Role of CRH in the effects of 5-HT-receptor agonists on food intake and metabolic rate

1996 ◽  
Vol 271 (5) ◽  
pp. R1231-R1238 ◽  
Author(s):  
S. Bovetto ◽  
C. Rouillard ◽  
D. Richard
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Metabolic Rate ◽  
Receptor Agonist ◽  
Plasma Corticosterone ◽  
Receptor Agonists ◽  
Ru 24969 ◽  
Fos Protein ◽  
Series Of Experiments

Two series of experiments were conducted to investigate the role of corticotropin-releasing hormone (CRH) in the effects of 5-hydroxytryptamine (5-HT) on energy intake and energy expenditure. The first set of experiments was carried out to confirm the influence of 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists on the activation of the hypothalamic-pituitary-adrenal axis. Plasma corticosterone levels were measured, and a double-immunolabeling procedure was used to determine whether the neuronal activity marker, c-Fos protein (Fos), could be found within brain neurons containing CRH after treatments with 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists. The second series of experiments was conducted to assess the involvement of CRH in the effects of 5-HT on food intake and metabolic rate (VO2). The effects of the 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists on food intake and VO2 were measured in rats treated with the CRH antagonist, alpha-helical CRH-(9-41). In both experiments rats were intraperitoneally injected with either a vehicle (NaCl 0.9%), the 5-HT1A-receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT), the 5-HT1B-receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU-24969), or the 5-HT2A/2C-receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). Fos immunoreactivity was detectable within the CRH-containing neurons of the paraventricular nucleus of the hypothalamus (PVH) after injection of each of the 5-HT-receptor agonists used. The CRH antagonist alpha-helical CRH-(9-41) attenuated the increases in metabolic rate induced by DOI and 8-OH-DPAT. alpha-Helical CRH did not, however, prevent the effects of RU-24969 and DOI on either nocturnal metabolic rate or food intake. The present results provide further evidence for a role of CRH in 5-HT-mediated thermogenic effect, which likely involves the 5-HT2A/2C receptor during the day and the 5-HT1A receptor during the night. Moreover, these results do not support a role for CRH in 5-HT anorectic effects, which likely involves 5-HT1B and 5-HT2A/2C receptors. Finally, the results of this study indicate that the stimulation of CRH-containing neurons located in the PVH does not necessarily predict changes in food intake and energy expenditure.

Functional assessment of the 5-HT 1A-, 1B-, 2A/2C-, and 3-receptor subtypes on food intake and metabolic rate in rats

1995 ◽  
Vol 268 (1) ◽  
pp. R14-R20 ◽  
Author(s):  
S. Bovetto ◽  
D. Richard
Keyword(s):  
Food Intake ◽  
Metabolic Rate ◽  
Receptor Subtypes ◽  
Dark Cycle ◽  
Daily Cycle ◽  
Ru 24969 ◽  
Male Wistar Rats ◽  
Series Of Experiments ◽  
Transient Elevation ◽  
Nocturnal Rise

The 5-hydroxytryptamine (5-HT) agonists (+/-)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), RU-24969, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), and 1-phenylbiguanide were administered to male Wistar rats to assess the respective involvement of the 5-HT 1A-, 1B-, 2A/2C-, and 3-receptor subtypes in the control of food intake and metabolic rate (VO2). Four series of experiments were carried out, each series addressing the effects of four doses (including saline or dose 0) of each of the agonists selected. The drugs were intraperitoneally injected in spontaneously fed animals. Injections were performed during the first 15 min of either the diurnal or the nocturnal phases of the light-dark daily cycle. Food intake and VO2 measurements were carried out over the 12-h periods ensuing after the agonist injections. The two highest doses of the 5-HT1A-receptor agonist 8-OH-DPAT led to a quickly appearing but transient elevation of diurnal VO2. During the night, VO2 was higher when the rats were treated with 8-OH-DPAT than when they were treated with saline. There was no significant effect of 8-OH-DPAT on either diurnal or noctural food intake. The highest dose of RU-24969 induced a significant increase in diurnal VO2, whereas all doses of RU-24969 blunted the nocturnal rise in metabolic rate characteristically observed in rats kept under a daily light-dark cycle. Importantly, RU-24969 induced marked diurnal and nocturnal hypophagia.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Red knots (Calidris canutus islandica) manage body mass with dieting and activity

2020 ◽  
Vol 223 (21) ◽  
pp. jeb231993
Author(s):  
Kimberley J. Mathot ◽  
Eva M. A. Kok ◽  
Piet van den Hout ◽  
Anne Dekinga ◽  
Theunis Piersma
Keyword(s):  
Food Intake ◽  
Metabolic Rate ◽  
Body Mass ◽  
Assimilation Efficiency ◽  
Adaptive Significance ◽  
Fine Scale ◽  
Calidris Canutus ◽  
Predation Danger ◽  
Mitochondrial Efficiency

ABSTRACTMass regulation in birds is well documented. For example, birds can increase body mass in response to lower availability and/or predictability of food and decrease body mass in response to increased predation danger. Birds also demonstrate an ability to maintain body mass across a range of food qualities. Although the adaptive significance of mass regulation has received a great deal of theoretical and empirical attention, the mechanisms by which birds achieve this have not. Several non-exclusive mechanisms could facilitate mass regulation in birds. Birds could regulate body mass by adjusting food intake (dieting), activity, baseline energetic requirements (basal metabolic rate), mitochondrial efficiency or assimilation efficiency. Here, we present the results of two experiments in captive red knots (Calidris canutus islandica) that assess three of these proposed mechanisms: dieting, activity and up- and down-regulation of metabolic rate. In the first experiment, knots were exposed to cues of predation risk that led them to exhibit presumably adaptive mass loss. In the second experiment, knots maintained constant body mass despite being fed alternating high- and low-quality diets. In both experiments, regulation of body mass was achieved through a combination of changes in food intake and activity. Both experiments also provide some evidence for a role of metabolic adjustments. Taken together, these two experiments demonstrate that fine-scale management of body mass in knots is achieved through multiple mechanisms acting simultaneously.

scholarly journals The role of RFamide peptides in feeding

2007 ◽  
Vol 192 (1) ◽  
pp. 3-15 ◽  
Author(s):  
David A Bechtold ◽  
Simon M Luckman
Keyword(s):  
Biological Activity ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Feeding Behaviour ◽  
Animal Kingdom ◽  
Primary Function

In the three decades since FMRFamide was isolated from the clam Macrocallista nimbosa, the list of RFamide peptides has been steadily growing. These peptides occur widely across the animal kingdom, including five groups of RFamide peptides identified in mammals. Although there is tremendous diversity in structure and biological activity in the RFamides, the involvement of these peptides in the regulation of energy balance and feeding behaviour appears consistently through evolution. Even so, questions remain as to whether feeding-related actions represent a primary function of the RFamides, especially within mammals. However, as we will discuss here, the study of RFamide function is rapidly expanding and with it so is our understanding of how these peptides can influence food intake directly as well as related aspects of feeding behaviour and energy expenditure.

scholarly journals STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons

2021 ◽  
Author(s):  
Gabriel Henrique Marques Gonçalves ◽  
Sabrina Mara Tristão ◽  
Rafaella Eduarda Volpi ◽  
Gislaine Almeida-Pereira ◽  
Beatriz de Carvalho Borges ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Specific Pattern ◽  
Conditional Knockout ◽  
Steroidogenic Factor 1 ◽  
Diet Induced Obesity ◽  
Affect Body Weight

Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH on energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure and glucose homeostasis in animals on regular chow. However, when challenged with high-fat diet (HFD), loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake and energy efficiency that was more remarkable in females which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role to protect against DIO in a sex-specific pattern.

scholarly journals The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

2021 ◽  
Author(s):  
◽  
Dane Aronsen
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Drugs Of Abuse ◽  
Receptor Activation ◽  
Self Administration ◽  
Response Curves ◽  
Ru 24969 ◽  
Gr 127935 ◽  
Way 100635

<p>Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse.   Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed.  Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed.   Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors.   Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.</p>

scholarly journals The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

2021 ◽  
Author(s):  
◽  
Dane Aronsen
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Drugs Of Abuse ◽  
Receptor Activation ◽  
Self Administration ◽  
Response Curves ◽  
Ru 24969 ◽  
Gr 127935 ◽  
Way 100635

<p>Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse.   Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed.  Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed.   Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors.   Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.</p>

scholarly journals The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide

2012 ◽  
Vol 62 (5-6) ◽  
pp. 1916-1927 ◽  
Author(s):  
Scott E. Kanoski ◽  
Laura E. Rupprecht ◽  
Samantha M. Fortin ◽  
Bart C. De Jonghe ◽  
Matthew R. Hayes
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Receptor Agonists ◽  
Weight Suppression

Abstract P249: ICV Infusion Of AgRP Modulates Feeding Behavior And Energy Expenditure In Mice

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Vanessa Oliveira ◽  
Kirthikaa Balapattabi ◽  
John J Reho ◽  
Sebastiao D Silva ◽  
Chetan N Patil ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Feeding Behavior ◽  
Body Mass ◽  
High Dose ◽  
Digestive Efficiency ◽  
Genetic Ablation ◽  
Total Food Intake ◽  
Intracerebroventricular Infusion

A subset of Agouti-related protein (AgRP) neurons within the arcuate nucleus express angiotensin type 1a receptors (AT1A), and genetic ablation of AT1A in these cells disinhibits AgRP gene expression and attenuates energy expenditure (EE) in mice. To further understand the role of AgRP in metabolic control, and to establish relevant dosing schedules in this species, here we tested the effect of intracerebroventricular infusion (icv) of recombinant AgRP on metabolic functions in C57BL/6J male mice. First, we examined the effects of AgRP(82-132) (21 days, 1 or 10 nmol/d, icv) or artificial cerebrospinal fluid (aCSF) using metabolic cages. High dose AgRP reduced body mass (aCSF n=12, +0.8±0.6 vs 1 nmol/d n=14, +0.6±0.6 vs 10 nmol/d n=11, -1.5±0.5 p<0.05 g/21d), without affecting food intake (15.1±1.2 vs 14.1±1.1 vs 16.3±1.1 kcal/d) or digestive efficiency (85.2±0.5 vs 84.5±0.7 vs 85.1±0.6 %), but a significant reduction in energy efficiency (+3.8±2.0 vs +2.7±2.8 vs -5.9±2.2 p<0.05 mg/kcal) indicated increased total EE. Next, we examined the effect of AgRP(82-132) (14 days, 1 nmol/d, icv) using a multiplexed system (Promethion, Sable). AgRP had no effect on body mass (25.1±1.2, n=8 vs 26.7±0.5, n=8), overall body composition (by NMR), heat production (Weir, 24h: 0.485±0.015 vs 0.490±0.022 kcal/h), or respiratory exchange ratio (0.88±0.01 vs 0.89±0.01). AgRP increased total food intake (10.1±0.6, n=8 vs 11.9±0.5, n=8, kcal/d, p=0.03) through a synergistic effect on number of meals and median meal mass. We conclude that AgRP (1-10 nmol/d, 2-3 wk, icv) infusion causes subtle changes in feeding behavior without effect on digestive efficiency. In contrast, EE is paradoxically increased by AgRP when infused at a high dose (10 nmol/d). We postulate that these differences may reflect differential accessibility of the peptide to relevant feeding vs autonomic control regions of the hypothalamus when infused into the cerebral ventricles, and/or compensatory increases in EE secondary to changes in feeding behavior. Future studies to deconvolute the role of AgRP in the control of EE in mice will require site-specific delivery of the peptide to relevant target regions or manipulation of its receptor in those regions. Funding: HL134850, HL084207

Insulin and metabolic efficiency in rats. II. Effects of NE and cold exposure

1986 ◽  
Vol 251 (6) ◽  
pp. R1118-R1125
Author(s):  
T. J. Bartness ◽  
C. J. Billington ◽  
A. S. Levine ◽  
J. E. Morley ◽  
N. E. Rowland ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Food Intake ◽  
Energy Expenditure ◽  
Cold Exposure ◽  
Diabetic Rats ◽  
Metabolic Efficiency ◽  
Maximal Energy ◽  
Brown Adipose

The role of insulin in metabolic efficiency (ME, i.e., efficiency of body wt gain) was examined under conditions of maximal energy expenditure in control and diabetic rats. Long-lasting insulin was administered using a protocol that did not affect food intake and increased ME in both groups. Half the animals were injected chronically with norepinephrine (NE). NE alone in controls decreased body weight and ME and increased brown adipose tissue (BAT) growth, thermogenic potential [cytochrome c oxidase activity (COA)], and lipoprotein lipases (LPL) activity; however, in diabetics, body weight, ME, and food intake all decreased and only BAT LPL activity and DNA content increased. The combination of NE and insulin increased BAT protein and COA in diabetics; in controls, all BAT measures were further increased and ME was intermediate to that of either treatment alone. Cold exposure decreased body weight and ME, increased food intake and qualitatively produced similar increases in BAT growth, COA, and LPL activity in both controls and diabetics. In diabetics, combined cold exposure and insulin did not affect the increase in BAT growth or LPL activity resulting from either treatment alone, but in controls this combination decreased BAT growth and COA. It is concluded that, even under conditions of maximal energy expenditure, both extremes of basal insulin status result in decreased BAT growth and thermogenic potential, but have opposite effects on ME.

scholarly journals Activation of the NPY Y5 receptor regulates both feeding and energy expenditure

1999 ◽  
Vol 277 (5) ◽  
pp. R1428-R1434 ◽  
Author(s):  
Joyce J. Hwa ◽  
Melanie B. Witten ◽  
Patricia Williams ◽  
Lorraine Ghibaudi ◽  
Jun Gao ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Interscapular Brown Adipose Tissue ◽  
Peptide Analogs ◽  
Brown Adipose ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Intracerebroventricular (ICV) administration of neuropeptide Y (NPY) has been shown to decrease energy expenditure, induce hypothermia, and stimulate food intake. Recent evidence has suggested that the Y5 receptor may be a significant mediator of NPY-stimulated feeding. The present study attempts to further characterize the role of NPY Y5-receptor subtypes in feeding and energy expenditure regulation. Satiated Long-Evans rats with temperature transponders implanted in the interscapular brown adipose tissue (BAT) displayed a dose-dependent decrease in BAT temperature and an increase in food intake after ICV infusion of NPY. Similar effects were induced by ICV administration of peptide analogs of NPY that activate the Y5 receptor, but not by analogs that activate Y1, Y2, or Y4 receptors. Furthermore, ICV infusion of the Y5 selective agonistd-[Trp32]-NPY significantly reduced oxygen consumption and energy expenditure of rats as measured by indirect calorimetry. These data suggest that the NPY Y5-receptor subtype not only mediates the feeding response of NPY but also contributes to brown fat temperature and energy expenditure regulation.

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