Hormone Infusion Research Articles

(1-34) Parathyroid Hormone Infusion Acutely Lowers Fibroblast Growth Factor 23 Concentrations in Adult Volunteers

Fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism. Parathyroid hormone (PTH) infusion for 24 hours stimulated FGF23 secretion in healthy volunteers. The extent to which this was due to a direct stimulatory effect of PTH versus an indirect effect of increasing 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels was unclear. Changes in FGF23 in 26 adults undergoing 6-hour (1-34) PTH infusion were examined, focusing particularly on the effects of PTH on FGF23 in the early period of infusion before sustained increases in 1,25(OH)(2)D. FGF23 levels declined in parallel with serum phosphate during infusion (P<0.05 for both), with both analytes decreasing within the first hour and reaching their respective nadirs at 6 hours. These changes were observed despite no change in 1,25(OH)(2)D levels during the first hour and a significant increase in 1,25(OH)(2)D from baseline after 6 hours (P<0.001). There were no differences in these responses by race. However, modest racial differences in the phosphaturic response to (1-34) PTH were observed (P=0.04 for interaction), with a higher rate of increase in fractional phosphate excretion in blacks than in whites. During short-term (1-34) PTH infusion, FGF23 levels decreased in parallel with serum phosphate levels and despite significant increases in 1,25(OH)(2)D. When coupled with the results of prior longer-term infusion studies, these findings suggest that acute increases in PTH initially act to suppress FGF23 secretion, perhaps to mitigate urinary phosphate losses, before the stimulatory effect of 1,25(OH)(2)D on FGF23 eventually begins to predominate.

Inhibition of maternal behaviour by central infusion of corticotrophin-releasing hormone in marmoset monkeys.

Stress can inhibit maternal behaviour and increase rates of child abuse in humans and other animals; however, the neuroendocrine mechanisms are not known. To determine whether corticotrophin-releasing hormone (CRH) plays a role in stress-induced disruption of maternal behaviour in primates, we characterised the effects of acute i.c.v. infusions of CRH on maternal and abusive behaviour in common marmoset monkeys (Callithrix jacchus). Nulliparous females were implanted with indwelling i.c.v. guide cannulae before conception. Between 18 and 58 days after the birth of her first infants, each female underwent a series of i.c.v. infusions of human CRH (0, 2, 8 and 25 μg) in 8 μl of artificial cerebrospinal fluid. In the 70 min after infusion, marmosets were tested with one of their infants, first in their home cage and, subsequently, in an unfamiliar cage in which the infant was confined in a transparent box on the cage floor. In the home cage, the highest dose of CRH significantly reduced the amount of time that mothers spent carrying their infants, as compared to vehicle alone, although it did not reliably affect aggression toward the infant or other behaviours. In the confined-infant test, the highest dose of CRH significantly reduced the amount of time that mothers spent on the cage floor, increased mothers' vocalisation rates, and tended to reduce their activity levels and time spent in proximity to their infant. Twenty-five micrograms of CRH also elicited significant elevations in plasma adrenocorticotrophic hormone and cortisol concentrations compared to vehicle. These results indicate that i.c.v.-administered CRH reduces maternal behaviour in marmoset mothers, in both familiar and unfamiliar environments, but does not increase infant abuse.

Hypogonadotrophic Hypogonadism and Diminished Gonadal Reserve Accounts for Dysfunctional Gametogenesis in Thalassaemia Patients with Iron Overload Presenting with Infertility

Improved care of β-thalassemia major (β-TM) patients has brought with it new challenges for the patient to have a family. We report our 15-year experience with 30 couples with 28 pregnancies following artificial reproductive techniques (ART). Sixty percent of females had hypogonadotrophic hypogonadism (HH) with diminished ovarian reserve and responded favorably to gonadotrophins with 80% success rate within three cycles. Pulsatile gonadotrophin-releasing hormone (GnRH) infusion was used in one and clomiphene in another patient which resulted in successful pregnancies. Males responded less favorably than females. Gonadotrophins were used in 14 pulsatile HH patients for 6-24 months with variable outcomes. Although successful paternity did not occur, successful spermatogenesis with oligoasthenospermia occurred in six men. Two had in vitro fertilization (IVF) and intracytoplasmic injections (ICSI), which resulted in healthy offspring. In conclusion, successful pregnancy and fertility are feasible in β-TM patients with diminished gonadal reserves. Better outcome is expected in females than males. We report the first two cases of paternity following IVF and ICSI in β-TM patients with HH.

What if Gut Hormones Aren't Really Hormones: DPP-4 Inhibition and Local Action of GLP-1 in the Gastrointestinal Tract

It is increasingly clear that the gastrointestinal (GI) tract plays a major role in glucose regulation after meal ingestion. A prominent mechanism of GI influence over blood glucose is through the secretion of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1), together termed incretins because of their actions to stimulate internal secretions (i.e., insulin). Indeed, common estimates are that 70% of β-cell release after meals is attributable to the incretins, and both of these peptides are necessary for normal glucose tolerance (1). Moreover, iv administration of GLP-1, and to a much lesser degree glucose-dependent insulinotropic polypeptide, enhances insulin secretion and improves glucose disposal in persons with type 2 diabetes. This has led to the development of two new classes of medication for diabetes, GLP-1 receptor agonists, which mimic the effects of endogenous GLP-1, and dipeptidyl peptidase IV (DPP-4) inhibitors, which prevent metabolism of the native peptide and extend its activity (2).

T helper (Th)1, Th2, and Th17 interleukin pathways in infertile patients with minimal/mild endometriosis

In the present study, interleukin (IL)-10, IL-12, IL-17, and IL-23 levels were measured in serum and peritoneal fluid of women with minimal or mild endometriosis and compared with levels in controls without endometriosis. Higher IL-23 levels were encountered in the peritoneal fluid of women with endometriosis, suggesting a possible role of this cytokine in these women's infertility.

Intra-pituitary administration revisited: Development of a novel in vivo approach to investigate the ovine hypophysis

The anterior pituitary gland regulates physiological processes via the secretion of hormones, which are under the control of factors produced either in the hypothalamus or the pituitary gland itself. Studies investigating how the pituitary gland functions have employed both in vitro and in vivo approaches. Although in vitro analysis has the advantage that it is pituitary specific, the results may be incomplete because the tissue is isolated from other physiological inputs that could affect function under natural conditions. Without vascular input, such studies are inherently of short duration. Conversely, in vivo experiments that rely upon systemic hormone injections require high doses, are non-target specific and the precise hormone concentrations reaching the pituitary gland are difficult to control. Intracerebroventricular hormone infusions are reliant on assumptions that factors are transported to the pituitary gland from the cerebrospinal fluid and are without cerebral effects. Here we describe an innovative method to investigate anterior pituitary function in conscious sheep by direct infusion of peptides into the pituitary tissue surrounding the hypophyseal portal blood vessels. This approach is an adaptation of the hypophyseal portal cannulation technique whereby an indwelling cannula provides direct access to the rostral aspect of the adenohypophysis. Peptide infusions were achieved by insertion of a needle through the implanted cannula such that it penetrated the pituitary. Using this technique, infusion of TRH (17ng/1μl/min for up to 6h) induced a sustained rise in systemic prolactin levels that lasted for the duration of the infusion.

Circadian Modulation of GABA-Mediated Cortical Inhibition

Circadian rhythms exert powerful influence on various aspects of human physiology and behavior. Here, we tested changes of human cerebral cortex excitability over the course of the day with transcranial magnetic stimulation (TMS). At different times of the day, intracortical and corticospinal excitability of the primary motor cortex (M1) was evaluated in 15 healthy subjects by TMS of left M1. While motor thresholds, short-interval intracortical inhibition and facilitation and input/output curves remained unchanged, we found that a specific form of γ-aminobutyric acid (GABA)-mediated intracortical inhibition, revealed by long-interval intracortical inhibition and cortical silent periods, progressively decreased during the course of the day. Additional experiments demonstrated that morning inhibition persisted irrespective of previous sleep or sleep deprivation. Corticotropin-releasing hormone (CRH) infusions in the evening lead to morning cortisol levels but did not restore levels of morning inhibition, whereas suppression of endogenous CRH release by repeated oral dexamethasone intake over 24 h prevented morning inhibition. The findings suggest a specific modulation of GABAergic motor cortex inhibition within the circadian cycle, possibly linked to the CRH system, and may indicate a neurobiological basis for variable neuroplasticity over the course of the day.

Effects of Acute Hyperglucagonemia on Hepatic and Intestinal Lipoprotein Production and Clearance in Healthy Humans

OBJECTIVEThe metabolism of hepatic- and intestinally derived lipoproteins is regulated in a complex fashion by nutrients, hormones, and neurologic and other factors. Recent studies in animal models suggest an important role for glucagon acting via the glucagon receptor in regulating hepatic triglyceride (TG) secretion. Here we examined the direct effects of glucagon on regulation of hepatic and intestinal lipoprotein metabolism in humans.RESEARCH DESIGN AND METHODSEight healthy men underwent two studies each, in random order, 4–6 weeks apart in which de novo lipogenesis, kinetics of larger VLDL1 TG, and kinetics of VLDL1 and smaller VLDL2 apolipoprotein (apo)B100 and B48 were studied using established stable isotope enrichment methods. Subjects were studied in the constant fed state under conditions of a pancreatic clamp (with infusion of somatostatin, insulin, and growth hormone) at either basal glucagon (BG study, 64.5 ± 2.1 pg/mL) or hyperglucagonemia (high glucagon [HG] study, 183.2 ± 5.1 pg/mL).RESULTSThere were no significant differences in plasma concentration of VLDL1 or VLDL2 TG, apoB100 or apoB48 between BG and HG studies. There was, however, lower (P < 0.05) VLDL1 apoB100 fractional catabolic rate (−39%) and production rate (−30%) in HG versus BG, but no difference in de novo lipogenesis or TG turnover, and glucagon had no effect on intestinal (B48-containing) lipoprotein metabolism.CONCLUSIONSGlucagon acutely regulates hepatic but not intestinal lipoprotein particle metabolism in humans both by decreasing hepatic lipoprotein particle production as well as by inhibiting particle clearance, with no net effect on particle concentration.

Effect of feeding fat or intrajugular infusion of glucagon-like peptide-1 and cholecystokinin on dry matter intake, digestibility, and digesta rate of passage in growing wethers1

A cause and effect relationship between glucagon-like peptide 1 (7, 36) amide (GLP-1) and cholecystokinin (CCK) and DMI regulation has not been established in ruminants. Three randomized complete block experiments were conducted to determine the effect of feeding fat or infusing GLP-1 or CCK intravenously on DMI, nutrient digestibility, and Cr rate of passage (using Cr(2)O(3) as a marker) in wethers. A total of 18 Targhee × Hampshire wethers (36.5 ± 2.5 kg of BW) were used, and each experiment consisted of four 21-d periods (14 d for adaptation and 7 d for infusion and sampling). Wethers allotted to the control treatments served as the controls for all 3 experiments; experiments were performed simultaneously. The basal diet was 60% concentrate and 40% forage. In Exp. 1, treatments were the control (0% added fat) and addition of 4 or 6% Ca salts of palm oil fatty acids (DM basis). Treatments in Exp. 2 and 3 were the control and 3 jugular vein infusion dosages of GLP-1 (0.052, 0.103, or 0.155 µg•kg of BW(-1)•d(-1)) or CCK (0.069, 0.138, or 0.207 µg•kg of BW(-1)•d(-1)), respectively. Increases in plasma GLP-1 and CCK concentrations during hormone infusions were comparable with increases observed when increasing amounts of fat were fed. Feeding fat and infusion of GLP-1 tended (linear, P = 0.12; quadratic, P = 0.13) to decrease DMI. Infusion of CCK did not affect (P > 0.21) DMI. Retention time of Cr in the total gastrointestinal tract decreased (linear, P < 0.01) when fat was fed, but was not affected by GLP-1 or CCK infusion. In conclusion, jugular vein infusion produced similar plasma CCK and GLP-1 concentrations as observed when fat was fed. The effects of feeding fat on DMI may be partially regulated by plasma concentration of GLP-1, but are not likely due solely to changes in a single hormone concentration.

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression

We have used a simple and efficient method to identify condition-specific transcriptional regulatory sites in vivo to help elucidate the molecular basis of sex-related differences in transcription, which are widespread in mammalian tissues and affect normal physiology, drug response, inflammation, and disease. To systematically uncover transcriptional regulators responsible for these differences, we used DNase hypersensitivity analysis coupled with high-throughput sequencing to produce condition-specific maps of regulatory sites in male and female mouse livers and in livers of male mice feminized by continuous infusion of growth hormone (GH). We identified 71,264 hypersensitive sites, with 1,284 showing robust sex-related differences. Continuous GH infusion suppressed the vast majority of male-specific sites and induced a subset of female-specific sites in male livers. We also identified broad genomic regions (up to ∼100 kb) showing sex-dependent hypersensitivity and similar patterns of GH responses. We found a strong association of sex-specific sites with sex-specific transcription; however, a majority of sex-specific sites were >100 kb from sex-specific genes. By analyzing sequence motifs within regulatory regions, we identified two known regulators of liver sexual dimorphism and several new candidates for further investigation. This approach can readily be applied to mapping condition-specific regulatory sites in mammalian tissues under a wide variety of physiological conditions.

Technical note: Bovine acute-phase response after corticotrophin-release hormone challenge1

The objective of this study was to evaluate plasma concentrations of cortisol, acute-phase proteins, and proinflammatory cytokines in beef steers after an intravenous corticotrophin-release hormone (CRH) infusion. Six weaned, halter-trained Angus steers (BW = 163 ± 7.0 kg; age = 203 ± 5.8 d) were fitted with indwelling jugular catheters on d -1 of the study and assigned to receive intravenously 0.1 μg of bovine CRH/kg of BW on d 0 of the study. Blood samples were collected every hour via jugular catheters from -1 to 8 h, and every 6 h via jugular venipuncture from 12 to 72 h relative to CRH infusion (0 h). Steer rectal temperature was assessed concurrently with each blood collection. Samples collected from -1 to 8 h relative to CRH infusion were analyzed for plasma concentrations of IL-1β and IL-6, tumor necrosis factor-α, interferon-γ, cortisol, ceruloplasmin, and haptoglobin, whereas samples collected from 12 to 72 h were analyzed for plasma concentrations of ceruloplasmin and haptoglobin only. Plasma cortisol concentrations were greater (P < 0.01) at 1, 2, and 3 h compared with prechallenge values (2.8, 2.3, 13.9, 8.2, and 5.7 ng/mL for -1, 0, 1, 2, and 3 h, respectively; SEM = 0.6). Mean postchallenge IL-6 concentrations were greater (P = 0.04) compared with mean prechallenge values (1.49 vs. 1.34 log pg/mL; SEM = 0.05), whereas IL-6 concentrations at 6 h were greater (P ≤ 0.05) compared with prechallenge values (1.36, 1.33, and 1.61 log pg/mL at -1, 0, and 6 h, respectively; SEM = 0.09). Rectal temperatures were greater (P < 0.01) at 2 and 8 h compared with prechallenge values (38.9, 39.0, 39.3, and 39.5°C at -1, 0, 2, and 8 h, respectively; SEM = 0.07). Plasma ceruloplasmin concentrations were greater (P = 0.03) at 54 h (29.6, 31.5, and 35.2 mg/dL at -1, 0, and 54 h, respectively; SEM = 1.7), whereas plasma haptoglobin concentrations were greater (P < 0.05) at 54, 66, and 72 h compared with prechallenge values (3.3, 2.8, 4.3, 4.6, and 4.1 absorbance at 450 nm × 100 at -1, 0, 54, 66, and 72 h, respectively; SEM = 0.24). In conclusion, intravenous CRH infusion at 0.1 μg/kg of BW increased circulating concentrations of cortisol and stimulated the acute-phase response in halter-trained beef steers.

Pooled-data analysis identifies pyloric pressures and plasma cholecystokinin concentrations as major determinants of acute energy intake in healthy, lean men

The interaction of nutrients with the small intestine modulates gastropyloroduodenal motility, stimulates the release of gut hormones, and suppresses appetite and energy intake. We evaluated which, if any, of these variables are independent determinants of acute energy intake in healthy, lean men. We pooled data from 8 published studies that involved a total of 67 healthy, lean men in whom antropyloroduodenal pressures, gastrointestinal hormones, and perceptions were measured during intraduodenal nutrient or intravenous hormone infusions. In all of the studies, the energy intake at a buffet lunch was quantified immediately after the infusions. To select specific motor, hormone, or perception variables for inclusion in a multivariable mixed-effects model for determination of independent predictors of energy intake, we assessed all variables for collinearity and determined within-subject correlations between energy intake and these variables by using bivariate analyses adjusted for repeated measures. Although correlations were shown between energy intake and antropyloroduodenal pressures, plasma hormone concentrations, and gastrointestinal perceptions, only the peak number of isolated pyloric-pressure waves, peak plasma cholecystokinin concentration, and area under the curve of nausea were identified as independent predictors of energy intake (all P < 0.05), so that increases of 1 pressure wave, 1 pmol/L, and 1 mm . min were associated with reductions in energy intake of approximately 36, approximately 88, and approximately 0.4, respectively. We identified specific changes in gastrointestinal motor and hormone functions (ie, stimulation of pyloric pressures and plasma cholecystokinin) and nausea that are associated with the suppression of acute energy intake.

Dose-related effects of cerulein short infusions on proximal small bowel motility in sheep

The effect of cholecystokinin (CCK) upon the intestinal motility has not been entirely explored in ruminants. The aim of this study was to examine the precise effects of CCK amphibian analogue, cerulein, on small-intestinal myoelectric activity in rams in the course of chronic experiments. Five rams underwent implantation of bipolar platinum electrodes to the duodenal bulb, the distal duodenum and jejunum. During continuous myoelectrical and motor recordings, 0.15 M NaCl or the various doses of cerulein were administered intravenously. Short infusions of the smallest dose of cerulein exerted a slight and mostly insignificant effect on the duodenalbulb and the duodenal myoelectric activity index (MAI) values. In the duodenal bulb, the effects of cerulein on myoelectric activity were dose-dependent and closely related to the phase of the MMC. In the duodenum, the higher doses of the hormone evoked short stimulatory response followed by longer inhibitory biphasic effects on MAI. These effects were inversely related to the duration of hormone injection. Infusions of hormones at the higher doses caused a less pronounced biphasic effect. It is concluded that cerulein exerts an inhibitory effect upon the myoelectric activity of the duodenal bulb and a strong stimulatory and inhibitory (biphasic) effect on duodenal motility in sheep.

Mechanisms of FSH synthesis: what we know, what we don't, and why you should care

The pituitary gonadotropin hormones, FSH and LH, are key regulators of reproductive physiology. Though the two hormones are produced by the same cell type, often in response to the same endocrine and paracrine regulators, they sub-serve different biological functions and their synthesis and secretion are differentially regulated. This stems largely from differences in transcriptional, post-transcriptional, and post-translational regulation of their unique beta subunits. That is, both hormones are dimeric glycoproteins and share a common alpha subunit. Their unique beta subunits, however, derive from different genes encoding distinct proteins. Past and recent research indicates synthesis and release of the two hormones are subject to extensive and independent regulation. LH appears to be secreted predominantly via the regulated secretory pathway, whereas FSH release is largely constitutive. As such, investigations of FSH-beta subunit synthesis may lend direct insight into mechanisms underlying patterns of secreted FSH, more so than investigations of the LHbeta subunit. Here, we review recent investigations of transcriptional regulation of the FSH-beta subunit gene from different mammalian species, including humans. The results reveal both conserved and species-specific regulatory mechanisms that might contribute to inter-species variation in FSH release.

Optimal Control of Blood Glucose: The Diabetic Patient or the Machine?

In this issue of Science Translational Medicine, El-Khatib et al. describe a "closed-loop" bihormonal artificial pancreas, designed to avert episodes of low blood sugar in patients with insulin-dependent diabetes. We discuss the benefits and challenges of therapy directed at tight control of blood glucose and ask whether this and similar technological breakthroughs can address as yet unanswered questions in the biology of diabetes.

Basal Follicle-Stimulating Hormone and Peak Gonadotropin Levels after Gonadotropin-Releasing Hormone Infusion Show High Diagnostic Accuracy in Boys with Suspicion of Hypogonadotropic Hypogonadism

Differential diagnosis between hypogonadotropic hypogonadism (HH) and constitutional delay of puberty in boys is challenging. Most tests use an acute GnRH stimulus, allowing only the release of previously synthesized gonadotropins. A constant GnRH infusion, inducing de novo gonadotropin synthesis, may allow a better discrimination. We evaluated the diagnostic accuracy of basal and peak gonadotropins after GnRH infusion, measured by ultrasensitive assays, to confirm the diagnosis in boys with suspected HH. We conducted a validation study following Standards for Reporting of Diagnostic Accuracy criteria at a tertiary public hospital. A GnRH i.v. infusion test was performed in 32 boys. LH and FSH were determined by immunofluorometric assay at 0-120 min. DIAGNOSIS ASCERTAINMENT: The following diagnoses were ascertained: complete HH (n = 19; testes < 4 ml at 18 yr), partial HH (n = 6; testes enlargement remained arrested for > or = 1 yr or did not reach 15 ml), and constitutional delay of puberty (n = 7; testes > or = 15 ml at 18 yr). Sensitivity, specificity, positive and negative predictive values, and diagnostic efficiency were assessed. Basal FSH less than 1.2 IU/liter confirmed HH with specificity of 1.00 (95% confidence interval = 0.59-1.00), rendering GnRH infusion unnecessary. In patients with basal FSH of at least 1.2 IU/liter, the coexistence of peak FSH less than 4.6 IU/liter and peak LH less than 5.8 IU/liter after GnRH infusion had high specificity (1.00; 95% confidence interval = 0.59-1.00) and diagnostic efficiency (76.9%) for HH. Basal FSH less than 1.2 IU/liter confirms HH, which precludes from further testing, reducing patient discomfort and healthcare system costs. In patients with basal FSH of at least 1.2 IU/liter, a GnRH infusion test has a high diagnostic efficiency.

PYY3–36 and Oxyntomodulin Can Be Additive in Their Effect on Food Intake in Overweight and Obese Humans

OBJECTIVEPeptide YY3–36 (PYY3–36), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY3–36 and oxyntomodulin can be additive.RESEARCH DESIGN AND METHODSTwelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY3–36 or oxyntomodulin or combined PYY3–36/oxyntomodulin.RESULTSEnergy intake during coadministration of PYY3–36 and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone.CONCLUSIONSThe anorectic effects of PYY3–36 and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity.

Expression analysis of key somatotropic axis and liporegulatory genes in ghrelin- and obestatin-infused dairy cows

Ghrelin, an orexigenic hormone, is the endogenous ligand for the growth hormone secretagogue receptor (GHSR). Obestatin is produced from the same precursor peptide as ghrelin, and although obestatin was initially thought to promote actions opposite to those of ghrelin, many studies have failed to confirm this hypothesis. In the current study, multiparous cows were continuously infused with ghrelin (n = 10) or obestatin (n = 10) for 8 wk and compared to an untreated group (n = 10) to examine the effects of these hormones on somatotropic and liporegulatory gene expression. The expression of key genes was measured by quantitative real-time polymerase chain reaction. Growth hormone secretagogue receptor mRNA expression was altered in ghrelin- and obestatin-infused cows in a similar manner, as expression was increased at 4 wk, however it had decreased by 8 wk. Obestatin-infused cows presented with a significant decrease in the expression of ATP-binding cassette A1 (ABCA1) in adipose tissue, suggesting changes in cholesterol transport. Liver insulin-like growth factor (IGF) binding protein-3 mRNA displayed a week-by-treatment interaction, as expression was increased in control and obestatin-infused cows; however, expression decreased in ghrelin-infused cows. Adipose expression of hormone sensitive lipase (LIPE) mRNA was not altered by treatment or time, suggesting hormone infusion is not initiating lipolysis. The expression of lipogenic genes in adipose tissue increased with time in all groups, consistent with the general lactational profile of lipogenesis in dairy cows. These data indicate that continuous infusion of ghrelin or obestatin does not alter the expression of key somatotropic or liporegulatory genes in the lactating dairy cow, although obestatin infusion may alter cholesterol transport.

Early-Life Stress Disrupts Attachment Learning: The Role of Amygdala Corticosterone, Locus Ceruleus Corticotropin Releasing Hormone, and Olfactory Bulb Norepinephrine

Infant rats require maternal odor learning to guide pups' proximity-seeking of the mother and nursing. Maternal odor learning occurs using a simple learning circuit including robust olfactory bulb norepinephrine (NE), release from the locus ceruleus (LC), and amygdala suppression by low corticosterone (CORT). Early-life stress increases NE but also CORT, and we questioned whether early-life stress disrupted attachment learning and its neural correlates [2-deoxyglucose (2-DG) autoradiography]. Neonatal rats were normally reared or stressed-reared during the first 6 d of life by providing the mother with insufficient bedding for nest building and were odor-0.5 mA shock conditioned at 7 d old. Normally reared paired pups exhibited typical odor approach learning and associated olfactory bulb enhanced 2-DG uptake. However, stressed-reared pups showed odor avoidance learning and both olfactory bulb and amygdala 2-DG uptake enhancement. Furthermore, stressed-reared pups had elevated CORT levels, and systemic CORT antagonist injection reestablished the age-appropriate odor-preference learning, enhanced olfactory bulb, and attenuated amygdala 2-DG. We also assessed the neural mechanism for stressed-reared pups' abnormal behavior in a more controlled environment by injecting normally reared pups with CORT. This was sufficient to produce odor aversion, as well as dual amygdala and olfactory bulb enhanced 2-DG uptake. Moreover, we assessed a unique cascade of neural events for the aberrant effects of stress rearing: the amygdala-LC-olfactory bulb pathway. Intra-amygdala CORT or intra-LC corticotropin releasing hormone (CRH) infusion supported aversion learning with intra-LC CRH infusion associated with increased olfactory bulb NE (microdialysis). These results suggest that early-life stress disturbs attachment behavior via a unique cascade of events (amygdala-LC-olfactory bulb).