Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus

Tracy L. Breen; Irene M. Conwell; Sharon L. Wardlaw

doi:10.1016/j.brainres.2004.11.008

Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus

Tracy L. Breen, Irene M. Conwell, Sharon L. Wardlaw

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

Abstract

Agouti-related protein (AGRP) and proopiomelanocortin (POMC) have opposing effects on melanocortin receptor (MC-R) signaling and energy balance, and are important targets for leptin and insulin in the hypothalamus. While food intake and leptin have documented effects on POMC and AGRP gene expression, and insulin has effects on POMC gene expression, little is known about their effects on POMC or AGRP peptide release. Here we have examined the effects of fasting, leptin, and insulin on the release of AGRP and the POMC-derived peptide γ₃-MSH from the perifused rat hypothalamus in vitro. In the first experiment, fasting (48 h) resulted in a significant overall decrease in γ₃-MSH release measured every 20 min during a 3-h baseline perifusion period and after depolarization with 56 mM KCl (p = 0.02); there was a trend towards an overall increase in the release of AGRP but this was not significant. When the ratio of γ₃-MSH/AGRP release was calculated at each time point, there was an overall decrease in γ₃-MSH/AGRP with fasting (p < 0.01). Further examination of the ratio of γ₃-MSH/AGRP revealed a 34% reduction (p < 0.05) in the basal area under the curve (AUC) and a 33% reduction (p < 0.01) in the post-KCl stimulated AUC in fasted vs. fed animals. In the second experiment, perifusion of hypothalamic slices with 10^-8 or 10^-7 M leptin for 2 h resulted in a significant decrease in the release of AGRP noted primarily after depolarization with KCl (p < 0.01); no effect was seen on γ₃-MSH release. Similarly, in a third experiment, perifusion with 10^-7 M insulin caused a significant decrease in AGRP release (p < 0.001) without affecting γ₃-MSH release. Thus, there is a significant decrease in γ₃-MSH and the ratio of γ₃-MSH to AGRP released during fasting, consistent with a net inhibition of hypothalamic MC-R signaling. In contrast, short-term treatment with leptin and insulin may inhibit MC-R signaling primarily by decreasing the release of AGRP.

Original language	English
Pages (from-to)	141-148
Number of pages	8
Journal	Brain Research
Volume	1032
Issue number	1-2
DOIs	https://doi.org/10.1016/j.brainres.2004.11.008
State	Published - 25 Jan 2005
Externally published	Yes

Keywords

AGRP
Insulin
Leptin
MSH
POMC

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10.1016/j.brainres.2004.11.008

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@article{8d1b7f50021447f3b1c99b542664b646,

title = "Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus",

abstract = "Agouti-related protein (AGRP) and proopiomelanocortin (POMC) have opposing effects on melanocortin receptor (MC-R) signaling and energy balance, and are important targets for leptin and insulin in the hypothalamus. While food intake and leptin have documented effects on POMC and AGRP gene expression, and insulin has effects on POMC gene expression, little is known about their effects on POMC or AGRP peptide release. Here we have examined the effects of fasting, leptin, and insulin on the release of AGRP and the POMC-derived peptide γ3-MSH from the perifused rat hypothalamus in vitro. In the first experiment, fasting (48 h) resulted in a significant overall decrease in γ3-MSH release measured every 20 min during a 3-h baseline perifusion period and after depolarization with 56 mM KCl (p = 0.02); there was a trend towards an overall increase in the release of AGRP but this was not significant. When the ratio of γ3-MSH/AGRP release was calculated at each time point, there was an overall decrease in γ3-MSH/AGRP with fasting (p < 0.01). Further examination of the ratio of γ3-MSH/AGRP revealed a 34% reduction (p < 0.05) in the basal area under the curve (AUC) and a 33% reduction (p < 0.01) in the post-KCl stimulated AUC in fasted vs. fed animals. In the second experiment, perifusion of hypothalamic slices with 10-8 or 10-7 M leptin for 2 h resulted in a significant decrease in the release of AGRP noted primarily after depolarization with KCl (p < 0.01); no effect was seen on γ3-MSH release. Similarly, in a third experiment, perifusion with 10-7 M insulin caused a significant decrease in AGRP release (p < 0.001) without affecting γ3-MSH release. Thus, there is a significant decrease in γ3-MSH and the ratio of γ3-MSH to AGRP released during fasting, consistent with a net inhibition of hypothalamic MC-R signaling. In contrast, short-term treatment with leptin and insulin may inhibit MC-R signaling primarily by decreasing the release of AGRP.",

keywords = "AGRP, Insulin, Leptin, MSH, POMC",

author = "Breen, {Tracy L.} and Conwell, {Irene M.} and Wardlaw, {Sharon L.}",

note = "Funding Information: This work was supported by NIH grant DK57561.",

year = "2005",

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doi = "10.1016/j.brainres.2004.11.008",

language = "English",

volume = "1032",

pages = "141--148",

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T1 - Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus

AU - Breen, Tracy L.

AU - Conwell, Irene M.

AU - Wardlaw, Sharon L.

N1 - Funding Information: This work was supported by NIH grant DK57561.

PY - 2005/1/25

Y1 - 2005/1/25

N2 - Agouti-related protein (AGRP) and proopiomelanocortin (POMC) have opposing effects on melanocortin receptor (MC-R) signaling and energy balance, and are important targets for leptin and insulin in the hypothalamus. While food intake and leptin have documented effects on POMC and AGRP gene expression, and insulin has effects on POMC gene expression, little is known about their effects on POMC or AGRP peptide release. Here we have examined the effects of fasting, leptin, and insulin on the release of AGRP and the POMC-derived peptide γ3-MSH from the perifused rat hypothalamus in vitro. In the first experiment, fasting (48 h) resulted in a significant overall decrease in γ3-MSH release measured every 20 min during a 3-h baseline perifusion period and after depolarization with 56 mM KCl (p = 0.02); there was a trend towards an overall increase in the release of AGRP but this was not significant. When the ratio of γ3-MSH/AGRP release was calculated at each time point, there was an overall decrease in γ3-MSH/AGRP with fasting (p < 0.01). Further examination of the ratio of γ3-MSH/AGRP revealed a 34% reduction (p < 0.05) in the basal area under the curve (AUC) and a 33% reduction (p < 0.01) in the post-KCl stimulated AUC in fasted vs. fed animals. In the second experiment, perifusion of hypothalamic slices with 10-8 or 10-7 M leptin for 2 h resulted in a significant decrease in the release of AGRP noted primarily after depolarization with KCl (p < 0.01); no effect was seen on γ3-MSH release. Similarly, in a third experiment, perifusion with 10-7 M insulin caused a significant decrease in AGRP release (p < 0.001) without affecting γ3-MSH release. Thus, there is a significant decrease in γ3-MSH and the ratio of γ3-MSH to AGRP released during fasting, consistent with a net inhibition of hypothalamic MC-R signaling. In contrast, short-term treatment with leptin and insulin may inhibit MC-R signaling primarily by decreasing the release of AGRP.

AB - Agouti-related protein (AGRP) and proopiomelanocortin (POMC) have opposing effects on melanocortin receptor (MC-R) signaling and energy balance, and are important targets for leptin and insulin in the hypothalamus. While food intake and leptin have documented effects on POMC and AGRP gene expression, and insulin has effects on POMC gene expression, little is known about their effects on POMC or AGRP peptide release. Here we have examined the effects of fasting, leptin, and insulin on the release of AGRP and the POMC-derived peptide γ3-MSH from the perifused rat hypothalamus in vitro. In the first experiment, fasting (48 h) resulted in a significant overall decrease in γ3-MSH release measured every 20 min during a 3-h baseline perifusion period and after depolarization with 56 mM KCl (p = 0.02); there was a trend towards an overall increase in the release of AGRP but this was not significant. When the ratio of γ3-MSH/AGRP release was calculated at each time point, there was an overall decrease in γ3-MSH/AGRP with fasting (p < 0.01). Further examination of the ratio of γ3-MSH/AGRP revealed a 34% reduction (p < 0.05) in the basal area under the curve (AUC) and a 33% reduction (p < 0.01) in the post-KCl stimulated AUC in fasted vs. fed animals. In the second experiment, perifusion of hypothalamic slices with 10-8 or 10-7 M leptin for 2 h resulted in a significant decrease in the release of AGRP noted primarily after depolarization with KCl (p < 0.01); no effect was seen on γ3-MSH release. Similarly, in a third experiment, perifusion with 10-7 M insulin caused a significant decrease in AGRP release (p < 0.001) without affecting γ3-MSH release. Thus, there is a significant decrease in γ3-MSH and the ratio of γ3-MSH to AGRP released during fasting, consistent with a net inhibition of hypothalamic MC-R signaling. In contrast, short-term treatment with leptin and insulin may inhibit MC-R signaling primarily by decreasing the release of AGRP.

KW - AGRP

KW - Insulin

KW - Leptin

KW - MSH

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ER -

Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus

Abstract

Keywords

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