗后模型组旷场试验水平和垂直运动均较空白组明显降低（23.28±4.13 vs 38.35±6.65,9.89±3.31 vs 19.34±2.56;27.19±3.72 vs 38.87±4.89,10.58±2.47vs 20.68±3.54;均P〈0.01）,而治疗后电针组和西药组水平和垂直运动较模型组显著增高（34.78±6.54 vs 27.19±3.72,33.24±4.54vs 27.19±3.72;17.78±2.09 vs 10.58±2.47,16.32±3.01 vs 10.58±2.47;均P〈0.01）.电针组和西药组溃疡指数比模型组有显著降低（2.14±0.75 vs 4.75±0.46;2.10±0.32 vs 4.75±0.46;均P〈0.01）.模型组胃黏膜和下丘脑中SS表达较空白组降低（0.09887±0.0073 vs0.16675±0.0046;0.09500±0.0063 vs 0.14462±0.0050;均P〈0.05）,电针组和西药组SS表达较模型组均增高（0.12562±0.0031 vs 0.09887±0.0073,0.12538±0.0043 vs 0.09887±0.0073;0.11312±0.0054 vs 0.09500±0.0063,0.11900±0.0056 v s 0.09500±0.0063;均P〈0.05）.模型组海马BDNF mRNA含量较空白组显著降低（0.2775±0

Expression of somatostatin and cDNA cloning in the thymus of the African ostrich

The thymus in addition to being a central lymphoid organ is also an endocrine organ which produces various neuropeptides that influence the function of this gland. Somatostatin is a neuropeptide that was isolated initially in the hypothalamus and which inhibits the release of growth hormone. The distribution of somatostatin-producing cells and the sequence of somatostatin have been determined in many species. In the present study, we investigated the expression of somatostatin in the thymus of the African ostrich and its sequence by reverse-transcriptase polymerase chain reaction and immunohistochemistry. The results showed that somatostatin mRNA was expressed in the thymus and somatostatin immunoreative cells were distributed in both the cortical and medullary regions of the thymus. Results of cDNA cloning revealed that the nucleotide sequence and the encoded protein of African ostrich somatostatin were 348 bases and 116 amino acids in length and that it is highly conserved to that of other reported species. These findings indicated that the somatostatin expressed in the thymus of ostrich might play an important role in the function of the gland. In addition, this research has provided novel molecular data allowing further study of somatostatin in the ostrich.

Ectopic expression of ghrelin affects gastric H+–K+-ATPase activity and expression of GHR/IGF-1 system in weaned mice

ObjectivesGhrelin has been implicated in the regulation of gastric growth and functional development, but it is yet to be determined whether and how ghrelin over-expression may modify gastric growth, gastric acid secretion and mRNA expression of other gastric endocrine hormones. 25-day-old mice were injected intramuscularly with vacant plasmid (VP) or recombinant plasmid expressing secretory ghrelin at the doses of 50μg (LG) and 100μg (HG). ResultsExpression of ghrelin mRNA was detected in muscles 15days post-injection, being most abundant in HG mice. In accordance with the ghrelin expression, gastric weight increased (P<0.05) in HG mice, compared with VP control group. Significant increase of gastric mucosa H+–K+-ATPase mRNA expression was detected in HG mice compared to VP control group (P<0.05). Compared with VP mice, gastric somatostatin (SS) mRNA expression decreased in LG and HG mice (P<0.05), while gastric gastrin expression had no significant difference. ConclusionsI.M. injection of plasmid encoding ghrelin improved gastric growth and gastric acid secretion with decreased SS mRNA in weaned mice.

Conditional deletion of menin results in antral G cell hyperplasia and hypergastrinemia

Antral gastrin is the hormone known to stimulate acid secretion and proliferation of the gastric corpus epithelium. Patients with mutations in the multiple endocrine neoplasia type 1 (MEN1) locus, which encodes the protein menin, develop pituitary hyperplasia, insulinomas, and gastrinomas in the duodenum. We previously hypothesized that loss of menin leads to derepression of the gastrin gene and hypergastrinemia. Indeed, we show that menin represses JunD induction of gastrin in vitro. Therefore, we examined whether conditional deletion of Men1 (Villin-Cre and Lgr5-EGFP-IRES-CreERT2), with subsequent loss of menin from the gastrointestinal epithelium, increases gastrin expression. We found that epithelium-specific deletion of Men1 using Villin-Cre increased plasma gastrin, antral G cell numbers, and gastrin expression in the antrum, but not the duodenum. Moreover, the mice were hypochlorhydric by 12 mo of age, and gastric somatostatin mRNA levels were reduced. However, duodenal mRNA levels of the cyclin-dependent kinase inhibitor p27(Kip1) were decreased, and cell proliferation determined by Ki67 staining was increased. About 11% of the menin-deficient mice developed antral tumors that were negative for gastrin; however, gastrinomas were not observed, even at 12 mo of age. No gastrinomas were observed with conditional deletion of Men1 in the Lgr5 stem cells 5 mo after Cre induction. In summary, epithelium-specific deletion of the Men1 locus resulted in hypergastrinemia due to antral G cell hyperplasia and a hyperproliferative epithelium, but no gastrinomas. This result suggests that additional mutations in gene targets other than the Men1 locus are required to produce gastrin-secreting tumors.

Effects of Zusanli Electroacupuncture on Somatostatin Expression in the Rat Brainstem

The aim of the present study was to investigate the effect of electroacupuncture (EA) at the Zusanli (ST36) acupoint on somatostatin mRNA expression in the rat brainstem. A total of 96 Sprague-Dawley rats were randomly assigned to a control (n = 24), restraint (n = 24), pseudopoint-EA (n = 24), or Zusanli-EA (n = 24) group. The rats received stimulation for 30min at 2, 4, 6, and 8h after stimulation. Brainstem samples (n = 6 for each group at each time point) were collected, and somatostatin expression was assessed by reverse transcription polymerase chain reaction, northern blot, and immunohistochemical staining. Somatostatin mRNA expression was inhibited at 2h after EA stimulation, but an increase was seen at 6 and 8h in the Zusanli-EA group compared to the three control groups. With respect to immunohistochemical staining, the number of somatostatin-positive cells in the brainstem was increased in the Zusanli-EA group at 6 and 8h after stimulation compared to the 2- and 4-h time point. These results indicate that Zusanli-EA increased somatostatin mRNA and protein expression in the brainstem. Somatostatin may therefore be involved in some of the analgesic effects of Zusanli-EA.

Somatostatin‐immunoreactive senile plaque‐like structures in the frontal cortex and nucleus accumbens of aged tree shrews and Japanese macaques

Previously, we demonstrated decreased expression of somatostatin mRNA in aged macaque brain, particularly in the prefrontal cortex. To investigate whether or not this age-dependent decrease in mRNA is related to morphological changes, we analyzed somatostatin cells in the cerebra of aged Japanese macaques and compared them with those in rats and tree shrews, the latter of which are closely related to primates. Brains of aged macaques, tree shrews, and rats were investigated by immunohistochemistry with special emphasis on somatostatin. We observed degenerating somatostatin-immunoreactive cells in the cortices of aged macaques and tree shrews. Somatostatin-immunoreactive senile plaque-like structures were found in areas 6 and 8 and in the nucleus accumbens of macaques, as well as in the nucleus accumbens and the cortex of aged tree shrews, where amyloid accumulations were observed. Somatostatin degenerations may be related to amyloid accumulations and may play roles in impairments of cognitive functions during aging.

Expression and cellular localization of somatostatin fromParalichthys olivaceus

Somatostatin(SS) called also somatotropin release-inhibiting factor is a peptide named for its ability to inhibit pituitary growth hormone release.To facilitate investigation of the SS function in the teleost,its coding sequence in paralichthys olivaceus was isolated by the technique of Rapid Amplification of cDNA Ends(RACE).SYBR Green I Quantitative Real-time PCR analysis and immunohistochemistry were used to assess the expression of SS at mRNA and protein level.The deduced protein sequence con-tains 126 amino acid residues and a predicted molecular mass of 14.3 kD.Very low level of SS mRNA is presented during the first three days after hatching.The expression level of the SS gene was increased con-stantly before metamorphosis and steadily during the metamorphosis,then increased significantly during post-metamorphosis.There was no SS-positive reaction in the oropharyngeal cavity and esophagus.SS secreting cells are only distributed in the stomach,pancreas and pituitary.Several types of SS secreting cells could be distinguished in above organs.In stomach,SS secreting cells are dispersively distributed among the epithelium cells,presenting various kinds of forms such as ovoid,globular,triangle,elongated or spindle-shaped aspects.The pancreas and liver of flounder combine into a single organ named hepato-pancreas,and SS-positive cells are only located in the pancreas,showing as globular-shaped,most of them are closed to blood vessels.SS-positive cells at high density are located in pars distalis of pituitary,so it is difficult to distinguish the shape of those cells.

Cysteamine improves growth performance and gastric ghrelin expression in preweaning piglets

The aim of the present study was to investigate the effect of cysteamine on growth performance of preweaning piglets and gastric expression of ghrelin mRNA in vivo and in vitro. Twelve litters of newborn piglets were allocated randomly to control and treatment groups. From 15 d of age, piglets in the control group were fed basal creep diet, whereas the treatment group received basal diet supplemented with 120 mg cysteamine per kg of diet until weaning on 35 d of age. Body weight gain, creep feed consumption, and diarrhea rates were recorded, and gastric mucosal tissues were collected for quantifying mRNA expression. To evaluate the direct effect of cysteamine on gastric ghrelin expression, primary cultures of gastric mucosal cells isolated from 35-d-old piglets were exposed to cysteamine for 20 h at 0, 1, 10, and 100 μg/mL, respectively. Dietary cysteamine increased (P < 0.05) average daily creep feed consumption and BW gain in preweaning pigs, which was accompanied by reduction in diarrhea rates. At 35 d of age, piglets treated with cysteamine showed increased (P < 0.05) ghrelin and gastrin and decreased (P < 0.05) somatostatin mRNA expression in gastric mucosa. Moreover, dietary cysteamine treatment increased serum concentration of gastrin (P < 0.05). In vitro, cysteamine significantly increased ghrelin mRNA expression in gastric mucosal cells at the concentration of 10 μg/mL. In conclusion, dietary cysteamine is effective in improving the growth performance and health condition of preweaning piglets, which is associated with its stimulatory effects on gastric ghrelin mRNA expression both in vivo and in vitro.

Regulation of gene expression and biochemical changes in small intestine of newborn diabetic rats by exogenous ghrelin

The aim of this study was to investigate (i) the cholecystokinin, somatostatin and apelin mRNA levels, (ii) the changes in levels and localization of these peptides, (iii) relation between these peptides, (iv) antiapoptotic effects and (v) antioxidant effects of ghrelin. The rats were divided into four groups second day after birth. These groups were respectively treated with physiological saline, ghrelin (100μg/kg/day), streptozotocin (100mg/kg), ghrelin and streptozotocin. After four weeks, small intestine and blood samples were taken from rats. Cholecystokinin mRNA and peptide, somatostatin mRNA, release to duodenal lumen of apelin peptide and apelin mRNA signals decreased in ghrelin-treated diabetic rats compared to the diabetic group. There was no statistically significant difference among the four groups for somatostatin and apelin peptides. Caspase-3 signals were not observed only in diabetic group treated with ghrelin. Caspase-8 signals were increased while PCNA signals were decreased in diabetic group given ghrelin compared to diabetic group. Small intestine CAT, SOD, GPx and GST activities and GSH levels were decreased and LPO, PC levels were increased in diabetic rats. Administration of ghrelin to diabetic rats caused an increase in intestinal CAT, SOD, GPx and GST activities and GSH levels, while PC levels decreased. As a result, we observed positive changes in diabetic rats treated with ghrelin in both microscopic and biochemical studies. We can suggest that ghrelin may be an important hormone for the treatment of diabetes.

The fate of cells expressing somatostatin mRNA and co-migrating with GnRH neurons from the olfactory epithelium to the forebrain

The fate of cells expressing somatostatin mRNA and co-migrating with GnRH neurons from the olfactory epithelium to the forebrain

The effect of intracerebroventricular infusions of ghrelin and/or short fasting on the gene expression and immunoreactivity of somatostatin in the hypothalamic neurons and on pituitary growth hormone in prepubertal female lambs. Morphological arguments

The effect of exogenous ghrelin on somatostatin distribution in the ruminant's hypothalamus has not been yet determined. The aim of the present study was to investigate the consequence of central infusion of ghrelin and/or short fasting on the secretory activity of the somatostatin/GH system in prepubertal female sheep. Animals were randomly divided into three groups, two standard fed and one fasted for 72 h. One standard group and one fasted group were infused icv with vehicle, while the remaining standard group was infused with ghrelin (25 μl/120 μl/h). Infusions were performed for 6 h during three consecutive days; blood samples were collected during the “day 0” (before the infusion) and “day 3” Immediately after the experiment the sheep were slaughtered. Parts of the brains were fixed in situ for further immunohistochemical analysis The remaining brains were frozen for RT-PCR analysis. Fasting and ghrelin infusion elicited the same kind of changes in the secretory activity of the somatostatin/GH system compared to standard fed sheep. The expression of somatostatin mRNA and ir somatostatin in the PEV nucleus and ir stores in the median eminence increased in both these groups compared to standard fed sheep (P < 0.001). The population of ir GH pituitary cells decreased (P < 0.001), the mean GH plasma concentrations increased in all fasted and ghrelin infused animals between day 0 and day 3 of infusions (P < 0.05) compared to the standard fed group. It can be suggested that ghrelin takes part in the mechanisms linking the nutritional status of an organism with an activity of the somatotrophic axis on the level of the CNS by stimulating GH release through suppression of the somatostatin output.

Oral arginine improves linear growth of long bones and the neuroendocrine mechanism

To investigate the effect of oral administration of arginine on linear growth of long bones in male pubertal rats and the underlying mechanisms, focusing on expression of genes related to the hypothalamus-pituitary growth axis and the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Rats were randomly divided into control and intervention groups. In the intervention group, arginine was solved in water (0.045 g L-arginine was mixed with 1 mL water) and administered in rats (10 mL/kg) through gastric perfusion once per day, for totally 28 d. Rats in the control group received normal saline treatment. Bone histomorphometry analysis was used to measure growth plate width and mineral apposition rate of the tibia, as well as trabecular bone volume fraction, osteoblast surface and osteoclast surface of the femur. Serum growth hormone (GH) concentration was determined by radioimmunoassay. Real-time PCR was used to measure the expression of neuronal nitric oxide synthase (nNOS), soluble guanylyl cyclases (sGCα1 and sGCβ1), growth hormone-releasing hormone (Ghrh) and somatostatin (SS) in hypothalamus, as well as Gh in pituitary. Western blot was used to detect the protein levels of nNOS, sGCα1 and sGCβ1 in hypothalamus. After treatment with arginine, the growth plate width of tibia and osteoblast surface of femur were increased (P < 0.05), and serum GH concentration was elevated (P < 0.05). Besides, mRNA and protein levels of nNOS and sGCα1 (P < 0.05), as well as the expression of Gh mRNA (P < 0.01), were significantly up-regulated, while the expression of SS mRNA was down-regulated (P < 0.05). Oral administration of arginine could improve linear growth of long bones by regulating mRNA expression of SS and Gh and inducing GH secretion, possibly via nNOS-NO-sGC-cGMP signal transduction pathway.

Somatostatin is involved in anorexia in mice fed a valine-deficient diet.

The ingestion of a valine (Val)-deficient diet results in a significant reduction of food intake and body weight within 24 h, and this phenomenon continues throughout the period over which such a diet is supplied. Both microarray and real-time PCR analyses revealed that the expression of somatostatin mRNA was increased in the hypothalamus in anorectic mice that received a Val-deficient diet. On the other hand, when somatostatin was administered intracerebroventricularly to intact animals that were fed a control diet, their 24-h food intake decreased significantly. In addition, Val-deficient but not pair-fed mice or those fasted for 24 h showed a less than 0.5-fold decrease in the hypothalamic mRNA expression levels of Crym, Foxg1, Itpka and two unknown EST clone genes and a more than twofold increase in those of Slc6a3, Bdh1, Ptgr2 and one unknown EST clone gene. These results suggest that hypothalamic somatostatin and genes responsive to Val deficiency may be involved in the central mechanism of anorexia induced by a Val-deficient diet.

Topography of somatostatin gene expression relative to molecular progenitor domains during ontogeny of the mouse hypothalamus

The hypothalamus comprises alar, basal, and floor plate developmental compartments. Recent molecular data support a rostrocaudal subdivision into rostral (terminal) and caudal (peduncular) halves. In this context, the distribution of neuronal populations expressing somatostatin (Sst) mRNA was analyzed in the developing mouse hypothalamus, comparing with the expression pattern of the genes Orthopedia (Otp), Distal-less 5 (Dlx5), Sonic Hedgehog (Shh), and Nk2 homeobox 1 (Nkx2.1). At embryonic day 10.5 (E10.5), Sst mRNA was first detectable in the anterobasal nucleus, a Nkx2.1-, Shh-, and Otp-positive basal domain. By E13.5, nascent Sst expression was also related to two additional Otp-positive domains within the alar plate and one in the basal plate. In the alar plate, Sst-positive cells were observed in rostral and caudal ventral subdomains of the Otp-positive paraventricular complex. An additional basal Sst-expressing cell group was found within a longitudinal Otp-positive periretromamillary band that separates the retromamillary area from tuberal areas. Apart of subsequent growth of these initial populations, at E13.5 and E15.5 some Sst-positive derivatives migrate tangentially into neighboring regions. A subset of cells produced at the anterobasal nucleus disperses ventralward into the shell of the ventromedial hypothalamic nucleus and the arcuate nucleus. Cells from the rostroventral paraventricular subdomain reach the suboptic nucleus, whereas a caudal contingent migrates radially into lateral paraventricular, perifornical, and entopeduncular nuclei. Our data provide a topologic map of molecularly defined progenitor areas originating a specific neuron type during early hypothalamic development. Identification of four main separate sources helps to understand causally its complex adult organization.

Regulation of somatostatin gene expression by brain derived neurotrophic factor in fetal rat cerebrocortical cells

Brain derived neurotrophic factor (BDNF) increases the levels of somatostatin (SS) and its mRNA. To test the hypothesis that the regulation of SS synthesis by BDNF occurs at the transcriptional level and requires specific promoter sequences, cerebrocortical and PC12trkB neurons were transiently transfected with different constructs of the SS promoter fused to the luciferase and CAT reporter genes. We demonstrated that BDNF triggered the transcription of the SS gene through the CRE sequence located in the SS promoter. BDNF and SS are genes regulated by K +-induced neuronal activity. Using BDNF blocking antibodies, we investigated whether K +-induced BDNF was required for K +-dependent SS mRNA induction. We found that K +-induced SS mRNA was partially prevented when BDNF was blocked. This finding indicated that BDNF mediated the induction of SS mRNA by K + depolarization. To identify the mechanisms by which BDNF activates SS gene transcription we first elucidated the signaling pathways activated by BDNF in cerebrocortical cells. We confirmed that BDNF activates the MAPK/ERKs and PI3K/Akt pathways. Both signaling pathways are, in turn, implicated in the activation of CREB by BDNF. In addition we observed that the PKA inhibitors, H89 and Rp-cAMPS decreased BDNF-induced CREB activation. These findings suggested that BDNF-induced CREB activation was also mediated by the cAMP/PKA pathway. We next elucidated the mechanism by which BDNF induces SS mRNA. We observed that H89, PD0998059, KN62 and LY294002 diminished BDNF-induced SS mRNA suggesting that BDNF-induced SS mRNA is mediated by the activation of cAMP/PKA, MAPK/ERKs, CaMK and PI3K pathways.

Abstract ED02-03: Gene, environment, and risk factor interaction in pancreatic cancer

Abstract ED02-03: Gene, environment, and risk factor interaction in pancreatic cancer

Peripheral Endocannabinoid System‐Mediated Actions of Rimonabant on Growth Hormone Secretion are Ghrelin‐Dependent

The somatotroph axis is a crucial pathway regulating metabolism. Despite the fact that the endocannabinoid system has been also revealed as a potent modulator of energy homeostasis, little information is available concerning a putative interaction between these two systems. The aim of the present study was to determine the in vivo effects of the blockade of the cannabinoid receptor type 1 (CB1) over growth hormone (GH) secretion using the CB1 antagonist rimonabant. The results obtained show that the blockade of the CB1 peripheral receptor by i.p. injection of rimonabant significantly inhibited pulsatile GH secretion. Similarly, it was found that this injection significantly decreased ghrelin-induced GH secretion without any effect on growth hormone-releasing hormone (GHRH)-induced GH discharge. In situ hybridisation showed that the peripheral blockade of CB1 did not affect hypothalamic somatostatin mRNA levels; however, GHRH mRNA expression was significantly decreased. The blockade of the vagus nerve signal by surgical vagotomy eliminated the inhibitory action of rimonabant on GHRH mRNA and consequently on GH. On the other hand, the central CB1 blockade by i.c.v. rimonabant treatment was unable to reproduce the effect of peripheral blockade on GHRH mRNA, nor the GH response to ghrelin. In conclusion, the data reported in the present study establish, from a physiological point of view, the existence of a novel mechanism of GH regulation implicating the action of the cannabinoid receptor on the somatotroph axis.

Differential neonatal testosterone imprinting of GH-dependent liver proteins and genes in female mice

Abnormal exposure to steroid hormones within a critical developmental period elicits permanent alterations in female reproductive physiology in rodents, but the impact on the female GH axis and the underlying sexual differences in hepatic enzymes have not been described in detail. We have investigated the effect of neonatal androgenization of female mice (achieved by s.c. injection of 100 μg testosterone propionate (TP) on the day of birth: TP females) on the GHRH-somatostatin-GH axis and downstream GH targets, which included female and male predominant liver enzymes and secreted proteins. At 4 months of age, an organizational effect of neonatal testosterone was evidenced on hypothalamic Ghrh mRNA level but not on somatostatin (stt) mRNA level. Ghrh mRNA levels were higher in males than in females, but not in TP females. Increased expression in TP females correlated with increased pituitary GH content and somatotrope population, increased serum and liver IGF-I concentration, and ultimately higher body weight. Murine urinary proteins (MUPs) that were excreted at higher levels in male urine, and whose expression requires pulsatile occupancy of liver GH receptors, were not modified in TP females and neither was liver Mup 1/2/6/8 mRNA expression. Furthermore, a male predominant liver gene (Cyp2d9) was not masculinized in TP females either, whereas two female predominant genes (Cyp2b9 and Cyp2a4) were defeminized. These data support the hypothesis that neonatal steroid exposure contributes to the remodeling of the GH axis and defeminization of hepatic steroid-metabolizing enzymes, which may compromise liver physiology.

Somatostatin Actions on Rat Supraoptic Nucleus Oxytocin and Vasopressin Neurones

Magnocellular neurones in the supraoptic nucleus (SON) receive major afferent inputs from the brainstem that have been implicated in the regulation of oxytocin and vasopressin secretion from the posterior pituitary. Notably, at parturition, some neurones that project from the nucleus tractus solitarii (NTS) in the brainstem directly to the SON are activated. Many of these are noradrenergic and regulate oxytocin secretion during parturition, whereas others contain somatostatin and their role is unclear. In the present study, we report that, at parturition, somatostatin mRNA expression in the NTS is significantly increased compared to pregnancy, suggesting an active role for these neurones at that time. Intracerebroventricular somatostatin infusion significantly increased plasma oxytocin secretion in both virgin female and pregnant rats. Intracerebroventricular somatostatin increased SON oxytocin and vasopressin neurone firing-rates, and increased Fos expression in the SON and paraventricular nucleus and in the subfornical organ. Retrodialysis of somatostatin onto the ventrally exposed SON also increased vasopressin neurone firing rate but, unexpectedly, decreased oxytocin neurone firing rate. The experiments indicate that somatostatin neurones in the NTS are activated during parturition but, because the direct effects of somatostatin on oxytocin neurones are inhibitory, this direct pathway does not appear to contribute to enhanced oxytocin release at this time, although indirect somatostatin effects may do so.

Targeted Deletion of Somatotroph Insulin-Like Growth Factor-I Signaling in a Cell-Specific Knockout Mouse Model

The role of IGF-I in the negative regulation of GH expression and release is demonstrated by in vitro and in vivo models; however, the targets and mechanisms of IGF-I remain unclear. We have developed a cell-specific knockout mouse in which the IGF-I receptor was ablated from the somatotroph in order to validate and characterize IGF-I negative regulation; we termed this the somatotroph IGF-I receptor knockout (SIGFRKO) mouse. The SIGFRKO mice demonstrated increased GH gene expression and secretion as well as increased serum IGF-I. Compensatory changes were noted with decreased GHRH and increased somatostatin mRNA expression levels. SIGFRKO mice had normal linear growth, but by 14 wk of age weighed significantly less than controls. Furthermore, metabolic studies revealed SIGFRKO mice had significantly less fat mass and body percent fat. These data support somatotroph IGF-I negative regulation and suggest that hypothalamic feedback limits the extent of GH release. The SIGFRKO mouse is a model delineating the mechanisms of IGF-I regulation in the hypothalamic-pituitary axis and demonstrates compensatory mechanisms that mediate growth and metabolic function in mammals.