umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Allopregnanolone effects on food intake and weight gain
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (Umeå Neurosteroid Research Center)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Obesity is currently one of the major causes of ill health and it is clear that overeatingis the cause of obesity. However, the actions of many endogenous factors that contribute to overeating are still not well understood. Gamma-aminobutyric acid (GABA)-ergic transmission has been shown to be of great importance for food intake regulation. The progesterone metabolite allopregnanolone is a potent positive GABAA receptor modulating steroid (GAMS) and in humans, elevated allopregnanolone levels have been suggested to be involved in increased food intake, and also with overweight and obesity. GABAA receptors that express the α2 and α3 subunits are proposed to be the main subtypes involved in food intake regulation. Therefore, the aims of the work in this thesis were to further investigate the effect of allopregnanolone on food intake, feeding behaviour, possible effects on weight gain and also to characterize a possible antagonist at α2β3γ2and α3β3γ2 GABAA receptors.

Methods Allopregnanolone effects on food intake of different food items were recorded in male Wistar rats. Feeding patterns were analyzed. Food preference tests were also conducted and rats were repeatedly exposed to allopregnanolone under different feeding conditions to elucidate possible effects on body weight gain. To deeper investigate GABAA receptor subtypes suggested to be involved in food intake regulation, electrophysiological whole-cell patch-clamp recordings were performed to identify the specificity of the GAMS antagonist UC1020, at human α2β3γ2 and α3β3γ2 GABAA receptors expressed in HEK293-cells.

Results Allopregnanolone increased the intake of standard chow, cookies and a high fat diet in male Wistar rats. Preferentially, allopregnanolone increased the rats´intake of the more calorie dense food type. Allopregnanolone reduced feeding latency and prolonged feeding duration. The increased chow intake induced by allopregnanolone was more pronounced at the beginning of the rats´ active period compared to the inactive. Repeated allopregnanolone administration during 5 consecutive days led to an increased body weight gain, more evident in schedule fed rats on a high fat diet. Both obesity prone and obesity resistant rats gained significantly more weight with repeated allopregnanolone exposure and the increased body weight gain correlated with increased food intake. The compound UC1020 was a potent antagonist of GAMS-enhanced GABA evoked currents at human α3β3γ2 GABAA receptors, whereas it had no effect at α2β3γ2 GABAA receptors.

Conclusions Our findings indicate that allopregnanolone induced hyperphagia may be one of the endogenous factors involved in weight gain, especially when the diet is energy-rich. The compound UC1020 may prove useful for investigating the involvement of the α2 and α3 GABAA receptor subtypes in GAMS-induced hyperphagia.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2015. , 88 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1711
Keyword [en]
allopregnanolone, neurosteroid, GABA, GABAA receptor, food intake, weight gain, obesity, hyperphagia, diurnal rhythm, schedule feeding, high fat diet, electrophysiology
National Category
Neurosciences Physiology Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:umu:diva-101806ISBN: 978-91-7601-253-6 (print)OAI: oai:DiVA.org:umu-101806DiVA: diva2:805045
Public defence
2015-05-13, Hörsal Betula, Norrlands universitetssjukhus, Umeå universitet, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Research Council, 4x-11198
Available from: 2015-04-22 Created: 2015-04-13 Last updated: 2015-05-04Bibliographically approved
List of papers
1. Allopregnanolone induces a diurnally dependent hyperphagic effect and alters feeding latency and duration in male Wistar rats
Open this publication in new window or tab >>Allopregnanolone induces a diurnally dependent hyperphagic effect and alters feeding latency and duration in male Wistar rats
Show others...
2013 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 208, no 4, 400-409 p.Article in journal (Refereed) Published
Abstract [en]

Aim: Gamma-aminobutyric acid (GABA)-ergic transmission from the hypothalamus is essential for normal feeding regulation, and hyperphagia can be induced by local application of GABA(A)-receptor agonists to different feeding-associated brain areas. The food intake in rats varies diurnally and that may influence the effect of GABA(A)-receptor active compounds. The progesterone metabolite allopregnanolone is a highly potent endogenous positive modulator of the GABA(A) receptor. Therefore, it is easy to envisage that allopregnanolone would have a hyperphagic effect, but earlier reports in rat have given ambiguous results. However, a contributing factor for the discrepancy may be the time point of the diurnal cycle in which the experiments were performed. The aim of this study was to investigate the effect of allopregnanolone on intake of standard chow in male Wistar rats at different time points of the day.

Methods: Chow intake was measured after acute administration of allopregnanolone, and feeding behaviour was analysed to detect meal patterns.

Results: We found that allopregnanolone increased chow intake by up to four times in the dark part of the 24-h cycle. The rats ate significantly more, and the effect of allopregnanolone was more prominent in the active (dark) compared with the inactive (light) period. Allopregnanolone also reduced feeding latency and prolonged the meal duration compared with vehicle.

Conclusion: Allopregnanolone seems to act at several levels of feeding regulation, that is, to initiate feeding and to prolong the duration of a meal, thereby increasing the meal size, especially in the dark period of the 24-h cycle.

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
Keyword
allopregnanolone, diurnal rhythm, food intake, Gamma-aminobutyric acid, hyperphagia, neurosteroids
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-79224 (URN)10.1111/apha.12100 (DOI)000321695000013 ()
Available from: 2013-09-16 Created: 2013-08-13 Last updated: 2017-12-06Bibliographically approved
2. Allopregnanolone preferentially induces energy-rich food intake in male Wistar rats
Open this publication in new window or tab >>Allopregnanolone preferentially induces energy-rich food intake in male Wistar rats
2014 (English)In: Physiological Reports, E-ISSN 2051-817X, Vol. 2, no 12, e12190- p.Article in journal (Refereed) Published
Abstract [en]

Obesity is an increasing problem and identification of the driving forces for overeating of energy-rich food is important. Previous studies show that the stress and sex steroid allopregnanolone has a hyperphagic effect on both bland food and palatable food. If allopregnanolone induces a preference for more palatable or for more energy-rich food is not known. The aim of this study  was to elucidate the influence of allopregnanolone on food preference. Male Wistar rats were subjected to two different food preference tests: a choice between standard chow and cookies (which have a higher energy content and also are more palatable than chow), and a choice between a low caloric sucrose solution and standard chow (which has a higher energy content and is less palatable than sucrose). Food intake was measured for 1 h after acute subcutaneous injections of allopregnanolone. In the choice between cookies and chow allopregnanolone significantly increased only the intake of cookies.When the standard chow was the item present with the highest caloric load, the chow intake was increased and allopregnanolone had no effect on intake of the 10% sucrose solution. The increased energy intakes induced by the high allopregnanolone dose compared to vehicle were very similar in the two tests,120% increase for cookies and 150% increase for chow. It appears that in allopregnanolone-induced hyperphagia, rats choose the food with the highest energy content regardless of its palatability.

Place, publisher, year, edition, pages
Wiley Periodicals Inc., 2014
Keyword
Allopregnanolone, energy need, food intake, neurosteroids GABA
National Category
Neurosciences Physiology
Identifiers
urn:nbn:se:umu:diva-101791 (URN)10.14814/12190 (DOI)
Available from: 2015-04-13 Created: 2015-04-13 Last updated: 2017-12-04Bibliographically approved
3. Repeated allopregnanolone exposure induces weight gain in schedule fed rats on high fat diet
Open this publication in new window or tab >>Repeated allopregnanolone exposure induces weight gain in schedule fed rats on high fat diet
Show others...
2015 (English)In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 140, 1-7 p.Article in journal (Refereed) Published
Abstract [en]

Ingestion of energy rich high fat diets is one of the determining factors associated with the obesity epidemic. Therefore, much can be learned from studies of obesity-related substances given to animals fed a high fat diet.The progesterone metabolite allopregnanolone is a potent positive modulator of the gamma-aminobutyric acid(GABA)A-receptor, and both allopregnanolone and GABA have been implicated in evoking hyperphagia. In this study, food intake and body weight gain were investigated during repeated allopregnanolone exposure. Male Wistar rats were studied when fed chow ad libitum, with chow access for 4h per day or with 45% high fat pellets for 4 h per day. Rats on the high fat diet were separated into obesity prone and obesity resistant individuals.Subcutaneous injections of allopregnanolone were given once daily overfive consecutive days. Repeated exposure to allopregnanolone lead to increased weight gain, significantly so in schedule fed rats on a high fat diet. The increased weight gain was correlated to an increased energy intake. Both obesity resistant and obesityprone rats responded to allopregnanolone with increased weight gain. Obesity resistant rats treated with allopregnanolone increased their energy intake and ate as much as vehicle treated obesity prone rats. Their weight gain was also increased to the level of obesity prone rats injected with just the vehicle carrier oil. Thus, it appears that allopregnanolone may be one of the endogenous factors involved in weight gain, especiallywhen the diet is rich in fat.

Place, publisher, year, edition, pages
Elsevier, 2015
Keyword
Allopregnanolone Neurosteroid Weight gain Food intake Scheduled feeding High fat diet
National Category
Neurosciences Physiology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-101793 (URN)10.1016/j.physbeh.2014.12.012 (DOI)000349588400001 ()
Available from: 2015-04-13 Created: 2015-04-13 Last updated: 2017-12-04Bibliographically approved
4. Subunit specific antagonism of allopregnanolone potentiation at GABAA receptor types suggested being involved in feeding
Open this publication in new window or tab >>Subunit specific antagonism of allopregnanolone potentiation at GABAA receptor types suggested being involved in feeding
Show others...
(English)Manuscript (preprint) (Other academic)
Keyword
allopregnanolone, food intake, gamma-aminobutyricacid, neuroactive steroids, HEK-293, electrophysiology
National Category
Neurosciences Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-101805 (URN)
Available from: 2015-04-13 Created: 2015-04-13 Last updated: 2015-04-16Bibliographically approved

Open Access in DiVA

Avhandling(1097 kB)1345 downloads
File information
File name FULLTEXT03.pdfFile size 1097 kBChecksum SHA-512
7125e68de31445d16bf4250f39bc1e7e5e8cd69f3341e0af0593a78fc6662d028801fe9d7bc4f992f18452178453e38b4cefd09c8c1cdb7455678a26fbccc409
Type fulltextMimetype application/pdf
Spikblad(99 kB)143 downloads
File information
File name FULLTEXT02.pdfFile size 99 kBChecksum SHA-512
d7e9a355d995a68d2e707cfd5be30933aa4f901ef14bb8984367211c5acfa00286153f136e595902cc356d36bf1d306f9d2ca55ae31aa3f8a8e24ebe35d88590
Type fulltextMimetype application/pdf
Omslag avhandling(121 kB)66 downloads
File information
File name FULLTEXT01.pdfFile size 121 kBChecksum SHA-512
73061aa51a6bebf6618af433069f6d807d6241493757d6419e08785c20dd1c58831c9cea253d9e753e6e40917d2f555bafda702fffef674be07911ca7f2b032b
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Holmberg, Ellinor
By organisation
Obstetrics and Gynaecology
NeurosciencesPhysiologyObstetrics, Gynecology and Reproductive Medicine

Search outside of DiVA

GoogleGoogle Scholar
Total: 1554 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1256 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf