title: GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet.
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 increased BW, POMC mRNA expression in the arcuate nucleus was significantly decreased in the KO mice compared to WT mice 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 obese KO mice suggests that the regulation of POMC expression through GABAB receptors is essential for proper energy balance.
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan, and Department of Biomedicine, University of Basel, Basel CH-4056, Switzerland.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ito
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Banno
authors.forename: Miyuki
authors.initials: M
authors.lastname: Shibata
authors.forename: Koichi
authors.initials: K
authors.lastname: Adachi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hagimoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hagiwara
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Motomitsu
authors.initials: M
authors.lastname: Goto
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Suga
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Sugimura
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arima
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D059305:Diet, High-Fat; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain
chemical_list: D015850:Interleukin-6; D018080:Receptors, GABA-B; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D011333:Pro-Opiomelanocortin