Ketogenic diet disrupts the circadian clock and increases hypofibrinolytic risk by inducing expression of plasminogen activator inhibitor-1.
OBJECTIVE
Metabolic disorders such as diabetes and obesity are considered risk factors for cardiovascular diseases by increasing levels of blood plasminogen activator inhibitor-1 (PAI-1). Ketogenic diets (KDs) have been used as an approach to weight loss in both obese and nonobese individuals. We examined circadian changes in plasma PAI-1 and its mRNA expression levels in tissues from mice fed with a KD (KD mice), to evaluate its effects on fibrinolytic functions.


RESULTS
Two weeks on the kDa increased plasma levels of free fatty acids and ketones accompanied by hypoglycemia in mice. Plasma PAI-1 concentrations were extremely elevated in accordance with mRNA expression levels in the heart and liver, but not in the kidneys of KD mice. Circadian expression of PAI-1 mRNA was phase-advanced for 4.7, 7.9, and 7.8 hours in the heart, kidney, and adipose tissues, respectively, as well as that of circadian genes mPer2 and DBP in KD mice, suggesting that peripheral clocks were phase-advanced by ketosis despite feeding ad libitum under a periodic light-dark cycle. The circadian clock that regulates behavioral activity rhythms was also phase-advanced, and its free-running period was significantly shortened in KD mice.


CONCLUSIONS
Our findings suggest that ketogenic status increases hypofibrinolytic risk by inducing abnormal circadian expression of PAI-1.
Oishi
Katsutaka
K
Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8566, Japan. k-ooishi@aist.go.jp
Uchida
Daisuke
D
Ohkura
Naoki
N
Doi
Ryosuke
R
Ishida
Norio
N
Kadota
Koji
K
Horie
Shuichi
S
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002940:Circadian Rhythm; D055423:Diet, Ketogenic; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005342:Fibrinolysis; D005346:Fibroblast Growth Factors / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009687:Nuclear Proteins / Q000235:genetics; D047493:PPAR alpha / Q000502:physiology; D056950:Period Circadian Proteins; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics
D018797:Cell Cycle Proteins; D005230:Fatty Acids, Nonesterified; D009687:Nuclear Proteins; D047493:PPAR alpha; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors