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Cited by 102Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesNeurotransmitter Receptor Influence on Behavior

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Sex and estrogens alter the action of glucagon-like peptide-1 on reward

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Richard, Jennifer E., Anderberg, Rozita H., López-Ferreras, Lorena, Olandersson, Kajsa, Skibicka, Karolina P.·2016·Biology of Sex Differences
DOI 10.1186/s13293-016-0059-9PMC PMC4715328
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Abstract

BACKGROUND: Feeding behavior is regulated through an intricate array of anorexic and orexigenic hormones acting on the central nervous system (CNS). Some of these hormones may have differential effects in males and females, effects potentially attributed to actions of gonadal steroids, especially estrogens. Central stimulation of the glucagon-like peptide-1 (GLP-1) receptors reduces feeding and food-reward behavior by acting on CNS regions important for the anorexic actions of estrogens. Thus, we propose that the action of GLP-1 on food intake and reward may differ between sexes. METHODS: Male and female rats were centrally injected with the GLP-1 analog exendin-4 (Ex4) in a non-deprived or food-restricted state; reward behavior was measured in a progressive ratio operant conditioning task. Intake of chow and palatable food were also measured. To determine if sex differences in the actions of Ex4 are due to interactions with estrogens, Ex4 treatment was preceded by treatment with a nonselective estrogen receptor-α (ERα) and ERβ or ERα-selective antagonist. RESULTS: Central injection of Ex4 revealed increased reward behavior suppression in females, compared to males, in the operant conditioning task. This increase was present in both non-deprived and food-restricted animals with larger differences in the fed state. Intake of chow and palatable food, after Ex4, were similar in males and females. Food reward, but not food intake, effect of Ex4 was attenuated by pretreatment with ER antagonist in both sexes, suggesting that estrogens may modulate effects of Ex4 in both sexes. Furthermore, central pretreatment with ERα-selective antagonist was sufficient to attenuate effects of Ex4 on reward. CONCLUSIONS: Collectively, these data reveal that females display much higher sensitivity to the food reward impact of central GLP-1 receptor activation. Surprisingly, they also demonstrate that central ERα signaling is necessary for the actions of GLP-1 on food-reward behavior in both sexes.

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Fig. 1 In non-deprived animals, central GLP-1R stimulation specifically decreases food-motivated behavior in females but not males. Ex4 injection into the LV significantly reduced sucrose rewards earned (a), and active lever presses for reward (c) in female but not male subjects. Sucrose rewards (b) and active lever presses (d) were also significantly lower in females compared to males after Ex4 treatment, at both doses, analyzed as percent relative to vehicle value. Central GLP-1R agonist treatment significantly reduced peanut butter consumption in both males and females (e), with no significant differences between the two sexes (f). Chow consumption was reduced in males and females after Ex4 treatment (g); no significant differences were present between sexes at either dose of the agonist (h). Chow and peanut butter consumption are displayed in grams. Data are expressed as mean ± SEM. n = 20 (females) and 18 (males) per treatment group. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001
Fig. 1 In non-deprived animals, central GLP-1R stimulation specifically decreases food-motivated behavior in females but not males. Ex4 injection into the LV significantly reduced sucrose rewards earned (a), and active lever presses for reward (c) in female but not male subjects. Sucrose rewards (b) and active lever presses (d) were also significantly lower in females compared to males after Ex4 treatment, at both doses, analyzed as percent relative to vehicle value. Central GLP-1R agonist treatment significantly reduced peanut butter consumption in both males and females (e), with no significant differences between the two sexes (f). Chow consumption was reduced in males and females after Ex4 treatment (g); no significant differences were present between sexes at either dose of the agonist (h). Chow and peanut butter consumption are displayed in grams. Data are expressed as mean ± SEM. n = 20 (females) and 18 (males) per treatment group. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001CC BY · PubMed Central
Fig. 2 Ex4 treatment in overnight food-restricted rats leads to a larger reduction in food-motivated behavior in females than males. After overnight food restriction, central Ex4 treatment reduced sucrose rewards earned in both males and females (a), an effect that was larger in females (b). Active lever presses were significantly reduced by Ex4 treatment in female subjects; a trend for reduction was present in male subjects but it did not reach statistical significance (c). Lever presses after Ex4 treatment in males and females analyzed as percent of vehicle treatment also revealed a significantly larger reduction in female subjects (d). Peanut butter consumption was significantly reduced in both sexes (e) with a slightly larger response to Ex4 in females (f). Twenty-four hour chow consumption was reduced in both males and females after GLP-1R agonist injection (g); no significant differences were found in chow intake between the two sexes (h). Chow and peanut butter consumption are displayed in grams. Data are expressed as mean ± SEM. n = 10 (females) and 9 (males) per treatment group. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001
Fig. 2 Ex4 treatment in overnight food-restricted rats leads to a larger reduction in food-motivated behavior in females than males. After overnight food restriction, central Ex4 treatment reduced sucrose rewards earned in both males and females (a), an effect that was larger in females (b). Active lever presses were significantly reduced by Ex4 treatment in female subjects; a trend for reduction was present in male subjects but it did not reach statistical significance (c). Lever presses after Ex4 treatment in males and females analyzed as percent of vehicle treatment also revealed a significantly larger reduction in female subjects (d). Peanut butter consumption was significantly reduced in both sexes (e) with a slightly larger response to Ex4 in females (f). Twenty-four hour chow consumption was reduced in both males and females after GLP-1R agonist injection (g); no significant differences were found in chow intake between the two sexes (h). Chow and peanut butter consumption are displayed in grams. Data are expressed as mean ± SEM. n = 10 (females) and 9 (males) per treatment group. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001CC BY · PubMed Central
Fig. 3 Central estrogen blockade attenuates the effects of Ex4 on food-motivated behavior. Concurrent administration of the selective estrogen antagonist ICI and Ex4 attenuated the reduction in sucrose rewards earned in females (c) and males (a) compared to Ex4 treatment alone, although this effect did not reach significance. Reduction of active lever presses for sucrose was also attenuated in both sexes after ICI treatment (b, d). The number of sucrose rewards earned for males and females combined was reduced after central Ex4 injection (e); this effect was attenuated after ICI treatment. Combined results for males and females also demonstrate a significant reduction in lever presses for sucrose after central GLP-1R stimulation; attenuation by the ICI treatment did not reach statistical significance (f). Data are expressed as mean ± SEM. n = 10 (females) and 18 (males) per treatment group. *p < 0.05, **p < 0.01, ****p < 0.0001
Fig. 3 Central estrogen blockade attenuates the effects of Ex4 on food-motivated behavior. Concurrent administration of the selective estrogen antagonist ICI and Ex4 attenuated the reduction in sucrose rewards earned in females (c) and males (a) compared to Ex4 treatment alone, although this effect did not reach significance. Reduction of active lever presses for sucrose was also attenuated in both sexes after ICI treatment (b, d). The number of sucrose rewards earned for males and females combined was reduced after central Ex4 injection (e); this effect was attenuated after ICI treatment. Combined results for males and females also demonstrate a significant reduction in lever presses for sucrose after central GLP-1R stimulation; attenuation by the ICI treatment did not reach statistical significance (f). Data are expressed as mean ± SEM. n = 10 (females) and 18 (males) per treatment group. *p < 0.05, **p < 0.01, ****p < 0.0001CC BY · PubMed Central
Fig. 4 Effect of central estrogen blockade on the actions of Ex4 on peanut butter consumption or chow intake is not divergent between the sexes. No significant changes in peanut butter consumption were observed in males (a), but a significant reduction in consumption was noted in females after injection of Ex4 or Ex4 and ICI (c). Ex4 reduced chow intake in both males and females (b, d). This reduction was attenuated by simultaneous ICI treatment only in females. Chow and peanut butter consumption are displayed in grams. Data are expressed as mean ± SEM. n = 10 (females) and 9 (males) per treatment group for peanut butter measurement and n = 10 (females) and 18 (males) per treatment group for chow intake. *p < 0.05, ***p < 0.001
Fig. 4 Effect of central estrogen blockade on the actions of Ex4 on peanut butter consumption or chow intake is not divergent between the sexes. No significant changes in peanut butter consumption were observed in males (a), but a significant reduction in consumption was noted in females after injection of Ex4 or Ex4 and ICI (c). Ex4 reduced chow intake in both males and females (b, d). This reduction was attenuated by simultaneous ICI treatment only in females. Chow and peanut butter consumption are displayed in grams. Data are expressed as mean ± SEM. n = 10 (females) and 9 (males) per treatment group for peanut butter measurement and n = 10 (females) and 18 (males) per treatment group for chow intake. *p < 0.05, ***p < 0.001CC BY · PubMed Central
Fig. 5 Central injection of the ERα-antagonist MPPd attenuated the effects of Ex4 on food-motivated behavior. As expected, central administration of Ex4 led to a reduction in sucrose rewards earned in females (c) and males (a). Ex4 no longer significantly reduced sucrose rewards earned after administration of the specific ERα-antagonist MPPd. Additionally, Ex4 treatment reduced lever presses for sucrose earned in females (d) and produced a trend for reduction in males (b), an effect which was also attenuated by co-treatment with MPPd. Compilation of female and male data revealed a significant reduction in sucrose rewards earned (e) and active lever presses (f) after EX4 treatment that was attenuated after combined MPP/Ex4 treatment. Data are expressed as mean ± SEM. n = 7–9 for males and females. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001
Fig. 5 Central injection of the ERα-antagonist MPPd attenuated the effects of Ex4 on food-motivated behavior. As expected, central administration of Ex4 led to a reduction in sucrose rewards earned in females (c) and males (a). Ex4 no longer significantly reduced sucrose rewards earned after administration of the specific ERα-antagonist MPPd. Additionally, Ex4 treatment reduced lever presses for sucrose earned in females (d) and produced a trend for reduction in males (b), an effect which was also attenuated by co-treatment with MPPd. Compilation of female and male data revealed a significant reduction in sucrose rewards earned (e) and active lever presses (f) after EX4 treatment that was attenuated after combined MPP/Ex4 treatment. Data are expressed as mean ± SEM. n = 7–9 for males and females. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001CC BY · PubMed Central
Fig. 6 MPPd treatment did not attenuate the effects of central Ex4 treatment on food intake. Central injection with the GLP-1R agonist Ex4 significantly reduced peanut butter intake and chow intake in males (a, b) and females (c, d). The reduction was still present after treatment with the ERα-antagonist MPPd. Chow and peanut butter consumption are displayed in grams. Data are expressed as mean ± SEM. n = 7–9 for males and females. **p < 0.01, ***p < 0.001
Fig. 6 MPPd treatment did not attenuate the effects of central Ex4 treatment on food intake. Central injection with the GLP-1R agonist Ex4 significantly reduced peanut butter intake and chow intake in males (a, b) and females (c, d). The reduction was still present after treatment with the ERα-antagonist MPPd. Chow and peanut butter consumption are displayed in grams. Data are expressed as mean ± SEM. n = 7–9 for males and females. **p < 0.01, ***p < 0.001CC BY · PubMed Central

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  1. Shirazi RH, Dickson SL, Skibicka KP. Gut peptide GLP-1 and its analogue, exendin-4, decrease alcohol intake and reward. Plos One. 2013;8(4). doi: 10.1371/journal.pone.0061965 . · DOI

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Metadata

Authors
Richard, J. E., Anderberg, R. H., López-Ferreras, L., Olandersson, K., & Skibicka, K. P.
Affiliations
University of Gothenburg (SE)
Corresponding author
Skibicka, Karolina P.
ORCID
Venue
Biology of Sex Differences
Publisher
Springer Science and Business Media LLC
Published
2016-01-16
Volume
7
Issue
1
Pages
6-6
ISSN
2042-6410 (ISSN-L)
DOI
10.1186/s13293-016-0059-9
PMC
PMC4715328
OpenAlex
W2272001501
Cited by
102
References
82
Citations by year
2026: 21 · 2025: 19 · 2024: 11 · 2023: 8 · 2022: 14 · 2021: 8 · 2020: 5 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 2
FWCI
3.39
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Biology of Sex Differences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Svenska Forskningsrådet Formas (2014-2945 and 2013-7107)
  • Novo Nordisk Foundation Excellence project grant
  • Ragnar Söderberg Foundation
  • Harald Jeanssons Stiftelse
  • Greta Jeanssons Stiftelse
  • Magnus Bergvalls Stiftelse
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
glucagon-like peptide-1, exendin-4, food reward, sex differences, estrogen receptor alpha, estrogen receptor beta, sex steroids, feeding behavior, dietary intake, palatable food, dietary restriction

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