Obesity alters circadian expressions of molecular clock genes in the brainstem.
Major components of energy homeostasis, including feeding behavior and glucose and lipid metabolism, are subject to circadian rhythms. Recent studies have suggested that dysfunctions of molecular clock genes are involved in the development of obesity and diabetes. To examine whether metabolic states per se alter the circadian clock in the central nervous system (CNS), we analyzed the daily mRNA expression profiles of core clock genes in the caudal brainstem nucleus of the solitary tract (NTS). In lean C57BL/6 mice, transcript levels of the core clock genes (Npas2, Bmal1, Per1, Per2 and Rev-erbalpha) clearly showed 24-h rhythmicity. On the other hand, the expression profiles of Bmal1 and Rev-erbalpha were attenuated in mice with high fat diet-induced obesity as well as genetically obese KK-A(y) and ob/ob mice. Clock expression levels were increased in mice with high fat diet-induced obesity and Cry1 expression levels were decreased in KK-A(y) and ob/ob mice. In addition, peroxisome proliferator-activated receptor alpha (PPARalpha), which reportedly increases the BMAL1 transcriptional level, was up-regulated in the NTS of these murine models of obesity and insulin resistance, suggesting involvement of PPARalpha in the attenuation of circadian rhythms in the NTS in obese states. Furthermore, a circadian expression profile of a downstream target of clock genes, the large conductance Ca(2+)-activated K(+)channel, was disturbed in the NTS of these murine obesity models. These perturbations might contribute to neuronal dysfunction in obese states. This is the first report showing that obesity perturbs the circadian expressions of core clock genes in the CNS.
Kaneko
Keizo
K
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
Yamada
Tetsuya
T
Tsukita
Sohei
S
Takahashi
Kei
K
Ishigaki
Yasushi
Y
Oka
Yoshitomo
Y
Katagiri
Hideki
H
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020738:Leptin / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D009765:Obesity / Q000503:physiopathology*; D047493:PPAR alpha / Q000378:metabolism; D056950:Period Circadian Proteins; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017552:Solitary Nucleus / Q000503:physiopathology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047493:PPAR alpha; D056950:Period Circadian Proteins; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C491259:Npas2 protein, mouse; C498262:Nr1d1 protein, mouse; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C538944:Clock protein, mouse