R Håkanson

Lund University, Lund, Skåne, Sweden

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Publications (738)2846.86 Total impact

  • R A Vigen · D Chen · U Syversen · K Stunes · R Hakanson · C-M Zhao
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    ABSTRACT: Histamine-containing enterochromaffin-like (ECL) cells are numerous in the gastric mucosa. They operate under the control of gastrin. ECL-cell tumors (gastric carcinoids) may arise as a consequence of sustained hypergastrinemia. For reasons unknown, such tumors have a female preponderance both in laboratory animals and humans. The present study consisted of four experiments exploring the possibility that gender-related factors might affect rat ECL cells. 1) A gender difference in terms of serum gastrin concentration and oxyntic mucosal histidine decarboxylase (HDC) activity appeared in Sprague-Dawley but not Wistar rats. Ultrastructural appearance of the ECL cells did not differ between genders. 2) During the different phases of the estrous cycle, the serum gastrin concentration, HDC activity and histamine concentration did not change. 3) During pregnancy, the serum gastrin concentration was suppressed, while it was increased during lactation. The HDC activity and the histamine concentration of the oxyntic mucosa were correlated with the levels of circulating gastrin. 4) Twelve-month treatment with estrogen-like agents, dieldrin and/or toxaphene (alone or in combination) was without any effect on the ECL cells neither in male nor in female rats. In conclusion, the ECL cells are under the control of gastrin, but probably not hormones that involve in the estrous cycle and pregnancy and lactation in rats. Possible gender-related factors behind the female preponderance of ECL-cell tumors remain unknown.
    No preview · Article · Jun 2011 · Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
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    ABSTRACT: Proghrelin, produced by the ghrelin (A-like) cells of the gastric mucosa, gives rise to cleavage products, including desacyl ghrelin, acyl ghrelin and obestatin. The products are thought to be secreted concomitantly. In an earlier study we found acyl ghrelin and obestatin, but not desacyl ghrelin, to suppress the release of hormones from isolated islets of mouse and rat pancreas. Using isolated mouse pancreatic islets to study the suppression of the spontaneous secretion of pancreatic polypeptide (PP) by acyl ghrelin and obestatin, we determined the EC(50) values for the two peptides. For acyl ghrelin it was 2 x 10(-13)M (ranging from 1.7 to 2.8 x 10(-13)M), for obestatin it was 10(-13)M (ranging from 0.3 to 1.1 x 10(-13)M). The Hill coefficient (i.e. the midpoint slope) for the acyl ghrelin dose-response curve was 0.30 (ranging from 0.21 to 0.35); the corresponding value for obestatin was 0.35 (ranging from 0.21 to 0.35). The PP-releasing effect of acyl ghrelin, but not that of obestatin, was counteracted by desacyl ghrelin. The acyl ghrelin dose-response curve was shifted to the right in a parallel manner by increasing concentrations of desacyl ghrelin. A Schild plot was constructed with a slope of 0.78, giving an apparent pA(2) value of 14. The results favour the view that acyl ghrelin and obestatin suppress spontaneous PP secretion at physiologically relevant concentrations and that they act on separate receptors. However, we conclude also that desacyl ghrelin acts as a competitive, surmountable (and quite potent) inhibitor of acyl ghrelin. In view of the allegedly high circulating concentrations of desacyl ghrelin it is to be expected that the effect of acyl ghrelin - but not that of obestatin - will be impaired, in fact probably severely blunted by desacyl ghrelin, thereby compromising the functional significance of circulating acyl ghrelin. In addition, we suggest that isolated pancreatic islets are well suited for studies of receptors to acyl ghrelin and obestatin, and that suppression of PP secretion represents a convenient way to measure the effect of both these peptides.
    No preview · Article · Sep 2010 · Regulatory Peptides
  • P Ericsson · R Håkanson · J F Rehfeld · P Norlén
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    ABSTRACT: We used microdialysis to monitor local gastrin release in response to food, acid blockade and acute vagal excitation. For the first time, gastrin release has been monitored continuously in intact conscious rats in a physiologically relevant experimental setting in a fashion that minimizes confounding systemic effects. Microdialysis probes were placed in the submucosa on either side of the antrum, 3 days before the experiments. The concentration of gastrin in the antral submucosal compartment was about 20 times higher than in the microdialysate and estimated to be 5-10 times higher than in serum regardless of the prandial state. The rats were conscious during microdialysis except when subjected to electrical vagal stimulation. Acid blockade (omeprazole treatment of freely fed rats for 4 days), or bilateral sectioning of the abdominal vagal trunks (fasted, 3 days post-op.), raised the gastrin concentration in blood as well as microdialysate. The high gastrin concentration following omeprazole treatment was not affected by vagotomy. Vagal excitation stimulated the G cells: electrical vagal stimulation and pylorus ligation (fasted rats) raised the gastrin concentration transiently in both serum and microdialysate. Food intake induced a 2- to 3-fold increase in serum gastrin, while gastrin in antral microdialysate increased 10- to 15-fold. In unilaterally vagotomized rats (fasted, 3 days post-op.), food evoked a prompt peak gastrin release followed by a gradual decline on the intact side. On the vagotomized side of the antrum, the peak response seemed to be reduced while the microdialysate gastrin concentration remained elevated. Thus, unilateral vagotomy surprisingly raised the integrated gastrin response to food on the denervated side compared to the intact side, indicating that vagotomy suppresses an inhibitory as well as a stimulating effect on the G cells. While local infusion of atropine was without effect, infusion of the neuronal blocker tetrodotoxin (TTX) (which had no effect on basal gastrin) virtually abolished the food-evoked gastrin response and lowered the high microdialysate gastrin concentration in omeprazole-treated rats by 65%. We conclude that activated gastrin release, unlike basal gastrin release, is highly dependent on a neural input: 1) Vagal excitation has a transient stimulating effect on the G cells. The transient nature of the response suggests that the vagus has not only a prompt stimulatory but also a slow inhibitory effect on gastrin release. 2) Although vagal denervation did not affect the gastrin response to anacidity, the TTX experiments revealed that both food-evoked and anacidity-evoked gastrin release depends on neural input.
    No preview · Article · Apr 2010 · Regulatory Peptides
  • Peter Ericsson · Rolf Håkanson · Per Norlén
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    ABSTRACT: We monitored gastrin release in response to locally applied candidate messengers in intact conscious rats. Earlier studies have been performed on anaesthetized animals, isolated pieces of antrum, or purified preparations of gastrin cells. In this study we created an experimental situation to resemble physiological conditions, using reverse microdialysis to administer regulatory peptides and amines that might affect gastrin secretion. Microdialysis probes were implanted in the submucosa of the antrum of the rat stomach. Three days later, putative messenger compounds were administered via the probe. Their effects on basal (24 h fast) and omeprazole-stimulated (400 micromol/kg/day, 4 days peroral administration) gastrin release were monitored by continuous measurement (3 h) of gastrin in the perfusate (radioimmunoassay). Fasted rats (low microdialysate gastrin, 2.1+/-0.1 pmol l(-1)) were used to study stimulation of gastrin release. Omeprazole-treated rats (high microdialysate gastrin, 95.8+/-6.7 pmol l(-1)) were used to study suppression of gastrin release. The following agents raised the concentration of microdialysate gastrin (peak response): gastrin-releasing peptide (GRP) (11-fold increase at a near-maximal dose), carbachol (5-fold increase), serotonin (2-fold increase) and isoprenaline (20-fold increase). Adrenaline and noradrenaline induced transient but powerful elevation (40- and 20-fold increase). Somatostatin, galanin and bradykinin (at near-maximal doses) suppressed omeprazole-stimulated gastrin release (50% decrease). Calcitonin gene-related peptide, ghrelin, gastric inhibitory peptide, motilin, neurotensin, neuromedin U-25, peptide YY and vasoactive intestinal peptide were without effect on gastrin release, as were aspartate, gamma-aminobutyric acid, glutamate, glycine, dopamine and histamine. The results support the view that G cells operate under neurocrine/paracrine control. They were stimulated by agents present in enteric neurons (GRP, galanin, choline ester and catechol amines) and in gastric endocrine cells (serotonin). They were inhibited by somatostatin (D cell peptide), galanin (neuropeptide) and by the inflammatory agent bradykinin.
    No preview · Article · Mar 2010 · Regulatory Peptides
  • R. Håkanson · F. Sundler
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    ABSTRACT: Håkanson R, Sundler F. Trophic effects of gastrin. Scand J Gastroenterol 1991, 26(suppl 180), 130–136 Gastrin is an important trophic hormone for the acid-producting part of the stomach. There is no solid evidence that gastrin is physiologically important as a trophic agent outside the stomach. The trophic effects in the stomach are manifested as an increased weight and thickness of the oxyntic mucosa and can be induced by both exogenous and endogenous gastrin—that is, in situations of long-lasting hypergastrinemia (treatment with effective antisecretagogues, partial fundectomy, or antrum exclusion). Removal of endogenous gastrin by antrectomy induces the opposite effects—that is, diminished weight and thickness of the oxyntic mucosa. Unlike all other peptide hormone-producing endocrine cells in the oxyntic mucosa, the so-called enterochromaffin-like (ECL) cells respond readily to gastrin. An acute gastrin challenge results in release of stored products from the ECL cells (such as histamine) and activation of cytoplasmic enzymes (such as histidine decarboxylase). Sustained elevation of circulating gastrin over days results in hypertrophy of the ECL cells and over weeks results in marked hyperplasia (at most a fivefold increase in the rat). The results in other species are similar but often somewhat less marked than in the rat.
    No preview · Article · Jul 2009 · Scandinavian Journal of Gastroenterology
  • Rolf Håkanson

    No preview · Article · Mar 2009 · Pharmacology & Toxicology
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    Erik Lindström · Maria Björkqvist · Rolf Håkanson
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    ABSTRACT: 1. Gastrin stimulates rat stomach ECL cells to secrete histamine and pacreastatin, a chromogranin A (CGA)-derived peptide. The present report describes the effect of nine cholecystokinin2 (CCK2) receptor antagonists and one CCK1 receptor antagonist on the gastrin-evoked secretion of pancreastatin from isolated ECL cells. 2. The CCK2 receptor antagonists comprised three benzodiazepine derivatives L-740,093, YM022 and YF476, one ureidoacetamide compound RP73870, one benzimidazole compound JB 93182, one ureidoindoline compound AG041R and three tryptophan dipeptoids PD 134308 (CI988), PD135158 and PD 136450. The CCK1 receptor antagonist was devazepide. 3. A preparation of well-functioning ECL cells (~ 80% purity) was prepared from rat oxyntic mucosa using counter-flow elutriation. The cells were cultured for 48 h in the presence of 0.1 nM gastrin; they were then washed and incubated with antagonist alone or with various concentrations of antagonist plus 10 nM gastrin (a maximally effective concentration) for 30 min. Gastrin dose-response curves were constructed in the absence or presence of increasing concentrations of antagonist. The amount of pancreastatin secreted was determined by radioimmunoassay. 4. The gastrin-evoked secretion of pancreastatin was inhibited in a dose-dependent manner. YM022, AG041R and YF476 had IC50 values of 0.5, 2.2 and 2.7 nM respectively. L-740,093, JB93182 and RP73870 had IC50 values of 7.8, 9.3 and 9.8 nM, while PD135158, PD136450 and PD134308 had IC50 values of 76, 135 and 145 nM. The CCK1 receptor antagonist devazepide was a poor CCK2 receptor antagonist with an IC50 of about 800 nM. 5. YM022, YF476 and AG041R were chosen for further analysis. YM022 and YF476 shifted the gastrin dose-response curve to the right in a manner suggesting competitive antagonism, while the effects of AG041R could not be explained by simple competitive antagonism. pK(B) values were 11.3 for YM022, 10.8 for YF476 and the apparent pK(B) for AG041R was 10.4.
    Full-text · Article · Jan 2009 · British Journal of Pharmacology
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    ABSTRACT: Wistar Kyoto (WKY) rats are more susceptible to stress-evoked ulcerations than Sprague-Dawley (SPD) rats. We have already demonstrated that gastrin cells are more active and ghrelin cells less active in WKY rats than in SPD rats. The purpose of this study was to compare endocrine cell activity and gastric acid output in WKY and SPD rats. Gastric acid output was determined in conscious rats with gastric fistula. Plasma gastrin and ghrelin levels were measured after an overnight fast. Acid secretagogues (gastrin, histamine and carbachol) were given by continuous subcutaneous infusion. The volume of gastric juice, and the acidity and acid output were all significantly lower (p <0.05) in fasted WKY rats than in fasted SPD rats. Gastrin evoked a 4-fold (p <0.01) and 3-fold (p <0.05) increase in gastric acid output in SPD rats and WKY rats, respectively. Histamine raised the acid output 1.6-fold in SPD rats (p=0.06) and 3-fold in WKY rats (p <0.05), while carbachol failed to affect the acid output (weak increase, p >0.05). Fasting plasma ghrelin levels were 2-fold higher in SPD rats than in WKY rats (p <0.01) while fasting gastrin levels were 10-fold higher in WKY rats than in SPD rats (p <0.05). Neither the parietal-cell density nor the oxyntic mucosal thickness differed between the two strains. The results of the present study suggest that a high gastrin cell activity in WKY rats is secondary to a low gastric acidity. Whether the high gastrin cell activity is linked to susceptibility to stress ulcer in WKY rats warrants further investigation.
    No preview · Article · Dec 2008 · Scandinavian Journal of Gastroenterology
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    ABSTRACT: Histamine in the rat stomach resides in enterochromaffin-like (ECL) cells and mast cells. The ECL cells are peptide-hormone-producing endocrine cells known to release histamine and chromogranin-A-derived peptides (such as pancreastatin) in response to gastrin. Ischemia (induced by clamping of the celiac artery or by gastric submucosal microinfusion of the vasoconstrictor endothelin) mobilizes large amounts of ECL-cell histamine in a burst-like manner. This report examines the ECL-cell response to ischemia and compares it with that induced by gastrin in rats. Arterial clamping (30 min) and gastric submucosal microinfusion (3 h) of endothelin, vasopressin, or adrenaline caused ischemia, manifested as a raised lactate/pyruvate ratio and mucosal damage. Whereas microinfusion of gastrin released both histamine and pancreastatin, ischemia mobilized histamine only. The mucosal concentrations of histamine and pancreastatin, the number and immunostaining intensity of the ECL cells, and the ultrastructure of the ECL cells were unchanged following ischemia. The long-term effects of ischemia and reperfusion (60-90 min) on gastric mucosa were examined in rats treated with the proton pump inhibitor omeprazole for 4 days. The activity of the ECL cells was suppressed (reflected in low histamine-forming capacity) but returned to normal within 1 week, illustrating the ability of the ECL cells to recover. We suggest that ischemia mobilizes cytosolic ECL-cell histamine without affecting the storage of histamine (and pancreastatin) in the secretory organelles and without causing lasting ECL-cell impairment.
    No preview · Article · Aug 2008 · Cell and Tissue Research

  • No preview · Article · Apr 2008 · Gastroenterology
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    ABSTRACT: We investigated whether ghrelin depletion (by gastrectomy surgery) and/or treatment/replacement with the gastric hormone ghrelin alters the expression of key hypothalamic genes involved in energy balance, in a manner consistent with ghrelin's pro-obesity effects. At 2 weeks after surgery mice were treated with ghrelin (12 nmol/mouse/day, sc) or vehicle for 8 weeks. Gastrectomy had little effect on the expression of these genes, with the exception of NPY mRNA in the arcuate nucleus that was increased. Ghrelin treatment (to gastrectomized and sham mice) increased the mRNA expression of orexigenic peptides NPY and AgRP while decreasing mRNA expression of the anorexigenic peptide POMC. Two weeks gavage treatment with the ghrelin mimetic, MK-0677, to rats increased NPY and POMC mRNA in the arcuate nucleus and MCH mRNA in the lateral hypothalamus. Thus, while predicted pro-obesity ghrelin signalling pathways were activated by ghrelin and ghrelin mimetics, these were largely unaffected by gastrectomy.
    Full-text · Article · Mar 2008 · Regulatory Peptides
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    ABSTRACT: Proghrelin, the precursor of the orexigenic and adipogenic peptide hormone ghrelin, is synthetized in endocrine (A-like) cells in the gastric mucosa. During its cellular processing, proghrelin gives rise to the 28-amino acid peptide desacyl ghrelin, which after octanoylation becomes active acyl ghrelin, and to the 23-amino acid peptide obestatin, claimed to be a physiological opponent of acyl ghrelin. This study examines the effects of the proghrelin products, alone and in combinations, on the secretion of insulin, glucagon, pancreatic polypeptide (PP) and somatostatin from isolated islets of mice and rats. Surprisingly, acyl ghrelin and obestatin had almost identical effects in that they stimulated the secretion of glucagon and inhibited that of PP and somatostatin from both mouse and rat islets. Obestatin inhibited insulin secretion more effectively than acyl ghrelin. In mouse islets, acyl ghrelin inhibited insulin secretion at low doses and stimulated at high. In rat islets, acyl ghrelin inhibited insulin secretion in a dose-dependent manner but the IC(50) for the acyl ghrelin-induced inhibition of insulin release was 7.5 x 10(-8) M, while the EC(50) and IC(50) values, with respect to stimulation of glucagon release and to inhibition of PP and somatostatin release, were in the 3 x 10(-12)-15 x 10(-12) M range. The corresponding EC(50) and IC(50) values for obestatin ranged from 5 x 10(-12) to 20 x 10(-12) M. Desacyl ghrelin per se did not affect islet hormone secretion. However, at a ten times higher concentration than acyl ghrelin (corresponding to the ratio of the two peptides in circulation), desacyl ghrelin abolished the effects of acyl ghrelin but not those of obestatin. Acyl ghrelin and obestatin affected the secretion of glucagon, PP and somatostatin at physiologically relevant concentrations; with obestatin this was the case also for insulin secretion. The combination of obestatin, acyl ghrelin and desacyl ghrelin in concentrations and proportions similar to those found in plasma resulted in effects that were indistinguishable from those induced by obestatin alone. From the data it seems that the effects of endogenous, circulating acyl ghrelin may be overshadowed by obestatin or blunted by desacyl ghrelin.
    No preview · Article · Mar 2008 · Regulatory Peptides
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    ABSTRACT: Surgical removal of the stomach (gastrectomy, Gx) leads to osteopenia in animals and in humans. In the rat, Gx adversely affects calvaria and trabecular bone. alpha-Ketoglutarate (AKG) is a precursor of hydroxyproline--the most abundant amino acid in bone collagen. The purpose of this study was to investigate the effects of dietary AKG on Gx-induced osteopenia. Twenty female Sprague-Dawley rats were subjected to Gx and divided between two groups: Gx+AKG in the drinking water and Gx+Vehicle (i.e. drinking water without AKG). Another 20 rats were sham-operated and divided between two groups: Sham+AKG and Sham+Vehicle. The daily dose of AKG was 0.43 g per 100 g rat. All the rats were killed 8 weeks later and the calvariae, femora and tibiae were collected. The integrity of the calvariae was analysed planimetrically, following transillumination and photography. The bone mineral content (BMC) and bone mineral density (BMD) were measured in the right femorae and tibiae (bone densitometry), leaving the left femorae and tibiae to be analysed histomorphometrically (measurement of trabecular bone volume and trabecular fractal dimension). Gx caused calvarial bone degradation, reduced trabecular bone (femur and tibia) and impaired trabecular architecture. In addition, Gx lowered the femoral/tibial BMC and BMD (mainly cortical bone). Dietary AKG counteracted the Gx-evoked impairment of calvaria and trabecular bone but failed to affect the BMC and the BMD in either sham- operated or Gx rats. Gx resulted in loss of calvarial, trabecular and cortical bone in the rat. AKG counteracted the effect of Gx on calvaria and trabecular bone but not on cortical bone.
    No preview · Article · Feb 2008 · Scandinavian Journal of Gastroenterology
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    ABSTRACT: Ghrelin is produced by A-like cells (ghrelin cells) in the mucosa of the acid-producing part of the stomach. The mobilization of ghrelin is stimulated by nutritional deficiency and suppressed by nutritional abundance. In an attempt to identify neurotransmitters and regulatory peptides that may contribute to the physiological, nutrient-related regulation of ghrelin secretion, we challenged the ghrelin cells in situ with a wide variety of candidate messengers, including known neurotransmitters (e.g. acetylcholine, catecholamines), candidate neurotransmitters (e.g. neuropeptides), local tissue hormones (e.g. serotonin, histamine, bradykinin, endothelin), circulating gut hormones (e.g. gastrin, CCK, GIP, neurotensin, PYY, secretin) and other circulating hormones/regulatory peptides (e.g. calcitonin, glucagon, insulin, PTH). Microdialysis probes were placed in the submucosa of the acid-producing part of the rat stomach. Three days later, the putative messenger compounds were administered via the microdialysis probe (reverse microdialysis) at a screening dose of 0.1 mmol l(-1) for regulatory peptides and 0.1 and 1 mmol l(-1) for amines and amino acids. The rats were awake during the experiments. The resulting microdialysate ghrelin concentration was monitored continuously for 3 h (radioimmunoassay), thereby revealing stimulators or inhibitors of ghrelin secretion. Dose-response curves were constructed for each candidate messenger that significantly (p<0.05) affected ghrelin mobilization at the screening dose. Peptides that showed a (non-significant) tendency to affect ghrelin release at the screening dose were also given at a dose of 0.3 or 1 mmol l(-1). Adrenaline, noradrenaline, endothelin and secretin stimulated ghrelin release, while somatostatin and GRP inhibited. Whether these agents act directly or indirectly on the ghrelin cells remains to be investigated. All other candidate messengers were without measurable effects, including acetylcholine, serotonin, histamine, GABA, aspartic acid, glutamic acid, glycine, VIP, PACAP, CGRP, substance P, NPY, PYY, PP, gastrin, CCK, GIP, insulin, glucagon, GLP and glucose.
    No preview · Article · Nov 2007 · Regulatory Peptides
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    M Bernsand · R Håkanson · P Norlén
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    ABSTRACT: Rat stomach ECL cells secrete histamine and pancreastatin in response to gastrin and pituitary adenylate cyclase-activating peptide-27 (PACAP). This study applies microdialysis to explore how ECL cells in situ respond to PACAP and gastrin. Both peptides were administered by microinfusion into the gastric submucosa. The microdialysate was analysed for histamine and pancreastatin (ECL-cell markers) and for somatostatin (D-cell marker). Microinfusion of PACAP (0.01-0.3 nmol microl(-1)) raised microdialysate histamine and pancreastatin dose-dependently. The response was powerful but short-lived. The response to gastrin was sustained at all doses tested. It is unlikely that the transient nature of the histamine response to PACAP reflects inadequate histamine synthesis, since the pancreastatin response to PACAP was short-lived too, and both gastrin and PACAP activated ECL-cell histidine decarboxylase. Unlike gastrin, PACAP mobilized somatostatin. Co-infusion of somatostatin abolished the histamine-mobilizing effect of PACAP. However, pretreatment with the somatostatin receptor type-2 antagonist (PRL-2903) did not prolong the histamine response to PACAP, suggesting that mobilization of somatostatin does not explain the transient nature of the response. Repeated administration of 0.1 nmol microl(-1) of PACAP (1 h infusions, 1 h intervals) failed to induce a second histamine response. Pretreatment with a low dose of PACAP (0.03 nmol microl(-1)) abolished the response to a subsequent near-maximal PACAP challenge (0.3 nmol microl(-1)). The transient nature of the histamine response to PACAP reflects desensitization of the PACAP receptor and/or exhaustion of a specific storage compartment that responds to PACAP but not to gastrin.
    Preview · Article · Oct 2007 · British Journal of Pharmacology
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    ABSTRACT: In this study we investigated the effects of gastrectomy (Gx) and of the gastric hormone, ghrelin, on the expression of proteins in brown adipose tissue (BAT) that are thought to be involved in thermogenesis. Heat production in BAT is known to depend upon activation and increased expression of beta3-adrenergic receptors (beta3-AR) and the consequent up-regulation of uncoupling protein 1 (UCP1). Mice were subjected to Gx or sham operation. One week later they started to receive daily subcutaneous injections of either saline or ghrelin (12 nmol) for two or eight weeks. Neither Gx nor ghrelin affected daily food intake. Gx did not lower body weight gain (except during the first post-operative week) but Gx mice responded to eight weeks of ghrelin treatment with a greater body weight increase (37%, p<0.05) than saline-injected Gx mice; sham-operated mice did not respond to ghrelin. Gx resulted in a greatly reduced expression of both UCP1 and beta3-AR mRNA in BAT (50% reduction or more, p<0.01) compared to sham-operated mice. Eight weeks of ghrelin treatment raised the UCP1 as well as the beta3-AR mRNA expression in the Gx mice, whereas two weeks of ghrelin treatment decreased UCP1 and beta3-AR mRNA expression compared to Gx mice receiving saline. In fact, mRNA expression in Gx mice after treatment with ghrelin for eight weeks was similar to that in saline-treated sham-operated mice. Ghrelin did not affect UCP1 and beta3-AR mRNA in sham-operated mice neither two nor eight weeks after the operation. The results suggest 1) that signals from the stomach stimulate BAT UCP1 (and possibly thermogenesis) and 2) that ghrelin may contribute to the control of UCP1 expression.
    No preview · Article · Jul 2007 · Regulatory Peptides
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    ABSTRACT: The ECL cells are histamine-producing endocrine cells in the oxyntic mucosa that synthesize and secrete proteins and peptides. They are the primary target for gastrin and mediate the control of gastrin on acid secretion and oxyntic mucosal growth. Knowledge of the molecular biology of the ECL cell is therefore important for understanding gastric physiology. Accordingly, we wanted to identify genes that are characteristically expressed in the ECL cells and controlled by gastrin. Using Affymetrix GeneChips, RNA expression profiles were generated from ECL cells isolated by counterflow elutriation from hyper- or hypogastrinemic rats. Contamination from non-endocrine cells was eliminated by subtraction of the expression profiles of the fundic and antral mucosa. The expression of 365 genes was ECL cell characteristic. Gastrin was found to control the expression of 120 which could be divided into two major groups depending on the known or anticipated biological function of the encoded protein: genes encoding proteins involved in the secretory process and genes encoding proteins needed to generate energy for secretion. Interestingly, gastrin stimulation also increased ECL cells expression of anti-apoptotic genes. The ECL cell specific expression profile is reminiscent of that of neurons and other endocrine cells exhibiting high expression of genes encoding proteins involved in the synthesis, storage and secretion of neuropeptides or peptide hormones. Gastrin regulated the expression of one third of these genes and is thus involved in the control of secretion from the ECL cells.
    No preview · Article · Jun 2007 · Regulatory Peptides
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    ABSTRACT: Ghrelin is produced by gastric A-like cells and released in response to food deprivation. Interestingly, psychological stress also raises circulating ghrelin levels. This study compared plasma ghrelin levels in Sprague-Dawley (SPD) rats and high-anxiety Wistar Kyoto (WKY) rats. The two strains were also compared with respect to plasma gastrin, a gastric hormone with a pre- and postprandial release pattern opposite to that of ghrelin, and to the activity of the gastrin-dependent, histamine-forming ECL cells in the gastric mucosa. The rats were killed after being freely fed or after an over-night fast. The stomachs were weighed and tissue samples were collected for histological and biochemical analysis. Plasma ghrelin and gastrin levels were determined by RIA. While fasted SPD rats had higher plasma ghrelin levels than fasted WKY rats (P < 0.001), plasma ghrelin did not differ between freely fed rats of the two strains. Gastrin levels were higher in fed WKY rats than in fed SPD rats (P < 0.001). Despite the higher plasma gastrin level, the oxyntic mucosal histidine decarboxylase (HDC) activity (a marker of ECL-cell activity) in fed rats and the mucosal thickness did not differ between the two strains. In a subsequent study, rats were subjected to water-avoidance stress for 60 min, causing plasma gastrin to increase in WKY rats (P < 0.001) but not in SPD rats. In conclusion, high-anxiety WKY rats had lower circulating ghrelin and higher gastrin than SPD rats in both the fasted and fed state, while the ECL-cell activity (HDC activity) was only moderately affected.
    Preview · Article · Jun 2007 · Journal of Endocrinology
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    ABSTRACT: Mice were subjected to gastrectomy (GX) or sham operation (controls). Four to six weeks later the pancreatic islets were isolated and analysed for cAMP or alternatively incubated in a Krebs-Ringer based medium in an effort to study insulin secretion and cAMP accumulation in response to glucose or the adenylate cyclase activator forskolin. Freshly isolated islets from GX mice had higher cAMP content than islets from control mice, a difference that persisted after incubation for 1 h at a glucose concentration of 4 mmol/l. Addition of forskolin to this medium induced much greater cAMP and insulin responses in islets from GX mice than in islets from control mice. In contrast, the insulin response to high glucose (16.7 mmol/l) was much weaker in GX islets than in control islets. Glucose-induced insulin release was associated with a 2-fold rise in the cAMP content in control islets. Surprisingly no rise in cAMP was noted in GX islets incubated at high glucose. Capacitance measurements conducted on isolated insulin cells from GX mice revealed a much lower exocytotic response to a single 500 ms depolarisation (from -70 mV to zero) than in control insulin cells. Addition of cAMP to the cytosol enhanced the exocytotic response in insulin cells from control mice but not from GX mice. The depolarisation-triggered inward Ca(2+) current in insulin cells from GX mice did not differ from that in control mice, and hence the reduced exocytotic response following GX cannot be ascribed to a decreased Ca(2+) influx. Experiments involving a train of ten 500 ms depolarisations revealed that the exocytotic response was prominent in control insulin cells but modest in GX insulin cells. It seems that cAMP is capable of eliciting insulin release from insulin cells of GX mice only when cAMP is generated in a specific microdomain conceivably through the intervention of membrane-associated adenylate cyclases that can be activated by forskolin. The GX-evoked impairment of depolarisation-induced exocytosis and glucose-stimulated insulin release may reflect the lack of a gastric agent that serves to maintain an appropriate insulin response to glucose and an appropriate exocytotic response to depolarisation by raising cAMP in a special glucose-sensitive compartment possibly regulated by a soluble adenylate cyclase.
    No preview · Article · Apr 2007 · Regulatory Peptides

  • No preview · Article · Mar 2007 · Annals of the New York Academy of Sciences

Publication Stats

28k Citations
2,846.86 Total Impact Points


  • 1965-2011
    • Lund University
      • • Department of Surgery
      • • Department of Experimental Medical Science
      • • Department of Clinical Pharmacology
      • • Department of Obstetrics and Gynecology
      Lund, Skåne, Sweden
  • 1978-2010
    • Malmö University
      Malmö, Skåne, Sweden
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 2000-2001
    • Queen's University Belfast
      • Institute of Clinical Sciences
      Béal Feirste, N Ireland, United Kingdom
  • 1996
    • University Hospital Linköping
      Linköping, Östergötland, Sweden
  • 1994
    • Université Bordeaux Montaigne
      Pessac, Aquitaine, France
    • Umeå University
      • Department of Odontology
      Umeå, Västerbotten, Sweden
  • 1989-1994
    • Free University of Brussels
      • Department of Surgery
      Bruxelles, Brussels Capital Region, Belgium
  • 1993
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1990
    • Linköping University
      • Faculty of Health Sciences
      Linköping, Östergötland, Sweden
  • 1984-1990
    • University of Texas at Austin
      • Institute for Biomedical Research
      Austin, Texas, United States
  • 1988
    • University of Cambridge
      • Department of Pharmacology
      Cambridge, England, United Kingdom
  • 1987
    • Karolinska University Hospital
      • Department of Surgery
      Tukholma, Stockholm, Sweden
    • Università degli studi di Parma
      Parma, Emilia-Romagna, Italy
  • 1977-1980
    • Aarhus University
      • Department of Medical Biochemistry
      Aarhus, Central Jutland, Denmark
  • 1975
    • Karolinska Institutet
      Solna, Stockholm, Sweden
  • 1973
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 1969
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1967-1968
    • University of California, Los Angeles
      • • Department of Biological Chemistry
      • • Department of Medicine
      Los Ángeles, California, United States