GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet

Yoshihiro Ito, Ryoichi Banno, Miyuki Shibata, Koichi Adachi, Shigeru Hagimoto, Daisuke Hagiwara, Yoshiharu Ozawa, Motomitsu Goto, Hidetaka Suga, Yoshihisa Sugimura, Bernhard Bettler, Yutaka Oiso, Hiroshi Arima

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Abstract

There is evidence suggesting that the GABA system in the arcuate nucleus, where orexigenic neuropeptide Y and agouti-related peptide as well as anorexigenic proopiomelanocortin (POMC) are expressed, plays an important role in energy balance. In this study, we generated POMC-specific GABAB receptor-deficient [knock-out (KO)] mice. Male KO mice on a high-fat diet (HFD) showed mild increases in body weight (BW) at the age of 9 weeks compared to wild-type (WT) mice, and the differences remained significant until 16 weeks old. However, there was no difference in BW in females between genotypes. While food intake was similar between genotypes, oxygen consumption was significantly decreased in the male KO mice. The insulin tolerance test revealed that the male KO mice were less insulin sensitive compared to WT mice at the age of 8 weeks, when there was no significant difference in BW between genotypes. Despite increasedBW,POMCmRNAexpression in the arcuate nucleus was significantly decreased in theKOmice compared toWTmice at the age of 16 weeks. Furthermore, the expression of TNFα as well as IL-6, proinflammatory markers in the hypothalamus, was significantly increased in the KO mice on a HFD compared to WT mice. This demonstrates that the deletion of GABAB receptors in POMC neurons in the male mice on a HFD results in obesity, insulin resistance, and hypothalamic inflammation. Furthermore, the decreased POMC expression in the obeseKOmice suggests that the regulation ofPOMCexpression throughGABAB receptors is essential for proper energy balance.

Original languageEnglish
Pages (from-to)17166-17173
Number of pages8
JournalJournal of Neuroscience
Volume33
Issue number43
DOIs
Publication statusPublished - 25-10-2013

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GABA-B Receptors
Pro-Opiomelanocortin
High Fat Diet
Knockout Mice
Insulin Resistance
Obesity
Inflammation
Neurons
Arcuate Nucleus of Hypothalamus
Genotype
Body Weight
Insulin
Neuropeptide Y
Oxygen Consumption
gamma-Aminobutyric Acid
Hypothalamus
Interleukin-6
Eating
Peptides

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Ito, Yoshihiro ; Banno, Ryoichi ; Shibata, Miyuki ; Adachi, Koichi ; Hagimoto, Shigeru ; Hagiwara, Daisuke ; Ozawa, Yoshiharu ; Goto, Motomitsu ; Suga, Hidetaka ; Sugimura, Yoshihisa ; Bettler, Bernhard ; Oiso, Yutaka ; Arima, Hiroshi. / GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 43. pp. 17166-17173.
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abstract = "There is evidence suggesting that the GABA system in the arcuate nucleus, where orexigenic neuropeptide Y and agouti-related peptide as well as anorexigenic proopiomelanocortin (POMC) are expressed, plays an important role in energy balance. In this study, we generated POMC-specific GABAB receptor-deficient [knock-out (KO)] mice. Male KO mice on a high-fat diet (HFD) showed mild increases in body weight (BW) at the age of 9 weeks compared to wild-type (WT) mice, and the differences remained significant until 16 weeks old. However, there was no difference in BW in females between genotypes. While food intake was similar between genotypes, oxygen consumption was significantly decreased in the male KO mice. The insulin tolerance test revealed that the male KO mice were less insulin sensitive compared to WT mice at the age of 8 weeks, when there was no significant difference in BW between genotypes. Despite increasedBW,POMCmRNAexpression in the arcuate nucleus was significantly decreased in theKOmice compared toWTmice at the age of 16 weeks. Furthermore, the expression of TNFα as well as IL-6, proinflammatory markers in the hypothalamus, was significantly increased in the KO mice on a HFD compared to WT mice. This demonstrates that the deletion of GABAB receptors in POMC neurons in the male mice on a HFD results in obesity, insulin resistance, and hypothalamic inflammation. Furthermore, the decreased POMC expression in the obeseKOmice suggests that the regulation ofPOMCexpression throughGABAB receptors is essential for proper energy balance.",
author = "Yoshihiro Ito and Ryoichi Banno and Miyuki Shibata and Koichi Adachi and Shigeru Hagimoto and Daisuke Hagiwara and Yoshiharu Ozawa and Motomitsu Goto and Hidetaka Suga and Yoshihisa Sugimura and Bernhard Bettler and Yutaka Oiso and Hiroshi Arima",
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Ito, Y, Banno, R, Shibata, M, Adachi, K, Hagimoto, S, Hagiwara, D, Ozawa, Y, Goto, M, Suga, H, Sugimura, Y, Bettler, B, Oiso, Y & Arima, H 2013, 'GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet', Journal of Neuroscience, vol. 33, no. 43, pp. 17166-17173. https://doi.org/10.1523/JNEUROSCI.0897-13.2013

GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet. / Ito, Yoshihiro; Banno, Ryoichi; Shibata, Miyuki; Adachi, Koichi; Hagimoto, Shigeru; Hagiwara, Daisuke; Ozawa, Yoshiharu; Goto, Motomitsu; Suga, Hidetaka; Sugimura, Yoshihisa; Bettler, Bernhard; Oiso, Yutaka; Arima, Hiroshi.

In: Journal of Neuroscience, Vol. 33, No. 43, 25.10.2013, p. 17166-17173.

Research output: Contribution to journalArticle

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T1 - GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet

AU - Ito, Yoshihiro

AU - Banno, Ryoichi

AU - Shibata, Miyuki

AU - Adachi, Koichi

AU - Hagimoto, Shigeru

AU - Hagiwara, Daisuke

AU - Ozawa, Yoshiharu

AU - Goto, Motomitsu

AU - Suga, Hidetaka

AU - Sugimura, Yoshihisa

AU - Bettler, Bernhard

AU - Oiso, Yutaka

AU - Arima, Hiroshi

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Y1 - 2013/10/25

N2 - There is evidence suggesting that the GABA system in the arcuate nucleus, where orexigenic neuropeptide Y and agouti-related peptide as well as anorexigenic proopiomelanocortin (POMC) are expressed, plays an important role in energy balance. In this study, we generated POMC-specific GABAB receptor-deficient [knock-out (KO)] mice. Male KO mice on a high-fat diet (HFD) showed mild increases in body weight (BW) at the age of 9 weeks compared to wild-type (WT) mice, and the differences remained significant until 16 weeks old. However, there was no difference in BW in females between genotypes. While food intake was similar between genotypes, oxygen consumption was significantly decreased in the male KO mice. The insulin tolerance test revealed that the male KO mice were less insulin sensitive compared to WT mice at the age of 8 weeks, when there was no significant difference in BW between genotypes. Despite increasedBW,POMCmRNAexpression in the arcuate nucleus was significantly decreased in theKOmice compared toWTmice at the age of 16 weeks. Furthermore, the expression of TNFα as well as IL-6, proinflammatory markers in the hypothalamus, was significantly increased in the KO mice on a HFD compared to WT mice. This demonstrates that the deletion of GABAB receptors in POMC neurons in the male mice on a HFD results in obesity, insulin resistance, and hypothalamic inflammation. Furthermore, the decreased POMC expression in the obeseKOmice suggests that the regulation ofPOMCexpression throughGABAB receptors is essential for proper energy balance.

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