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Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice

AIMS/HYPOTHESIS: The pancreas and hypothalamus are critical for maintaining nutrient and energy homeostasis, and combined disorders in these organs account for the onset of the metabolic syndrome. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. The physiologica...

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Autores principales: Lee, Y.-S., Sasaki, T., Kobayashi, M., Kikuchi, O., Kim, H.-J., Yokota-Hashimoto, H., Shimpuku, M., Susanti, V.-Y., Ido-Kitamura, Y., Kimura, K., Inoue, H., Tanaka-Okamoto, M., Ishizaki, H., Miyoshi, J., Ohya, S., Tanaka, Y., Kitajima, S., Kitamura, T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer-Verlag 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648686/
https://www.ncbi.nlm.nih.gov/pubmed/23462798
http://dx.doi.org/10.1007/s00125-013-2879-z
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author Lee, Y.-S.
Sasaki, T.
Kobayashi, M.
Kikuchi, O.
Kim, H.-J.
Yokota-Hashimoto, H.
Shimpuku, M.
Susanti, V.-Y.
Ido-Kitamura, Y.
Kimura, K.
Inoue, H.
Tanaka-Okamoto, M.
Ishizaki, H.
Miyoshi, J.
Ohya, S.
Tanaka, Y.
Kitajima, S.
Kitamura, T.
author_facet Lee, Y.-S.
Sasaki, T.
Kobayashi, M.
Kikuchi, O.
Kim, H.-J.
Yokota-Hashimoto, H.
Shimpuku, M.
Susanti, V.-Y.
Ido-Kitamura, Y.
Kimura, K.
Inoue, H.
Tanaka-Okamoto, M.
Ishizaki, H.
Miyoshi, J.
Ohya, S.
Tanaka, Y.
Kitajima, S.
Kitamura, T.
author_sort Lee, Y.-S.
collection PubMed
description AIMS/HYPOTHESIS: The pancreas and hypothalamus are critical for maintaining nutrient and energy homeostasis, and combined disorders in these organs account for the onset of the metabolic syndrome. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. The physiological role of ATF3 in the pancreas has been controversial, and its role in the hypothalamus remains unknown. To elucidate the roles of ATF3 in these organs, we generated pancreas- and hypothalamus-specific Atf3 knockout (PHT-Atf3-KO) mice in this study. METHODS: We crossed mice bearing floxed Atf3 alleles with Pdx1-cre mice, in which cre is specifically expressed in the pancreas and hypothalamus, and analysed metabolic variables, pancreatic morphology, food intake, energy expenditure and sympathetic activity in adipose tissue. We also used a hypothalamic cell line to investigate the molecular mechanism by which ATF3 regulates transcription of the gene encoding agouti-related protein (Agrp). RESULTS: Although PHT-Atf3-KO mice displayed better glucose tolerance, neither plasma glucagon nor insulin level was altered in these mice. However, these mice exhibited higher insulin sensitivity, which was accompanied by a leaner phenotype due to decreased food intake and increased energy expenditure. We also observed decreased hypothalamic Agrp expression in PHT-Atf3-KO mice. Importantly, an increase in ATF3 levels is induced by fasting or low glucose in the hypothalamus. We also showed that ATF3 interacts with forkhead box-containing protein, O subfamily 1 (FoxO1) on the Agrp promoter and activates Agrp transcription. CONCLUSIONS/INTERPRETATION: Our results suggest that ATF3 plays an important role in the control of glucose and energy metabolism by regulating Agrp. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-013-2879-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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spelling pubmed-36486862013-05-09 Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice Lee, Y.-S. Sasaki, T. Kobayashi, M. Kikuchi, O. Kim, H.-J. Yokota-Hashimoto, H. Shimpuku, M. Susanti, V.-Y. Ido-Kitamura, Y. Kimura, K. Inoue, H. Tanaka-Okamoto, M. Ishizaki, H. Miyoshi, J. Ohya, S. Tanaka, Y. Kitajima, S. Kitamura, T. Diabetologia Article AIMS/HYPOTHESIS: The pancreas and hypothalamus are critical for maintaining nutrient and energy homeostasis, and combined disorders in these organs account for the onset of the metabolic syndrome. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. The physiological role of ATF3 in the pancreas has been controversial, and its role in the hypothalamus remains unknown. To elucidate the roles of ATF3 in these organs, we generated pancreas- and hypothalamus-specific Atf3 knockout (PHT-Atf3-KO) mice in this study. METHODS: We crossed mice bearing floxed Atf3 alleles with Pdx1-cre mice, in which cre is specifically expressed in the pancreas and hypothalamus, and analysed metabolic variables, pancreatic morphology, food intake, energy expenditure and sympathetic activity in adipose tissue. We also used a hypothalamic cell line to investigate the molecular mechanism by which ATF3 regulates transcription of the gene encoding agouti-related protein (Agrp). RESULTS: Although PHT-Atf3-KO mice displayed better glucose tolerance, neither plasma glucagon nor insulin level was altered in these mice. However, these mice exhibited higher insulin sensitivity, which was accompanied by a leaner phenotype due to decreased food intake and increased energy expenditure. We also observed decreased hypothalamic Agrp expression in PHT-Atf3-KO mice. Importantly, an increase in ATF3 levels is induced by fasting or low glucose in the hypothalamus. We also showed that ATF3 interacts with forkhead box-containing protein, O subfamily 1 (FoxO1) on the Agrp promoter and activates Agrp transcription. CONCLUSIONS/INTERPRETATION: Our results suggest that ATF3 plays an important role in the control of glucose and energy metabolism by regulating Agrp. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-013-2879-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Springer-Verlag 2013-03-06 2013 /pmc/articles/PMC3648686/ /pubmed/23462798 http://dx.doi.org/10.1007/s00125-013-2879-z Text en © The Author(s) 2013 https://creativecommons.org/licenses/by-nc/2.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Article
Lee, Y.-S.
Sasaki, T.
Kobayashi, M.
Kikuchi, O.
Kim, H.-J.
Yokota-Hashimoto, H.
Shimpuku, M.
Susanti, V.-Y.
Ido-Kitamura, Y.
Kimura, K.
Inoue, H.
Tanaka-Okamoto, M.
Ishizaki, H.
Miyoshi, J.
Ohya, S.
Tanaka, Y.
Kitajima, S.
Kitamura, T.
Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice
title Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice
title_full Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice
title_fullStr Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice
title_full_unstemmed Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice
title_short Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice
title_sort hypothalamic atf3 is involved in regulating glucose and energy metabolism in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648686/
https://www.ncbi.nlm.nih.gov/pubmed/23462798
http://dx.doi.org/10.1007/s00125-013-2879-z
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