Morphological analysis of the hindbrain glucose sensor-hypothalamic neural pathway activated by hindbrain glucoprivation

Endocrinology ◽  
2021 ◽  
Author(s):  
Marimo Sato ◽  
Shiori Minabe ◽  
Takahiro Sakono ◽  
Fumie Magata ◽  
Sho Nakamura ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Food Intake ◽  
Glucose Sensor ◽  
Third Ventricle ◽  
Male Rats ◽  
Ependymal Cells ◽  
Neural Pathway ◽  
Testosterone Levels ◽  
Glucose Availability

Abstract Lowered glucose availability, sensed by the hindbrain, has been suggested to enhance gluconeogenesis and food intake as well as suppress reproductive function. In fact, our previous histological and in vitro studies suggest that hindbrain ependymal cells function as a glucose sensor. The present study aimed to clarify the hindbrain glucose sensor-hypothalamic neural pathway activated in response to hindbrain glucoprivation to mediate counterregulatory physiological responses. Administration of 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, into the fourth ventricle (4V) of male rats for 0.5 h induced mRNA expression of c-fos, a marker for cellular activation, in ependymal cells in the 4V, but not in the lateral ventricle, the third ventricle or the central canal without a significant change in blood glucose and testosterone levels. Administration of 2DG into the 4V for 1 h significantly increased blood glucose levels, food intake, and decreased blood testosterone levels. Simultaneously, the expression of c-Fos protein was detected in the 4V ependymal cells; dopamine β-hydroxylase-immunoreactive cells in the C1, C2, and A6 regions; neuropeptide Y (NPY) mRNA-positive cells in the C2; corticotropin-releasing hormone (CRH) mRNA-positive cells in the hypothalamic paraventricular nucleus (PVN); and NPY mRNA-positive cells in the arcuate nucleus (ARC). Taken together, these results suggest that lowered glucose availability, sensed by 4V ependymal cells, activates hindbrain catecholaminergic and/or NPY neurons followed by CRH neurons in the PVN and NPY neurons in the ARC, thereby leading to counterregulatory responses, such as an enhancement of gluconeogenesis, increased food intake, and suppression of sex steroid secretion.

scholarly journals Obestatin Partially Affects Ghrelin Stimulation of Food Intake and Growth Hormone Secretion in Rodents

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1648-1653 ◽  
Author(s):  
Philippe Zizzari ◽  
Romaine Longchamps ◽  
Jacques Epelbaum ◽  
Marie Thérèse Bluet-Pajot
Keyword(s):  
Food Intake ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Male Rats ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Freely Moving ◽  
Stimulation Of

Administration of ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHSR 1a), induces potent stimulating effects on GH secretion and food intake. However, more than 7 yr after its discovery, the role of endogenous ghrelin remains elusive. Recently, a second peptide, obestatin, also generated from proteolytic cleavage of preproghrelin has been identified. This peptide inhibits food intake and gastrointestinal motility but does not modify in vitro GH release from pituitary cells. In this study, we have reinvestigated obestatin functions by measuring plasma ghrelin and obestatin levels in a period of spontaneous feeding in ad libitum-fed and 24-h fasted mice. Whereas fasting resulted in elevated ghrelin levels, obestatin levels were significantly reduced. Exogenous obestatin per se did not modify food intake in fasted and fed mice. However, it inhibited ghrelin orexigenic effect that were evident in fed mice only. The effects of obestatin on GH secretion were monitored in superfused pituitary explants and in freely moving rats. Obestatin was only effective in vivo to inhibit ghrelin stimulation of GH levels. Finally, the relationship between octanoylated ghrelin, obestatin, and GH secretions was evaluated by iterative blood sampling every 20 min during 6 h in freely moving adult male rats. The half-life of exogenous obestatin (10 μg iv) in plasma was about 22 min. Plasma obestatin levels exhibited an ultradian pulsatility with a frequency slightly lower than octanoylated ghrelin and GH. Ghrelin and obestatin levels were not strictly correlated. In conclusion, these results show that obestatin, like ghrelin, is secreted in a pulsatile manner and that in some conditions; obestatin can modulate exogenous ghrelin action. It remains to be determined whether obestatin modulates endogenous ghrelin actions.

scholarly journals The lack of specificity of neuropeptide Y (NPY) antisense oligodeoxynucleotides administered intracerebroventricularly in inhibiting food intake and NPY gene expression in the rat hypothalamus

1998 ◽  
Vol 157 (1) ◽  
pp. 169-175 ◽  
Author(s):  
S Dryden ◽  
L Pickavance ◽  
D Tidd ◽  
G Williams
Keyword(s):  
Gene Expression ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Third Ventricle ◽  
Antisense Oligodeoxynucleotides ◽  
Mrna Levels ◽  
Inhibit Gene Expression ◽  
Negative Findings ◽  
Antisense Odns

To evaluate the role of neuropeptide Y (NPY), a potent appetite stimulant, in controlling food intake and body weight, we investigated the use of antisense oligodeoxynucleotides (ODNs) to inhibit NPY gene expression in the hypothalamus. We compared the hypothalamic distribution of fluorescein-labelled ODNs administered intracerebroventricularly, and effects on food intake and NPY gene expression, of three different structural modifications of an antisense ODN sequence against NPY. Rats had either the antisense or missense ODNs (24 micrograms/day) or saline infused into the third ventricle by osmotic minipumps for 7 days. The unmodified phosphodiester ODN was not detectable in the hypothalamus after 7 days and had no effects on food intake. The phosphorothioate ODN was widely distributed throughout the hypothalamus but had nonselective effects, with similar changes in food intake and NPY mRNA levels in the antisense and missense groups, and was severely toxic. The propyl-protected ODN appeared to penetrate the hypothalamus well but had no antisense-selective effects on NPY mRNA levels or food intake. Antisense ODNs are increasingly used to inhibit gene expression in vitro and in intact animals. These negative findings underline the need for rigorous evaluation of any effects of antisense ODNs administered into the central nervous system, and raise doubts about the validity of this approach in physiological or pharmacological studies.

Antibodies against the melanocortin-4 receptor act as inverse agonists in vitro and in vivo

2007 ◽  
Vol 292 (6) ◽  
pp. R2151-R2158 ◽  
Author(s):  
Jean-Christophe Peter ◽  
Janet R. Nicholson ◽  
Déborah Heydet ◽  
Anne-Catherine Lecourt ◽  
Johan Hoebeke ◽  
...  
Keyword(s):  
Food Intake ◽  
Third Ventricle ◽  
Separate Experiment ◽  
Inverse Agonists ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
Melanocortin 4 Receptor ◽  
293 Cells ◽  
Immunofluorescence Labeling

Functionally active antibodies (Abs) against central G-protein-coupled receptors have not yet been reported. We selected the hypothalamic melanocortin-4 receptor (MC4-R) as a target because of its crucial role in the regulation of energy homeostasis. A 15 amino acid sequence of the N-terminal (NT) domain was used as an antigen. This peptide showed functional activity in surface plasmon resonance experiments and in studies on HEK-293 cells overexpressing the human MC4-R (hMC4-R). Rats immunized against the NT peptide produced specific antibodies, which were purified and characterized in vitro. In HEK-293 cells, rat anti-NT Abs showed specific immunofluorescence labeling of hMC4-R. They reduced the production of cAMP under basal conditions and after stimulation with a synthetic MC4-R agonist. Rats immunized against the NT peptide developed a phenotype consistent with MC4-R blockade, that is, increased food intake and body weight, increased liver and fat pad weight, and elevated plasma triglycerides. In a separate experiment in rats, an increase in food intake could be produced after injection of purified Abs into the third ventricle. Similar results were obtained in rats injected with anti-NT Abs raised in rabbits. Our data show for the first time that active immunization of rats against the NT sequence of the MC4-R results in specific Abs, which appear to stimulate food intake by acting as inverse agonists in the hypothalamus.

MEAL-EATING AND LIPOGENESIS IN VITRO OF RATS FED A LOW-PROTEIN DIET

1964 ◽  
Vol 42 (5) ◽  
pp. 665-670 ◽  
Author(s):  
J. R. Beaton ◽  
V. Feleki ◽  
A. J. Szlavko ◽  
J. A. F. Stevenson
Keyword(s):  
Adipose Tissue ◽  
Food Intake ◽  
Body Weight Gain ◽  
Liver Glycogen ◽  
Male Rats ◽  
Acetate Incorporation ◽  
Casein Diet ◽  
Low Protein ◽  
Daily Food

The response of male rats to the restriction of food intake to 2 hours each day for 14 to 16 days has been assessed by the measurement of food intakes, body weights, liver glycogen concentrations, and lipogenesis of adipose tissue (C14-acetate incorporation in vitro). The animals were fed either a 20% casein diet (controls) or an isocaloric 5% casein diet. As a consequence of meal-eating, and regardless of dietary protein level, the average daily food intake and body weight gain were decreased whereas the lipogenesis in vitro and liver glycogen concentration were increased in comparison with rats fed ad libitum,which is in agreement with earlier findings using normal diets. These observations suggest that the decreased body fat of rats fed a 5% casein diet is not a consequence of an impaired ability of adipose tissue to synthesize fat.

scholarly journals Changes in RFamide-Related Peptide-1 (RFRP-1)-Immunoreactivity During Postnatal Development and the Estrous Cycle

Endocrinology ◽  
2014 ◽  
Vol 155 (11) ◽  
pp. 4402-4410 ◽  
Author(s):  
Sara R. Jørgensen ◽  
Mille D. Andersen ◽  
Agnete Overgaard ◽  
Jens D. Mikkelsen
Keyword(s):  
Postnatal Development ◽  
Estrous Cycle ◽  
Third Ventricle ◽  
Female Rats ◽  
Male Rats ◽  
Relative Distribution ◽  
Gonadotropin Secretion ◽  
Related Peptide

Abstract GnRH is a key player in the hypothalamic control of gonadotropin secretion from the anterior pituitary gland. It has been shown that the mammalian counterpart of the avian gonadotropin inhibitory hormone named RFamide-related peptide (RFRP) is expressed in hypothalamic neurons that innervate and inhibit GnRH neurons. The RFRP precursor is processed into 2 mature peptides, RFRP-1 and RFRP-3. These are characterized by a conserved C-terminal motif RF-NH2 but display highly different N termini. Even though the 2 peptides are equally potent in vitro, little is known about their relative distribution and their distinct roles in vivo. In this study, we raised an antiserum selective for RFRP-1 and defined the distribution of RFRP-1-immunoreactive (ir) neurons in the rat brain. Next, we analyzed the level of RFRP-1-ir during postnatal development in males and females and investigated changes in RFRP-1-ir during the estrous cycle. RFRP-1-ir neurons were distributed along the third ventricle from the caudal part of the medial anterior hypothalamus throughout the medial tuberal hypothalamus and were localized in, but mostly in between, the dorsomedial hypothalamic, ventromedial hypothalamic, and arcuate nuclei. The number of RFRP-1-ir neurons and the density of cellular immunoreactivity were unchanged from juvenile to adulthood in male rats during the postnatal development. However, both parameters were significantly increased in female rats from peripuberty to adulthood, demonstrating prominent gender difference in the developmental control of RFRP-1 expression. The percentage of c-Fos-positive RFRP-1-ir neurons was significantly higher in diestrus as compared with proestrus and estrus. In conclusion, we found that adult females, as compared with males, have significantly more RFRP-1-ir per cell, and these cells are regulated during the estrous cycle.

scholarly journals Paraventricular Nucleus Administration of Calcitonin Gene-Related Peptide Inhibits Food Intake and Stimulates the Hypothalamo-Pituitary-Adrenal Axis

Endocrinology ◽  
2003 ◽  
Vol 144 (4) ◽  
pp. 1420-1425 ◽  
Author(s):  
Waljit S. Dhillo ◽  
Caroline J. Small ◽  
Preeti H. Jethwa ◽  
Sabina H. Russell ◽  
James V. Gardiner ◽  
...  
Keyword(s):  
Food Intake ◽  
Hpa Axis ◽  
Male Rats ◽  
Mrna Levels ◽  
Related Protein ◽  
Melanocyte Stimulating Hormone ◽  
Calcitonin Gene ◽  
Agouti Related Protein ◽  
Prior Administration

Abstract Calcitonin gene-related protein (CGRP) inhibits food intake and stimulates the hypothalamo-pituitary-adrenal (HPA) axis after intracerebroventricular injection in rats. However, the hypothalamic site and mechanism of action are unknown. We investigated the effects of intraparaventricular nucleus administration (iPVN) of CGRP on food intake and the HPA axis in rats and the effect of CGRP on the release of hypothalamic neuropeptides in vitro. In addition, we investigated the effects of food deprivation on hypothalamic CGRP expression. CGRP dose-dependently reduced food intake in the first hour after iPVN injection in fasted male rats (saline, 5.1 ± 0.8 g; 0.3 nmol CGRP, 1.1 ± 0.5 g; P < 0.001 vs. saline). iPVN injection of CGRP8–37 (a CGRP1 receptor antagonist) alone had no effect on food intake. However, the reduction in food intake by iPVN CGRP was attenuated by prior administration of CGRP8–37 [CGRP8–37 (10 nmol)/CGRP (0.3 nmol), 3.0 ± 0.8 g; P < 0.05 vs. 0.3 nmol CGRP]. CGRP (100 nm) stimulated the release of α-melanocyte stimulating hormone, cocaine- and amphetamine-related transcript, corticotropin-releasing hormone, and arginine vasopressin from hypothalamic explants to 127 ± 19%, 148 ± 10%, 158 ± 17%, and 198 ± 21% of basal levels, respectively (P < 0.05 vs. basal), but did not alter the release of either neuropeptide Y or agouti-related protein. Hypothalamic CGRP mRNA levels in 24-h fasted rats were increased to 130 ± 8% of control levels [CGRP mRNA (arbitrary units), 4.75 ± 0.4; controls, 3.65 ± 0.34; P < 0.05]. Our data suggest that CGRP administered to the PVN inhibits food intake and stimulates the HPA axis.

scholarly journals Pyroglutamylated RFamide Peptide 43 Stimulates the Hypothalamic-Pituitary-Gonadal Axis via Gonadotropin-Releasing Hormone in Rats

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4747-4754 ◽  
Author(s):  
Sejal R. Patel ◽  
Kevin G. Murphy ◽  
Emily L. Thompson ◽  
Michael Patterson ◽  
Annette E. Curtis ◽  
...  
Keyword(s):  
Food Intake ◽  
Intraperitoneal Administration ◽  
Gonadotropin Releasing Hormone ◽  
Male Rats ◽  
Sex Steroid ◽  
The Novel ◽  
Gnrh Release ◽  
Ad Libitum ◽  
Influence Behavior

Although it is established that other members of the RFamide family stimulate the hypothalamic-pituitary-gonadal axis, the influence of the novel pyroglutamylated RFamide peptide 43 (QRFP43) is not known. We show intracerebroventricular (icv) administration of QRFP43 (2 nmol) to male rats increased plasma LH and FSH levels at 40 min after injection. icv administration of 3 nmol QRFP43 did not affect food intake in ad-libitum-fed male rats. The icv administration of 2 nmol QRFP43 did not significantly influence behavior in male rats. Intraperitoneal administration of doses up to 1200 nmol/kg QRFP43 in male rats did not significantly influence circulating gonadotropin or sex steroid levels. In vitro, QRFP43 stimulated GnRH release from hypothalamic explants from male rats and from GT1-7 cells. Pretreatment with a GnRH receptor antagonist, cetrorelix, blocked the increase in plasma LH levels after icv administration of QRFP43 (2 nmol). These results suggest that icv QRFP43 activates the hypothalamic-pituitary-gonadal axis via GnRH.

scholarly journals Integrated Effects of Leptin in the Forebrain and Hindbrain of Male Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2663-2675 ◽  
Author(s):  
Bhavna N. Desai ◽  
Ruth B. S. Harris
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Body Fat ◽  
Fourth Ventricle ◽  
Third Ventricle ◽  
Male Rats ◽  
Low Doses ◽  
Sprague Dawley ◽  
The Third ◽  
Stat3 Phosphorylation

Abstract Leptin receptors (ObRs) in the forebrain and hindbrain have been independently recognized as important mediators of leptin responses. It is unclear how leptin activity in these areas is integrated. We tested whether both forebrain and hindbrain ObRs have to be activated simultaneously to change energy balance and to maintain metabolic homeostasis. Previous studies used acute leptin injections in either the third ventricle (1–5 μg) or the fourth ventricle (3–10 μg); here we used 12-day infusions of low doses of leptin in one or both ventricles (0.1 μg/24 h in third, 0.6 μg/24 h in fourth). Male Sprague Dawley rats were fitted with third and fourth ventricle cannulas, and saline or leptin was infused from Alzet pumps for 6 or 12 days. Rats that received leptin into only the third or the fourth ventricle were not different from controls that received saline in both ventricles. By contrast, rats with low-dose leptin infusions into both the third and fourth ventricle showed a dramatic 60% reduction in food intake that was reversed on day 6, a 20% weight loss that stabilized on day 6, and a 50% decrease in body fat at day 12 despite the correction of food intake. They displayed normal activity and maintained energy expenditure despite weight loss, indicating inappropriately high thermogenesis that coincided with increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in the brainstem. Altogether, these findings show that with low doses of leptin, chronic activation of both hypothalamic and brainstem ObRs is required to reduce body fat.

Locally and systemically active glucocorticosteroids modify intestinal absorption of sugars in rats

2003 ◽  
Vol 94 (2) ◽  
pp. 583-590 ◽  
Author(s):  
A. Thiesen ◽  
G. E. Wild ◽  
M. Keelan ◽  
M. T. Clandinin ◽  
A. B. R. Thomson
Keyword(s):  
Clinical Practice ◽  
Food Intake ◽  
Mrna Expression ◽  
Glucose Uptake ◽  
Intestinal Mucosa ◽  
Glucose Transporter ◽  
Male Rats ◽  
Adult Rats ◽  
Glucose Transporter 1

Glucocorticosteroids enhance digestive and absorptive functions of the intestine of weaning and adult rats. This study was undertaken to assess the influence of treatment of weaning male rats with budesonide (Bud), prednisone (Pred), or control vehicle on the in vitro jejunal and ileal uptake of glucose and fructose. Bud and Pred had no effect on the uptake ofd-glucose by sodium glucose transporter-1. In contrast, the uptake of d-fructose by GLUT-5 was similarly increased with Bud and with Pred. The increases in the uptake of fructose were not due to variations in the weight of the intestinal mucosa, food intake, or in GLUT-5 protein or mRNA expression. There were no steroid-associated changes in mRNA expression of c- myc, c- jun, c- fos, proglucagon, or selected cytokines. However, the abundance of ileal ornithine decarboxylase mRNA was increased with Pred. Giving postweaning rats 4 wk of Bud or Pred in doses equivalent to those used in clinical practice increases fructose but not glucose uptake. This enhanced uptake of fructose was likely regulated by posttranslational processes.

Calibration of a Wearable Glucose Sensor

1992 ◽  
Vol 15 (1) ◽  
pp. 55-61 ◽  
Author(s):  
F.J. Schmidt ◽  
A.L. Aalders ◽  
A.J.M. Schoonen ◽  
H. Doorenbos
Keyword(s):  
Blood Glucose ◽  
Healthy Volunteers ◽  
Glucose Oxidase ◽  
Glucose Sensor ◽  
Subcutaneous Tissue ◽  
The Body ◽  
Diabetic Patients ◽  
Type I

Calibration of glucose sensors proved difficult for electrodes with immobilized glucose-oxidase. The correlation between the sensitivity of the electrodes in vitro and in vivo appeared to be poor. We developed a new type of glucose sensor, based on a microdialysis system, in which an oxygen electrode is used as detector outside the body and the enzyme glucose-oxidase dissolved in water is used as a dynamic selector. The enzyme solution is pumped through a hollow fiber placed subcutaneously, before the fluid passes the detector. The glucose sensor was tested in the subcutaneous abdominal tissue of 12 healthy volunteers and 12 type I diabetic patients. Blood glucose was clamped at two levels to permit a two-point calibration of the sensor in vivo. These values correlated well with the in vitro calibration factors (r=0.949). In subcutaneous tissue the sensor measures 43 ± 9% of the blood glucose value, using the in vitro calibration factor. No differences were detected between healthy volunteers and diabetic patients.

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