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Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats

We previously reported that the type 2 diabetic Goto–Kakizaki (GK) rats at young adult ages (6–12 weeks) exhibited increased visceral fat mass and hyperleptinemia, due to hyperphagia caused primarily by neuropeptide Y (NPY) overexpression in the hypothalamic arcuate nucleus. Later, we found that GK...

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Autores principales: Maekawa, Fumihiko, Fujiwara, Ken, Toriya, Masako, Maejima, Yuko, Nishio, Takashi, Toyoda, Yukiyasu, Nohara, Keiko, Yashiro, Takashi, Yada, Toshihiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788348/
https://www.ncbi.nlm.nih.gov/pubmed/24106476
http://dx.doi.org/10.3389/fnsyn.2013.00007
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author Maekawa, Fumihiko
Fujiwara, Ken
Toriya, Masako
Maejima, Yuko
Nishio, Takashi
Toyoda, Yukiyasu
Nohara, Keiko
Yashiro, Takashi
Yada, Toshihiko
author_facet Maekawa, Fumihiko
Fujiwara, Ken
Toriya, Masako
Maejima, Yuko
Nishio, Takashi
Toyoda, Yukiyasu
Nohara, Keiko
Yashiro, Takashi
Yada, Toshihiko
author_sort Maekawa, Fumihiko
collection PubMed
description We previously reported that the type 2 diabetic Goto–Kakizaki (GK) rats at young adult ages (6–12 weeks) exhibited increased visceral fat mass and hyperleptinemia, due to hyperphagia caused primarily by neuropeptide Y (NPY) overexpression in the hypothalamic arcuate nucleus. Later, we found that GK rats continued to exhibit mesenteric fat accumulation and hyperleptinemia at least until 26 weeks of age, while hyperphagia and NPY overexpression ceased at 15 weeks of age. Therefore, we hypothesized that the long-lasting fat accumulation and hyperleptinemia are due to unidentified brain dysfunction other than NPY overexpression. In GK rats aged 26 weeks, glucose transporter-2 (GLUT2) mRNA expression in ventromedial hypothalamus (VMH) was markedly reduced in parallel with significant decreases in brain-derived neurotrophic factor (BDNF) mRNA level and BDNF-expressing cell numbers in the VMH. Pharmacologic inhibition of glucose utilization reduced BDNF mRNA expression in VMH in vivo and in vitro. The results suggested that impaired glucose utilization caused the reduction of BDNF. On the other hand, intracerebroventricular injection of BDNF for 6 days ameliorated hyperleptinemia in a long-lasting manner concurrently with feeding suppression in GK rats. Restricted feeding paired to BDNF-treated rats reduced plasma leptin level only transiently. BDNF treatment also reduced mesenteric fat mass in GK rats. These results reveal a novel action mode of BDNF to long-lastingly counteract visceral adiposity and hyperleptinemia in addition to and independently of its anorexigenic action. These results suggest that visceral fat accumulation and hyperleptinemia are at least partly due to the reduction of BDNF in VMH primarily caused by impaired glucose utilization in GK rats. The BDNF supplementation could provide an effective treatment of visceral obesity, hyperleptinemia and leptin resistance in type 2 diabetes.
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spelling pubmed-37883482013-10-08 Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats Maekawa, Fumihiko Fujiwara, Ken Toriya, Masako Maejima, Yuko Nishio, Takashi Toyoda, Yukiyasu Nohara, Keiko Yashiro, Takashi Yada, Toshihiko Front Synaptic Neurosci Neuroscience We previously reported that the type 2 diabetic Goto–Kakizaki (GK) rats at young adult ages (6–12 weeks) exhibited increased visceral fat mass and hyperleptinemia, due to hyperphagia caused primarily by neuropeptide Y (NPY) overexpression in the hypothalamic arcuate nucleus. Later, we found that GK rats continued to exhibit mesenteric fat accumulation and hyperleptinemia at least until 26 weeks of age, while hyperphagia and NPY overexpression ceased at 15 weeks of age. Therefore, we hypothesized that the long-lasting fat accumulation and hyperleptinemia are due to unidentified brain dysfunction other than NPY overexpression. In GK rats aged 26 weeks, glucose transporter-2 (GLUT2) mRNA expression in ventromedial hypothalamus (VMH) was markedly reduced in parallel with significant decreases in brain-derived neurotrophic factor (BDNF) mRNA level and BDNF-expressing cell numbers in the VMH. Pharmacologic inhibition of glucose utilization reduced BDNF mRNA expression in VMH in vivo and in vitro. The results suggested that impaired glucose utilization caused the reduction of BDNF. On the other hand, intracerebroventricular injection of BDNF for 6 days ameliorated hyperleptinemia in a long-lasting manner concurrently with feeding suppression in GK rats. Restricted feeding paired to BDNF-treated rats reduced plasma leptin level only transiently. BDNF treatment also reduced mesenteric fat mass in GK rats. These results reveal a novel action mode of BDNF to long-lastingly counteract visceral adiposity and hyperleptinemia in addition to and independently of its anorexigenic action. These results suggest that visceral fat accumulation and hyperleptinemia are at least partly due to the reduction of BDNF in VMH primarily caused by impaired glucose utilization in GK rats. The BDNF supplementation could provide an effective treatment of visceral obesity, hyperleptinemia and leptin resistance in type 2 diabetes. Frontiers Media S.A. 2013-10-02 /pmc/articles/PMC3788348/ /pubmed/24106476 http://dx.doi.org/10.3389/fnsyn.2013.00007 Text en Copyright © 2013 Maekawa, Fujiwara, Toriya, Maejima, Nishio, Toyoda, Nohara, Yashiro and Yada. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Maekawa, Fumihiko
Fujiwara, Ken
Toriya, Masako
Maejima, Yuko
Nishio, Takashi
Toyoda, Yukiyasu
Nohara, Keiko
Yashiro, Takashi
Yada, Toshihiko
Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats
title Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats
title_full Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats
title_fullStr Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats
title_full_unstemmed Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats
title_short Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats
title_sort brain-derived neurotrophic factor in vmh as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic goto–kakizaki rats
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788348/
https://www.ncbi.nlm.nih.gov/pubmed/24106476
http://dx.doi.org/10.3389/fnsyn.2013.00007
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